New Zealand’s chocolate exports grow by 40% in three years – 1News

Wine, lamb and kiwifruit are among the produce New Zealand's famous for, and one expert is hopeful chocolate could be added to that list.

New Zealand's exports of the sweet treat have grown by 40% since 2019, and local boutique companies are celebrating their success too this World Chocolate Day.

Kiwi chocolatiers are capitalising on uniquely Kiwi flavours and products in their chocolate creations.

Devonport Chocolates owner Sarah Gardner said they're using the likes of horopito and kawakawa in their recipes.

"And using local ingredients like Man O' War wines and strawberries," she said.

"I think for New Zealanders it really connects us to where we grew up."

Tourists love it too, according to Gardner.

"This year we're seeing a 20% growth on our 2019 numbers."

"There have been some challenges over the last few years with Covid, but even then, the company found Kiwis were buying chocolate to make themselves feel better."

AUT patisserie lecturer Arno Sturny wrote his dissertation on New Zealand chocolate, so he's an expert.

He said the growth of the the industry's down to the introduction of small 'bean to bar' companies like Devonport Chocolates, but also the work of Whittaker's.

He said it has, "really, really pushed hard, especially since Cadbury left their premises in Dunedin."

Whittaker's says while their largest market is still here, it's exporting to a growing number of international markets including Australia, Canada, China and the Middle East.

"While this means we are making more chocolate, our priority is still to be the best chocolate manufacturer, rather than to be the biggest," said Whittakers co-Chief Operating Officers Holly and Matt Whittaker.

"We make all of our Whittakers Chocolate at our one factory in Porirua, which enables us to ensure quality by controlling the whole manufacturing process from bean to bar."

Sturny believes chocolate will eventually be one of the products New Zealand's known for, and that Whittaker's will be the "force" behind it.

But the potential for our smaller chocolatiers to sell their products further afield is promising too, he said.

Gardner said their Devonport boutique is about to feature products in Japan.

"We can see there's a real global opportunity to have our product overseas, and we feel incredibly proud of it."

Along with uniquely Kiwi flavours, Sturny says our relationship with Pacific Island Cacao Growers could be a big advantage.

"I think we've got a real opportunity to work much closer with the Pacific and that could really be the difference.

"We need to create a product range which really reflects us as part of the Pacific."

More and more chocolate companies are utilising beans from the likes of Samoa.

Floris Niu owns a plantation there, and is the fourth generation of her family to grow cacao on the Samoan island of Upolu.

She works in conjunction with 18 other women running Cacao farms and said, "We're hoping to be able supply up to 25 to 30 tonnes a year.

"When we first started, we were only supplying about 3 tonnes every year."

Later this month, Pacific Island cacao farmers will be in the spotlight with New Zealands first ever show dedicated to their work.

Visitors to 'The Pacific Cacao & Chocolate 2022' show on Saturday 23 July will be able to participate in the chocolate making process and taste organically grown cacao from Samoa, Vanuatu, Solomon Islands, Fiji, Papua New Guinea, Bougainville and the Philippines.

"We're talking about hundreds of thousands of tonnes that are coming out of these countries," Niu said.

"[New Zealand companies] love the idea we don't have to look at these huge freight costs from across the great divide, when it's right there on New Zealand's doorstep."

"The chocolate makers here love experimenting, they love that they can come and actually get to know the farmers, and the beans and the processes."

Gardner said Devonport Chocolates has used Samoan beans in the past, and is looking to re-connect with a supplier there.

"The Samoan chocolate has quite a unique flavour that goes with it," she said.

Niu said, "The flavour changes and varies from plantation to plantation and island to island."

More:

New Zealand's chocolate exports grow by 40% in three years - 1News

Air New Zealand hiring hundreds of staff to avoid travel chaos hitting airlines and airports overseas – New Zealand Herald

Cheree Kinnear talks to Air New Zealand's Head of Aircraft Programmes Kerry Reeves about the exciting changes coming to their cabins.Video / Jed Bradley / NZ Herald / Air NZ

Air New Zealand is recruiting another 1100 staff to avoid the chaos suffered by some other airlines due to labour shortages.

The airline is building back to more than 10,000 staff compared to 12,500 just before the pandemic as travel recovers quickly with the removal of most border restrictions.

It is introducing a series of measures to attract workers. A bonus of up to $1400 is being paid to entice people to work for the airline's airports division, where it is battling to find another 250 staff. Over the past year bonuses of $2400 have been paid to existing staff and incentive schemes for salary and unionised staff are being reintroduced.

The airline is also recruiting up to 700 cabin crew, primarily for its widebody international aircraft, 70 regional pilots and a further 100 people for its contact centre, where complex customer inquiries have pushed up wait times.

Air New Zealand chief people officer Nikki Dines said the airline was rebuilding at a carefully calibrated rate even though there was enough demand for more flights.

"The decision that we've made is that we will rebuild carefully. So rather than putting a whole lot of capacity on that we then have to cancel because we don't have enough staff, we're taking quite a cautious approach."

Overseas, shortages of staff in airlines and airports have led to chaos, especially in the Northern Hemisphere summer holidays, as travel builds rapidly towards pre-pandemic levels. Thousands of flights put into the system have been cancelled even though passengers are paying high fares.

Dines said New Zealand's lag behind he rest of the world in opening up had helped the airline's response, although it had to react quickly to the announcement in March that the country would drop quarantine requirements for Australians from mid-April.

"It takes us about 12 weeks to really be able to restart the airline and obviously we didn't get 12 weeks' notice back in March; we got about four weeks' notice the country was opening."

The recruitment drive is nationwide. The biggest choke point at the moment is training.

"You can go out and recruit a bunch of people but then actually being able to put them through the system in terms of whether it's pilots or cabin crew or contact centre, takes some time. The two big milestones for us are going into the July school holidays and making sure that we can increase capacity over that time. The next peak comes from October onwards."

Unlike some workplaces, the airline was also building an additional buffer for sickness.

"We're still seeing really high levels of sickness from Covid and the flu and other things. We're just building quite a reasonable margin - we may have trainers who are out sick, then the whole system stalls."

There were longer relief call lines to provide substitutes for crew or pilots who were sick, to ensure planes are kept flying.

She said on time performance (OTP) was looking good as there had been few cancellations.

Soon after the pandemic hit the airline in early 2020, job cuts came quickly and deeply. About 4000 staff were laid off or put on furlough as the airline was bleeding cash and struggling to stay afloat.

"We did what we thought we needed to do in the circumstances," said Dines. "And this has been a guessing game for us the whole time."

In December of 2020, the airline brought back more than 600 cabin crew to fly in the transtasman bubble but that only lasted a few months in the middle of 2021.

"We decided to keep those people on because we just didn't know when borders would reopen. Although we kept them on with no flying to do for quite a period of time," said Dines.

"We're pleased now that we did that, because it's enabling us to ramp up more quickly."

Some people who had been paid redundancy had been hired back.

"That's just how it works, that's part of our contracts. It's been part of what we offer for a very long time and that compensation is for them losing their role. For some people, it was only a very short period of time and they came back to us within a couple of months, and some people it's been 18 months."

Pay rates for some workers, especially those on lower wages, had gone up as much as 10 per cent over the past year as the airline competes in an increasingly tight labour market.

Staff travel was also a strong lure for staff, and had even more appeal now that the international network was expanding again.

The airline is also going through an organisational change to break down barriers between different work groups.

Air New Zealand was highly unionised, with 34 collective agreements, she said.

"They'll [workers] come back if they're in one of our unionised parts of the business, they come back into the collective agreement so that in some cases they'll come back into the same role and same level and in other cases they haven't."

While pilots and engineers have mainly stayed with the airline, an estimated third of cabin crew who lost jobs during the pandemic have been lost to the industry. Dines said those in customer-facing roles could more easily take their skills elsewhere.

The union representing most flight attendants is E t and when asked to rate Air NZ as an employer, its head of aviation, Savage, said all employers were assessed on whether they offer decent work.

"We look at their workers' income levels, at the security and stability of the work on offer, and at the quality and safety of the work environment. We also look at their commitment to giving workers a real say at work," he said.

While Air New Zealand led the way in terms of safety and the quality of the work environment, there were still parts of the company where the pay was low and the hours unreliable.

E t and Air New Zealand are working to address concerns about low pay.When the pandemic struck aviation, the union was critical of Air New Zealand because of the speed at which it rushed workers out the door during lockdown, said Savage.

''We all understood that the company had to downsize, but disagreed with how it was handled. We warned that it would decrease staff engagement and make it hard to hire staff when the time came to start rebuilding especially with airport and cargo workers who all had transferable skills, and that has proven to be the case right now.

"E t members have a vested interest in Air New Zealand becoming profitable again, but like all workers, they need decent, stable, and reliable work."

The airline has revealed its plans for long haul cabins aimed at competing harder against rivals, and concedes that crew have done most of the heavy lifting to keep customers satisfied.

One feature of the revamp, the Skynest sleep pod in Economy where up to six passengers can sleep for several hours on long haul flights, has another union concerned.

Flight Attendants' Association president Craig Featherby said the revamp was needed. "It's a great product but they've just got to make sure they have the right crew complement on board for Skynest. If they execute that with the right crew complement, I think it's a great idea."

Dines said the new cabins were two years away and there would be deep discussions in the meantime.

"That's part of what we're doing now with bringing in these new ways of working ... is making sure that the sales team and the customer experience team and the product team are working really closely with the people who are actually delivering the service or the product."

Dines said that while airport workers in particular were hard to find, more cabin crew were available.

Pay for flight attendants varies depending on whether they work on domestic, transtasman or international flights.

Government data shows flight attendants usually earn between minimum wage and $45,000 a year and inflight service managers can earn up to $60,000.

Flight attendants also get meal, accommodation, uniform and grooming allowances of between $7000 and $12,000 a year, says careers.govt.nz.

While overseas airlines are also aggressively recruiting, with some such as Emirates offering tax-free salaries, Dines said the lure of working overseas wasn't much of a barrier to finding staff.

"So far we haven't met the same challenges that we are having in airports."

When looking for staff, the airline first tries people on its "staying connected" register.

"We've got some good uptake from there. Now we're going out into the wider job market."

Jobs in the regions were harder to fill than in the main centres.

Dines said the airline was working on lifting its conversion rates. "When we bring people in for interviews, we want to obviously try to convert as many of those as possible."

The airline's customer base was diverse and the airline wanted that reflected in its workforce.

"Customer service is what we try to differentiate on so we want people that are passionate about customer service and about travel, who want to work in a really fast paced environment."

The airline promotes some core values to prospective staff, including the ability to welcome customers as a friend, being "can-do", being yourself and being passionate about representing and sharing Aotearoa.

Dines says "being yourself" is very important. "That kind of authenticity when people come to us and share their experience, whether it's work experience or community experience makes people stand out."

In corporate areas in particular, the ability to work collaboratively was the skill that the airline was looking for.

"Above all else it's people that can work really well cross functionally."

The airline is moving its corporate headquarters from The Hub in downtown Auckland to a leased property at Auckland Airport, just beside the runway apron and close to its engineering base.

Dines said the re-fitted building would help encourage the collaborative approach.

"The Hub is a traditional style of office. It's not that great for kind of getting a great culture and energy going because it's all quite compartmentalised."

At the new office - a longer commute for some staff - there would be more flexible work arrangements. The work from home trend is the biggest workplace shift Dines has seen during the pandemic.

She's been with Air New Zealand for more than nine years and has ridden the waves of rapid growth when fuel prices were low and travel was booming, to the trauma of it nearly stopping completely when the pandemic hit.

The rebuild provides a great opportunity.

"I think those of us who are here see it as a real privilege. This is the restart of the airline and is really attracting people who want to be part of rebuilding the airline and getting it back to better than it was."

View original post here:

Air New Zealand hiring hundreds of staff to avoid travel chaos hitting airlines and airports overseas - New Zealand Herald

NZ-Australia relationship appears to be on the way up under the Albanese government – Stuff

In the early years of the John Key Government, then Australian Prime Minister Kevin Rudd liked to hold trans-Tasman Cabinet meetings.

These meetings often organised around a Bledisloe cup match were a chance for Cabinet ministers from each side to talk.

According to sources familiar with one of these meetings, each minister was supposed to speak for about five minutes to take up the assigned hour.

Instead, Rudd stood up, lectured the room for the best part of the hour, before Key stood up and said words to the effect of, well, I think Kevins just about covered it all.

READ MORE:* PM says Russia's war 'morally bankrupt' but should not be seen as broader conflict* Jacinda Ardern feels the fresh breeze blowing through Australian politics* PM: Flood assistance talk shows 'fundamental change' in Australian Government view of Kiwis living there

Although that story is mostly a funny one of Rudds erratic behaviour, it also speaks to a deeper truth. Australian political leaders can either ignore or simply lecture New Zealand ones. And that New Zealand, being the smaller country, values Australia in a way that is not always reciprocated.

Australia sees itself as a thrusting middle power looking outwards into Asia. For political players in Canberra and around the states, successful New Zealand political parties are worth keeping an eye on (the Australian Liberal Party studied John Keys success closely). But for broader lessons on how to do things, New Zealand has been basically ignored or talked down to.

This has manifested itself most clearly in the politicisation of 501 deportees and with at times less than subtle suggestions that New Zealand is really a bunch of panda-huggers who dont take China seriously.

Lisa Maree Williams/Getty Images

The trans-Tasman relationship has been a bit fraught over recent years, but there are signs it could be heading into more positive territory.

There have also been grumbles from Australia Governments over the past few years, that while New Zealand happily talks a big game on climate change, the actions of the Ardern Government have not matched the rhetoric. And in times of labour shortage, Australia is very happy to get as much skilled labour from New Zealand as possible.

However, New Zealands foreign policy stance on China has stiffened rhetorically while also attempting to do so respectfully. New Zealand has adopted the language the free and open indo-Pacific and it has heartily lined up along with other liberal democracies to support Ukraine in its war with Russia. New Zealand want more US economic engagement in the region.

And further change in the relationship could be on the horizon says Natasha Kassam, a former Australian diplomat and director of the Lowy Institutes public opinion and foreign policy program.

Kassam is in charge of Lowys polling programme which gauge Australian perceptions of other countries and leaders.

Luke Malpass/Stuff/Stuff

Natasha Kassam, the Lowy Institutes director of public opinion and its foreign policy program.

One thing that I think is shifting a little bit is, say 10 years ago, if you asked Australians who our best friend in the world was, they would be divided between New Zealand, the United Kingdom, the United States, that's very much shifted now. And it's a majority view that New Zealand is Australia's best friend in the world, she says.

Australians have always felt very warmly towards New Zealand. New Zealand is consistently the country which we see as our best friend and Prime Minister Ardern is the leader that Australians have the most confidence in.

Kassam says that there is also a level of disillusionment at play as world events have become more complicated - with both Brexit and the Trump Presidency being deeply unpopular in Australia

These things have made Australians question some of those traditional partnerships and I think look closer to home. she says.

1 NEWS

The Prime Minister delivered a major foreign policy speech in Australia, focusing on influence in the Pacific and the impact of Russias invasion of Ukraine.

The New Zealand Australian relationship is like no other. Two highly integrated economies, free flow of people and a big Kiwi Diaspora across the Tasman. It is New Zealands second-largest trading partner with $22 billion in two-way trade and a significant source of tourists. Many regulatory settings are aligned.

Government body NZ Story has done some qualitative, focus group research on how Australians feel about themselves and others. The research will be released on July 27.

Headed by David Downs, NZ Story just what its name suggests, its objective is to craft a compelling backstory about New Zealand and what doing business in the country and with its companies means. The goal is to move beyond the old clean green tropes push hard on a broader understanding of New Zealands reputation, values and what it has to offer.

RICKY WILSON/STUFF/Stuff

David Downs, CEO of NZ Story.

But it is in the context of Australia that NZ Story has done this recent work, trying to understand what perceptions are of New Zealand.

According to the research, since 2015 New Zealand has become more admired for its approach to life, is viewed as a more caring society than it was, however as a result of lockdowns and closed borders is viewed as less welcoming. Although that could change as travel and open borders become normal again.

Downs says that it five years since this sort of work was last done and that the perceptions of New Zealand have changed mostly for the better.

The fact that it's changed a lot is important, I think, for not just export businesses, but education providers, tourism providers, everyone should know, he says.

The good news is, largely, it's for the benefit of New Zealand. I think there's sort of an increasing respect for New Zealand that comes through this report more kind of understanding of us as an equal partner, not the little cousin they look down on but actually someone theyve quite a lot of respect for and thats across multiple things.

It's our leadership, it's our Covid response, it's our indigenous culture and the way that we work, integrated Mori culture into our society. So there are a lot of positives, which is fantastic.

Integration of Mori culture is also seen as a positive by Australians in the research, perhaps reflecting the fact that, although New Zealand is very far from perfect, indigenous relations and life outcomes still significantly lag in Australia.

From business focus groups, however, the research found that there is a perception that would-be New Zealand exporters neglect matters after sending the first container, that they dont show up when it matters and meet customers. There also can be the perception that the small scale of the country makes it difficult for large Australian firms to do business with it. But, New Zealand is viewed as hungry for success.

Unknown

Prime Ministers Anthony Albanese and Jacinda Ardern take a selfie in Sydney.

New Zealand can be seen as a country where we don't really show up properly, we don't kind of follow through on some of our commitments, were sort of half-hearted a little bit in the market. And so those are things that we have to be quite conscious about, Downs says.

Lots of New Zealand businesses do do well, but in general, the perception ... and this is not us saying this, this is Australian buyers telling us that we need to lift our game a little bit and really see the scale of the opportunity and take the market seriously.

New Zealand is also viewed as expensive, but having a lot of the same regulation rules is an advantage that should not be underestimated.

Basically the upshot is that, since Covid-19, perhaps as a result of the fractious Australian political culture of the past few years, Australian public attitudes have shifted to more closely align with New Zealands.

Already the relationship with new Prime Minister Anthony Albanese and Treasurer Jim Chalmers is more positive. In opening remarks to the Australia-New Zealand Leadership Forum yesterday he said that his affinity with New Zealand was personal.

I come from, grew up in, and now represent an electorate in South-East Queensland, which has the largest number of New Zealand-born residents of any community in Australia, and big Mori and Pasifika communities.

This will continue to shape my thinking as Treasurer, as I work with you and my colleagues to build a stronger and more inclusive economy.

Chalmers is even keen to talk to Minister of Finance Grant Robertson about his wellbeing budgets.

Mark Baker/AP

Already the relationship with new Prime Minister Anthony Albanese is more positive for NZ.

Our new Government also has a lot to learn from New Zealand, and tomorrow [Friday] I will speak with Grant about New Zealands Wellbeing Budget and how to reshape the discussion around the economy and the budget in terms of measuring what matters, he said.

Kassam says that, particularly on climate policy, the views of Australian politicians have, for at least four years has been out of step with public opinion. New Zealands approach to it is viewed as being something worth emulating.

What we've seen in the recent election in Australia is that the public is more progressive than our politics have let on.

I think that means that Australians look at New Zealand with a progressive foreign policy with climate change at the centre of what they do; with a young female leader and they see a style of governing and politics that we would like - in some ways - to emulate here and have not yet been able to do, she says.

Lisa Maree Williams/Getty Images

Treasurer Jim Chalmers is keen to talk to Minister of Finance Grant Robertson about his wellbeing budgets.

She says the election of Albanese Government and the change of direction it is likely to bring, could also bring the two countries close together.

We suddenly now have leaders from the same side of politics in office. Leaders that agree, for example, on the climate crisis in office.

And one could anticipate that some of the friction in the past few years - whether that's been from being tough on China or the treatment of New Zealand citizens in Australia - I think some of that will be dealt with differently going forward, Kassam says.

For New Zealand it does look as if the relationship will continue to improve under this new Australian regime, and that there are opportunities in this post-Covid world. This week was a first salvo in taking advantage of it.

Follow this link:

NZ-Australia relationship appears to be on the way up under the Albanese government - Stuff

PM meeting with Prime Minister of New Zealand: 1 July 2022 – GOV.UK

The Prime Minister hosted the Prime Minister of New Zealand, Jacinda Ardern, today to discuss how the two countries could approach shared global challenges together.

The two Prime Ministers welcomed the Free Trade Agreement signed between the two countries in February this year, and the Prime Minister thanked New Zealand for its support for UK accession to CPTPP.

The two leaders welcomed the agreement to expand the Youth Mobility Scheme, allowing young British nationals and New Zealanders to work more easily in both countries. They also signed the Research, Science and Innovation Arrangement, strengthening the UK and New Zealands collaboration across all three areas to address issues such as climate change.

Reflecting on the Commonwealth Heads of Government Meeting and NATO summit in Madrid this week, the leaders discussed current geopolitical challenges and agreed on the importance supporting countries around the world in defending their sovereignty.The Prime Minister also thanked Prime Minister Ardern for New Zealands support in training Ukrainian Armed Forces in the UK.

The leaders discussed the UKs increased engagement and investment in the Pacific region, and agreed on the importance of working closely with Pacific Island leaders to support their economic resilience.

Prime Minister Ardern updated on her work tackling violent extremism online as part of the Christchurch Call to Action,and the Prime Minister agreed more needed to be done to combat disinformation and drive the use of responsible algorithms.

Continued here:

PM meeting with Prime Minister of New Zealand: 1 July 2022 - GOV.UK

New Zealand Baha’is concerned for nephew imprisoned in Iran – Stuff

New Zealand relatives of an Iranian man sentenced to imprisonment and banishment for his Bahai faith say not being able to help is terrible, but they fear being identified could lead to further reprisals against their family in Iran.

The mans aunt, who has lived in New Zealand for around 40 years, said their nephew is one of 26 Bahai sentenced to a total of 85 years in prison.

He was arrested and charged around five years ago, she said.

They were doing voluntary work in villages in Shiraz, teaching the village kids how to read and write, assisting with sanitation projects, and they had permission to do that from the local authorities.

They were put in jail for around three months, then released on bail.

Theyve been living with this ever since, waiting and waiting. They couldnt get on with their normal lives, because they never knew when they were going to be called [back to court].

We don't congregate into our own clusters, we try to live in and be part of the community and serve in the community, in fact, it's one of our tenets, we really try and work for the benefit of communities that we live in. And that's what exactly what these young people were trying to do, his uncle said.

In a statement released earlier in the week, the New Zealand Bahai Community spokesperson Paddy Payne said sentences of between two and five years had been handed down to all 26 members of the group.

The recent prison sentences, exiles and travel bans are the latest in more than 40 years of systematic persecution of Iranian Bahais, Payne said.

The fear of speaking publicly against the Iranian regime, even in a country like New Zealand, is very real to members of the Bahai faith who have come here from Iran.

They would like to express their alarm at having a family member jailed following a campaign by Iranian authorities to uproot the Bahai community in Shiraz, but they are wary of reprisals.

The mans aunt said she hoped to speak with her MP, and believed coverage of the situation was good, despite fears for her family in Iran.

It's good for the world to know whats going on - they haven't committed any crime, it is really not just.

The mans uncle said the sentence will leave his nephews wife and their two young children in a precarious situation.

He's the breadwinner, and he will be out of action for four years, and of course, there's no social welfare system, they just have to rely on family supports.

The thing is they live in fear all the time, not knowing what is going to happen or when it will happen. It's so hard on the children and families.

The situation is ongoing, the mans aunt said, with several more arrests happening recently.

There are waves of this kind of injustice.

Her husband said the Iranian regime doesnt want to appear to be persecuting Bahai for their faith.

When the verdicts are being read they don't mention the faith at all, because they dont want to be seen as openly prejudiced towards a religious minority, but at the same time, its obvious the only reason they are being arrested and imprisoned is because they are Bahai.

Bahai are still very much persecuted in Iran in a general way, for example, Bahai youth cannot enter university, but for Bahai education is very important, so we developed our own educational systems, and even that comes under pressure from the authorities.

The Bahai, which are the largest religious minority in Iran, have long been persecuted, but the mans uncle said it has intensified since the Iranian Revolution in 1979.

All the other minority religions came before Islam and have some recognition, but the Bahai faith came after, and is not recognised by the Islamic state.

The mans aunt said theres almost no chance of being able to bring family members to New Zealand, pointing to Immigration New Zealands refusal to allow other relatives to obtain tourist visas before the pandemic.

Besides, she said, her relatives do not want to leave Iran forever.

They work there, their families and friends are there, its their country, they want to live and serve there, but unfortunately they dont have rights.

The mans uncle said they are in frequent contact with their family in Iran.

Its easier now with encrypted ways of talking to them like Whats App or Zoom, but traditionally, its been very difficult because we know any letters or phone calls can be intercepted quite easily.

I don't think New Zealanders really know what its like, that as a Bahai you can get a prison sentence for doing volunteer work, his aunt said.

The hardest part is that we cant do anything about it.

The mans aunt said while the accused are waiting to hear the result of their appeal, their lives are again in limbo.

She said the group have appealed their sentences, but she is not hopeful this will succeed.

The Bahai faith has been in New Zealand since 1913, and is considered the second most geographically widespread religion on Earth, with more than five million members in over 200 countries, but Iran has one of the largest Baha'i populations in the world.

Originally posted here:

New Zealand Baha'is concerned for nephew imprisoned in Iran - Stuff

UK and New Zealand govt advise citizens against non-essential travel to Sri Lanka – Times of India

The governments of New Zealand and the United Kingdom have warned their citizens against non-essential travel to Sri Lanka. Given the current political upheaval in the country, the UK and New Zealand have revised their travel advisory level issued for Sri Lanka.

Micheal Appleton, New Zealand High Commissioner to Sri Lanka said that their citizens have have been advised against non-essential travel to Sri Lanka because of the current scenario. The country is going through a bad economic crisis and suffering from many issues such as fuel shortages.

On the other hand, the UKs Foreign Office also put Sri Lanka on its No Go travel list. The UKs Foreign Office said, Sri Lanka is experiencing a severe economic crisis which has led to shortages of basic necessities including medicines, cooking gas, fuel and food. There is a major shortage of fuel (diesel and petrol) affecting transport, businesses, and emergency services. There are daily power cuts due to electricity rationing. This has led to protests and violent unrest. Further protests, demonstrations, roadblocks and violent unrest could occur at short notice.

Sri Lanka was visited by nearly 200,000 British tourists back in 2019 (before pandemic). In 2020, the number went down to over 55,000 because of the COVID-19 pandemic restrictions.

See the article here:

UK and New Zealand govt advise citizens against non-essential travel to Sri Lanka - Times of India

Over 100 Moriori ancestral remains returned to New Zealand in biggest repatriation yet – Newshub

As the rain falls so do the tears, as 111 Moriori ancestral remains and two Mori ancestral remains are finally welcomed home.

An emotional ceremony that has been long in the making.

"The negotiations have taken over 20 years with the Natural History Museum in London," Te Papa's Kaihaut/Mori co-leader Dr Arapata Hakiwai said.

The remains, which include skulls, jaw bones, and a small number of complete skeletons, were taken from the Chatham Islands in the 19th century for trading and collection.

They were kept inside the London museum's archives and were not on public display.

"The world is starting to, I think, mature, to confront their past and own their past," Dr Hakiwai said.

About 200 or so karpuna or Moriori ancestral remains have also been received by Te Papa Museum, from other institutions across Aotearoa.

The skeletons will be stored in Te Papa's Wahi Tapu until researchers can find out where they best belong.

"To have them brought back, and eventually taken back to their Rkohu, in two or three years' time, is probably one of the most important things this generation of Moriori will ever do," Hokotehi Moriori Trust chair Maui Solomon said.

Up to 100 more Moriori ancestral remains are understood to still be overseas.

So the mahi isn't over just yet for the Karanga Repatriation Programme, which is the team that negotiates the return of indigenous remains.

"Give them back, where they can be embraced in the warmth, love and aroha of those who really treasure and value them," Solomon said.

A plea, from a community that wants to see their ancestors returned to their homeland.

Visit link:

Over 100 Moriori ancestral remains returned to New Zealand in biggest repatriation yet - Newshub

Ireland rugby tour of New Zealand 2022: When is it, how many fixtures are planned, and how to watch – The Telegraph

What TV channel are the games on?

The three Tests will be shown live on Sky Sports in the UK. Alternatively, you can follow Telegraph Sport's live coverage of all three matches.

Andy Farrell is confident Ireland can quickly learn lessons from being dismantled by New Zealand in order to remain alive in the series.

The Irish already face an uphill task to salvage their three-Test tour after slipping to a comprehensive 42-19 defeat in Auckland.

Ian Foster's formidable All Blacks ran in six tries on Saturday, including four in the space of just 18 first-half minutes, to maintain their country's remarkable 28-year unbeaten streak at Eden Park.

Despite falling well short of snapping that run, Farrell insists his squad are far from feeling dejected ahead of next week's crucial clash in Dunedin.

"You don't get many opportunities to break a record; it's an outstanding record and you can see why they hold that," he said.

"We're gutted to lose but, having said that, the players know what they did well and they know how the game flowed and things that we need to fix to stay in a series next week.

"It isn't a dejected changing room; it's one that will dust itself off, learn the lessons and attack next week."

Captain Johnny Sexton must pass further head injury assessments in order to be in contention for the second Test after being taken off in the aftermath of Reece's try, while back-up hooker Dave Heffernan is out due to concussion.

Farrell and his coaching staff now have a full week to get ready for the second instalment of the series, having played a warm-up match against the Maori All Blacks in the build-up to the opener.

Asked if that simplifies preparations, he replied: "Of course it's easier but having it easy, is that what we want? I don't know.

"We're here to test ourselves in all different types of manner and we're here to test ourselves as staff to see how we cope with two matches (in a week) and we're here to see if our players have got excuses or not in regard to backing up and different ways of training.

"Doing it that way makes us stronger as a group, makes our culture stronger, makes our environment stronger and makes us ready for obstacles that are going to get in our way certainly over the next 18 months."

See the original post here:

Ireland rugby tour of New Zealand 2022: When is it, how many fixtures are planned, and how to watch - The Telegraph

Matt Williams: Irish side must find way to play best rugby of their lives if New Zealand are to be beaten – The Irish Times

The savage basics, performed at high tempo with ruthless efficiency and accurate aggression.

In their powerful opening display at Eden Park, New Zealand personified this famous coaching quote.

The New Zealanders commanding display contained nothing but the basics of the game, executed with brilliant efficiency, at a lightning pace. Their scrum, lineout, maul, ball carrying, short kicking, tackling, clear-outs, catching and passing were almost flawless.

All executed with a bucket of aggression tossed on top.

The ruthless efficiency of the Kiwi attack had a simple strategy at its core. Utilising Aaron Smiths long and accurate pass, New Zealand ran their forwards at the outside shoulder of Irelands fourth defender.

This created separation between the Irish defenders as they were forced to constantly reorganise and move laterally in their line, adjusting their positioning, rather than moving forward to take time and space from New Zealand. The end result was that Irelands line speed dropped to that of a slug.

[Johnny Sexton: You go off for HIA and dont come back, everyone presumes thats a concussion, its not]

[New Zealand v Ireland: Under the roof and cornered but opportunity remains for biggest one-off win ever]

Smith and Ardie Savea eventually ran through gaping holes this simple but aggressively implemented tactic created.

The New Zealanders attacking strategy had another key element. Ireland position their scrum-half in their defensive line and place fullback Hugo Keenan, wrongly in my opinion and it would seem that of the Kiwis, wide of the ruck, covering the open side.

Ireland position zero defenders in the backfield in line with the ball.

The Irish gamble of maintaining 14 defenders in the line, deep into their own half was exploited by both Smith and Beauden Barrett, who executed exquisite short attacking kicks that exposed the acres of unmarked space embarrassingly left vacant by the poor positioning of Irelands back three and scrum-half while defending in their own 22.

Irelands defensive line was manipulated by the combination of masterful strategy and superb execution.

The final act, in a long disastrous list of Irish defensive errors, came when the Kiwi replacement number eight, Pita Gus Sowakula, picked the ball up at the base of an attacking 5m scrum and simply strolled over without a hand being laid on him.

Defensively, Ireland had taken a knife to a gunfight.

To state the bleeding obvious, both the Irish defensive backfield system and the players mindset of desperation to make the tackle must change for any hope in Dunedin.

In stark contrast, the New Zealanders defensive display was a lesson in strategic and physical domination. New Zealand used perfect tackle technique, mixed with ruthlessly controlled aggression to create a defensive system that was like the incoming tide after an horrific oil spill. Wave after wave of strong fluid black unyieldingly engulfed anything green in its path.

In the dying moments of the match, New Zealand sent Ireland a clear message. As Joey Carbery was astonishingly held up over the try line and Josh van der Flier had the ball belted from his grip before he could touch down, the Kiwis yelled in Irish ears that never ever, under any circumstances, will there be easy points against New Zealand.

Compare that to the Wallabies who were about to notch up a brave win over England, only to mentally switch off in the final 120 seconds and surrender 14 points.

Those two minutes of low-intensity concentration from an otherwise courageous Australia injected hope into English hearts for their second test. Perhaps it was to reinforce the widespread belief that Australians are far more hospitable than their New Zealand cousins. Then again, maybe Ozzies are just soft.

Irelands Joey Carbery misses out on a try. File photograph: Billy Stickland/Inpho

England and Ireland share a common dilemma. English outhalf Marcus Smith and Joey Carbery have both not been capable of igniting their teams offensive system.

Smith is beginning to look like a player who cannot transfer his attacking form from his club to the International stage. As he repeatedly did during the Six Nations, Smith constantly positions himself to accept the ball far too deep. Which meant he once again failed to attack the defensive line as a real threat.

In Carberys defence, when he took the field after Sextons injury his forward pack had fallen under the domination of New Zealand. It is close to impossible for any outhalf to create a positive attack with no platform being established by his forwards.

That said, when Carbery comes on this week he must be far more positive in his body language and leadership. Presently, his agonised self-doubt is yelling at his team-mates and the opposition without him uttering a word.

Good leaders exude positive body language that expresses a strategic belief. Confidence is contagious and so is the lack of it.

Both Carbery and Smith are expressing their lack of confidence in how they accept the pass. As an outhalf you dont just catch the ball, you must attack it. Far too often Joey is stationary when accepting the ball, which makes it close to impossible for him to commit the defensive line before passing.

Like Carbery, this Irish team appears to have totally underestimated the intensity of the mindset that is required for success in Aotearoa.

The mindset that delivered Irish wins in Chicago and Dublin was never going to be enough.

I have found that the mantra of mindset drives belief. Belief drives performance and performance determines outcomes to be absolute.

Last week New Zealand displayed the highest standards of character and mindset. For victory, Ireland will have to raise their mindset above that of New Zealand.

Ireland have the talent and the skill to win a test in New Zealand but without great mental change, every piece of evaluation says New Zealand will win the next two matches by a considerable margin.

That does not mean that winning for Ireland is an impossible task. What it does mean is that like every other team that has ever won a test match in New Zealand, each individual in the Irish team must find a way to play the best rugby of their lives in order to win.

That has always been the challenge for teams touring New Zealand.

Across the final two tests, we will learn a great deal about the true character of this Irish team. As the cliche goes: Test match rugby does not create character, it reveals it.

To overcome the enormity of the New Zealand challenge, the Irish players must have the mindset willing to journey into the depths of their character and find a belief they previously did not know they possessed.

That deeply personal journey to truly believe in victory in New Zealand is not easy to navigate. That is why so few have ever accomplished it.

The chance for this group of players to create history at Eden Park has gone, never to return. Yet, the opportunity of a lifetime still awaits Ireland.

More here:

Matt Williams: Irish side must find way to play best rugby of their lives if New Zealand are to be beaten - The Irish Times

Is living in Australia really better than New Zealand? – Stuff

Jake Howie is a New Zealand writer living in Sydney.

OPINION: Kia ora, my fellow Kiwis. Im coming to you from the other side of the Tasman, where according to most New Zealand media everything is better, cheaper, faster, easier and did I mention cheaper?

My husbands job brought us to Sydney three years ago, and Im enjoying living in such a beautiful city. The sun! The beaches! The bridge! What Im about to divulge is in no way an outdated anti-Australian sentiment I love Australia.

I also love Aotearoa. Its just a different perspective from a Kiwi who isnt a moaning, informationally selective New Zealander complaining with gusto about Auckland, or New Zealand, or the weather in Wellington, or wages, or how Australia is better, or NZ is worse, or NZ is better AND worse and cheaper and expensive. Did I mention cheaper?

READ MORE:* Do you still need to use cash when you travel overseas? * World's most expensive cities: Auckland and Wellington drop in ranking * The truth about life in Australia v New Zealand

This is just my experience living in Australia and a sobering reminder that New Zealand has an unhealthy obsession with painting Australia as this perfect place. Spoiler alert: its not. There. I said it. Watch the Kiwis obsessed with using Australia as an example of the dream get their feathers in a ruffle. But..cheaper! Less expensive! Money! Wages! Sun!

Yeah, yeah we get it. But I live it, so heres a few things a Kiwi living in Australia has learnt.

Brook Sabin

Living in Australia might sound like a dream for some Kiwis, but it has its own set of challenges.

Okay, I live in Sydney so may be slightly more traumatised than some. But, as an Aucklander, I know an expensive housing market when I see one. And Sydney is expensive. Not only is it wild and unpredictable (something Kiwis will be used to), but Australians have stamp duty (a government tax) on any property you buy. The tax depends on the price of the property, but the average house in Australia means youre looking at an extra $40,000 plus when buying a home. Theyre removing this in some cases but are keeping the legacy with a land tax that means you pay roughly the same amount over time rather than one lump sum. Yikes!

Supplied

The average house price in Sydney is peaking upwards of $1.6 million.

While certain parts of Australia may vary, property experts at Domain say the average property in Australia is over $1 million, peaking at upwards of $1.6 million in Sydney. On our side of the Tasman, the Real Estate Institute of New Zealand says the average house price is around $840k with Barfoot & Thompson suggesting the figure bumps up to $1.2 million in Auckland.

Overpriced? Hell yes. More expensive? Sorry, Kiwis Australia has us beat. And lets not forget to add those pesky taxes to the average property price.

This brings me to groceries. Kiwis are obsessed with it. On a recent trip home, I had three people ask me how much a cauliflower was in Australia. My response? Theyre not in season, my darling. So why are you even buying them at a time when feijoas are essentially free?

Upon going to PaknSave, I was startled by how much cheaper some things were and how much more expensive other things were. Potatoes, po-taaa-toes. It all somehow equalled out. According to global cost of living database Numbeo, grocery prices in Australia are 7.29% higher than in New Zealand. Milk and eggs are cheaper in Australia, but bread and apples cheaper in New Zealand.

Long story short, its all overpriced. Theres no raw deal New Zealand is getting that Australia is somehow magically freed from. New Zealands duopoly is being addressed by the government, which should help. But, quite frankly, theyre just as ridiculous as each other with data suggesting it could be just a little bit more ridiculous in Australia, overall.

But the wages are more?! I can hear the chorus of Kiwis asking this. This one is slightly true. According to the Australian Bureau of Statistics, the average Aussie earns AU$36 per hour. Back home, Stats NZs research says Kiwis earn NZ$36.18 per hour. Boom. Facts. Arent they brilliant?

Aussies do earn around NZ$3.50 more per hour when you factor in the exchange rate, but youre going to need it for bread, apples and those darn house prices, am I right? Youll also need it for the flights home when you realise how much you love your friends, family and our beautiful whenua. And with the global situation, itll take more than $3.50 an hour to pay for flights.

If I had to get one message across to New Zealanders, it would be this: it aint that bad. Im not trivialising the global crises were all facing and the very real impact it has on families but looking outside for a reason wont make things better.

The truth is, New Zealand, Australia is hurting just like you. Prices are rising sharply, wages arent growing, crime is up, homelessness is noticeably increasing.

These issues are issues we face as a global community, and the once quaint comparisons between two sister nations are now pointless, whingey and quite frankly wildly privileged. Were lucky we havent had to be as resilient as so many other nations have been forced to be. Were lucky weve made it through a global pandemic and international conflict as unscathed as we can be. Were lucky were discussing two wonderful countries that offer so much hope for the future. Were so, so lucky.

So rather than looking across the ditch for bitter Kiwis claiming things are so much better, look closer to home for all the beauty being born into such a wonderful country provides. Whether you want to admit it or not, New Zealand just aint that bad.

See the original post here:

Is living in Australia really better than New Zealand? - Stuff

Car pollution kills thousands in New Zealand every year – 1News

In findings which have startled scientists, new data shows car pollution is killing thousands of New Zealanders each year and costing the country billions of dollars.

File image: Car pollution. (Source: istock.com)

By Kirsty Frame of rnz.co.nz

The first-of-its-kind study has measured the health impacts of nitrogen dioxide, a toxic gas emitted by fossil fuel cars.

It found 3300 people were dying yearly because of air pollution, and it was mostly because of cars.

That meant as a whole, 10% of the people who died each year in the country were dying because of air pollution.

Exposure was also sending more than 13,000 people to hospital for respiratory and cardiac illnesses and giving the same number of children asthma.

The social cost of these health impacts was estimated to be $15.6 billion.

The study, Health and Air Pollution in New Zealand, was conducted by New Zealand experts in air quality, health, and economics.

It was the study's third instalment since 2012, but for the first time, pollution data from vehicles was measured.

The new numbers were more substantial than previous records of air pollution - making car pollution more harmful than the damage household fires caused.

Researchers said the extent of the nitrogen dioxide impacts were "unexpected" and "startling".

Nitrogen dioxide emission in New Zealand is almost exclusively from burning petrol and diesel.

The country has almost 4.4 million motor vehicles and that figure is on an upwards trend.

Previously, air pollution measured in the country had been largely from fine pollution particles - which came from domestic fires, car breaks, and industry.

That pollution caused an estimated 1300 deaths in adults per year.

A closer look now showed that a further 2000 people were dying because of exposure to nitrogen dioxide.

That was because the pollutant was a major factor in stroke, heart disease, lung cancer and chronic respiratory diseases.

Young children, elderly, asthmatics and people with pre-existing heart or lung diseases were most vulnerable to both forms of air pollution.

The new figures more than doubled Aotearoa's air pollution hospitalisation statistics.

Nitrogen dioxide is sending an estimated 8500 people to hospital with cardiovascular or respiratory illness, compared to 4600 from other air pollutants.

An extra 6000 people are being hospitalised with a respiratory condition from nitrogen dioxide exposure.

It brings the total annual hospitalisations from all air pollution to 13,100.

New Zealand already has some of the highest asthma rates in the world, and the new research estimated that 13,200 cases of asthma in children were exclusively because of car pollution.

Not only is air pollution killing people and harming their health, it is costing the country $15.6b; and 60 percent of that is because of nitrogen dioxide.

The "social costs" of air pollution calculated in the study took into account the costs to society when people were sick or died from exposure.

It was not just in terms of the direct medical costs with illness and death, but a loss of output from people taking time off work, school and the loss of income.

The study used a "value of statistical life" which was the same used to cost road crash deaths.

At 2019 prices, that was $4.5 million per person's premature death.

It also estimated a cost of $36,000 for each person admitted to hospital with cardiac issues, and $31,700 for people with respiratory issues triggered by air pollution.

Childhood asthma hospitalisations are costing the country $1800 per case.

Air pollution is also causing 1.745 million restricted activity days - days where people cannot do the things they normally would because of the bad air.

Increased air pollution also makes people less likely to engage in physical activity, which of itself has wide-ranging public health impacts.

Data for the study was collected from 2016 statistics because at the study's commencement in 2019, it was the most suitable on hand.

Excerpt from:

Car pollution kills thousands in New Zealand every year - 1News

Gene & Cell Therapy FAQs | ASGCT – American Society of Gene & Cell …

For more in-depth learning, we recommend Different Approaches in our Patient Education program.

The challenges of gene and cell therapists can be divided into three broad categories based on disease, development of therapy, and funding.

Challenges based on the disease characteristics: Disease symptoms of most genetic diseases, such as Fabrys, hemophilia, cystic fibrosis, muscular dystrophy, Huntingtons, and lysosomal storage diseases are caused by distinct mutations in single genes. Other diseases with a hereditary predisposition, such as Parkinsons disease, Alzheimers disease, cancer, and dystonia may be caused by variations/mutations in several different genes combined with environmental causes. Note that there are many susceptible genes and additional mutations yet to be discovered. Gene replacement therapy for single gene defects is the most conceptually straightforward. However, even then the gene therapy agent may not equally reduce symptoms in patients with the same disease caused by different mutations, and even the samemutationcan be associated with different degrees of disease severity. Gene therapists often screen their patients to determine the type of mutation causing the disease before enrollment into a clinical trial.

The mutated gene may cause symptoms in more than one cell type. Cystic fibrosis, for example, affects lung cells and the digestive tract, so the gene therapy agent may need to replace the defective gene or compensate for its consequences in more than one tissue for maximum benefit. Alternatively, cell therapy can utilizestem cellswith the potential to mature into the multiple cell types to replace defective cells in different tissues.

In diseases like muscular dystrophy, for example, the high number of cells in muscles throughout the body that need to be corrected in order to substantially improve the symptoms makes delivery of genes and cells a challenging problem.

Some diseases, like cancer, are caused by mutations in multiple genes. Although different types of cancers have some common mutations, every tumor from a single type of cancer does not contain the same mutations. This phenomenon complicates the choice of a single gene therapy tactic and has led to the use of combination therapies and cell elimination strategies. For more information on gene and cell therapy strategies to treat cancer, please refer to the Cancer and Immunotherapy summary in the Disease Treatment section.

Disease models in animals do not completely mimic the human diseases and viralvectorsmay infect various species differently. The testing of vectors in animal models often resemble the responses obtained in humans, but the larger size of humans in comparison to rodents presents additional challenges in the efficiency of delivery and penetration of tissue.Gene therapy, cell therapy, and oligonucleotide-based therapy agents are often tested in larger animal models, including rabbit, dog, pig and nonhuman primate models. Testing human cell therapy in animal models is complicated by immune rejections. Furthermore, humans are a very heterogeneous population. Their immune responses to the vectors, altered cells, or cell therapy products may differ or be similar to results obtained in animal models.

Challenges in the development of gene and cell therapy agents: Scientific challenges include the development of gene therapy agents that express the gene in the relevant tissue at the appropriate level for the desired duration of time. There are a lot of issues in that once sentence, and while these issues are easy to state, each one requires extensive research to identify the best means of delivery, how to control sufficient levels or numbers of cells, and factors that influence duration of gene expression or cell survival. After the delivery modalities are determined, identification and engineering of a promoter and control elements (on/off switch and dimmer switch) that will produce the appropriate amount of protein in the target cell can be combined with the relevant gene. This gene cassette is engineered into a vector or introduced into thegenomeof a cell and the properties of the delivery vehicle are tested in different types of cells in tissue culture. Sometimes things go as planned and then studies can be moved onto examination in animal models. In most cases, the gene/cell therapy agent may need to be improved further by adding new control elements to obtain the desired responses in cells and animal models.

Furthermore, the response of the immune system needs to be considered based on the type of gene or cell therapy being undertaken. For example, in gene or cell therapy for cancer, one aim is to selectively boost the existing immune response to cancer cells. In contrast, to treat genetic diseases like hemophilia and cystic fibrosis the goal is for the therapeutic protein to be accepted as an addition to the patients immune system.

If the new gene is inserted into the patients cellularDNA, the intrinsic sequences surrounding the new gene can affect its expression and vice versa. Scientists are now examining short DNA segments that may insulate the new gene from surrounding control elements. Theoretically, these insulator sequences would also reduce the effect of vector control signals in the gene cassette on adjacent cellular genes. Studies are also focusing on means to target insertion of the new gene into safe areas of the genome, to avoid influence on surrounding genes and to reduce the risk of insertional mutagenesis.

Challenges of cell therapy include the harvesting of the appropriate cell populations and expansion or isolation of sufficient cells for one or multiple patients. Cell harvesting may require specific media to maintain the stem cells ability toself-renew and mature into the appropriate cells. Ideally extra cells are taken from the individual receiving therapy. Those additional cells can expand in culture and can be induced to becomepluripotent stem cells(iPS), thus allowing them to assume a wide variety of cell types and avoiding immune rejection by the patient. The long term benefit of stem cell administration requires that the cells be introduced into the correct target tissue and become established functioning cells within the tissue. Several approaches are being investigated to increase the number of stem cells that become established in the relevant tissue.

Another challenge is developing methods that allow manipulation of the stem cells outside the body while maintaining the ability of those cells to produce more cells that mature into the desired specialized cell type. They need to provide the correct number of specialized cells and maintain their normal control of growth and cell division, otherwise there is the risk that these new cells may grow into tumors.

Challenges in funding: In most fields, funding for basic or applied research for gene and cell therapy is available through the National Institutes of Health (NIH) and private foundations. These are usually sufficient to cover the preclinical studies that suggest a potential benefit from a particular gene and cell therapy. Moving into clinical trials remains a huge challenge as it requires additional funding for manufacturing of clinical grade reagents, formal toxicology studies in animals, preparation of extensive regulatory documents, and costs of clinical trials.Biotechnology companies and the NIH are trying to meet the demand for this large expenditure, but many promising therapies are slowed down by lack of funding for this critical next phase.

Read more:

Gene & Cell Therapy FAQs | ASGCT - American Society of Gene & Cell ...

Document: Big Pharma exec: COVID shots are ‘gene therapy’

An Air Force medical technician draws a dose of the COVID-19 vaccine to inoculate Air Force reservists at Joint Base Lewis McChord, Washington, Sept. 12, 2021. (U.S. Air Force photo by Staff Sgt. Paolo Felicitas)

Many skeptics have contended that the mRNA-based Pfizer and Moderna COVID-19 shots are not "vaccines" but rather a form of gene therapy that poses untold risks by altering a recipient's DNA.

The federal government and health-care experts have denied that claim. But the president of Bayer's Pharmaceuticals Division is on record describing the mRNA shots as "cell and gene therapy" and acknowledging public wariness of the technology.

Bayer executive Stefan Oelrich, LifeSiteNews reported, made the statement at the World Health Summit, which took place in Berlin Oct. 24-26, drawing 6,000 people from 120 countries.

Oelrich said his company is "really taking that leap" to drive innovation "in cell and gene therapies."

"Ultimately, the mRNA vaccines are an example for that cell and gene therapy," he said.

"I always like to say: If we had surveyed two years ago in the public 'would you be willing to take a gene or cell therapy and inject it into your body?' we probably would have had a 95% refusal rate," Oelrich said.

In August, Reuters ran a "fact check" citing experts who contend that the technology in the Pfizer/BioNTech and Moderna shots are not gene therapy.

Both shots usea piece of genetic code from SARS-CoV-2 to prompt an immune response in recipients. But Dr. Adam Taylor, a virologist and researcher at Griffith University in Australia, insisted that while it's "a genetic-based therapy," it doesn't alter a person's genes.

Gene therapy, in the classical sense, involves making deliberate changes to a patients DNA in order to treat or cure them," he said. "mRNA vaccines will not enter a cells nucleus that houses your DNA genome. There is zero risk of these vaccines integrating into our own genome or altering our genetic makeup."

At the Berlin summit, the Bayer executive said that his company's "successes" over the 18 months of the pandemic "should embolden us to fully focus much more closely on access, innovation and collaboration to unleash health for all, especially as we enter, on top of everything else that is happening, a new era of science a lot of people talk about the Bio Revolution in this context."

LifeSiteNews noted that, according to the McKinsey Global Institute, the "Bio Revolution" is "a confluence of advances in biological science and accelerating development of computing, automation, and artificial intelligence [that] is fueling a new wave of innovation."

"This Bio Revolution could have significant impact on economies and our lives, from health and agriculture to consumer goods, and energy and materials."

Oelrich said Bayer also is working at reducing the populations of Third World countries, investing $400 million in "long-acting contraceptives" and partnering with the Bill and Melinda Gates Foundation on "family planning initiatives."

EDITOR'S NOTE: Last year, America's doctors, nurses and paramedics were celebrated as frontline heroes battling a fearsome new pandemic. Today, under Joe Biden, tens of thousands of these same heroes are denounced as rebels, conspiracy theorists, extremists and potential terrorists. Along with massive numbers of police, firemen, Border Patrol agents, Navy SEALs, pilots, air-traffic controllers, and countless other truly essential Americans, they're all considered so dangerous as to merit termination, their professional and personal lives turned upside down due to their decision not to be injected with the experimental COVID vaccines. Bidens tyrannical mandate threatens to cripple American society from law enforcement to airlines to commercial supply chains to hospitals. It's already happening. But the good news is that huge numbers of "yesterdays heroes" are now fighting back bravely and boldly. The whole epic showdown is laid out as never before in the sensational October issue of WND's monthly Whistleblower magazine, titled "THE GREAT AMERICAN REBELLION: 'We will not comply!' COVID-19 power grab ignites bold new era of national defiance."

Content created by the WND News Center is available for re-publication without charge to any eligible news publisher that can provide a large audience. For licensing opportunities of our original content, please contact licensing@wndnewscenter.org.

SUPPORT TRUTHFUL JOURNALISM. MAKE A DONATION TO THE NONPROFIT WND NEWS CENTER. THANK YOU!

The post Big Pharma exec: COVID shots are 'gene therapy' appeared first on WND.

Originally posted here:

Document: Big Pharma exec: COVID shots are 'gene therapy'

Gene therapy – Mayo Clinic

Overview

Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body's form and function, from making you grow taller to regulating your body systems. Genes that don't work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body's ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can't easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells' genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren't the only vectors that can be used to carry altered genes into your body's cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies of tests and procedures to help prevent, detect, treat or manage conditions.

Dec. 29, 2017

Excerpt from:

Gene therapy - Mayo Clinic

FDA approves novel gene therapy to treat patients with a rare form of …

For Immediate Release: December 18, 2017

Espaol

The U.S. Food and Drug Administration today approved Luxturna (voretigene neparvovec-rzyl), a new gene therapy, to treat children and adult patients with an inherited form of vision loss that may result in blindness. Luxturna is the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene.

Todays approval marks another first in the field of gene therapy both in how the therapy works and in expanding the use of gene therapy beyond the treatment of cancer to the treatment of vision loss and this milestone reinforces the potential of this breakthrough approach in treating a wide-range of challenging diseases. The culmination of decades of research has resulted in three gene therapy approvals this year for patients with serious and rare diseases. I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses, said FDA Commissioner Scott Gottlieb, M.D. Were at a turning point when it comes to this novel form of therapy and at the FDA, were focused on establishing the right policy framework to capitalize on this scientific opening. Next year, well begin issuing a suite of disease-specific guidance documents on the development of specific gene therapy products to lay out modern and more efficient parameters including new clinical measures for the evaluation and review of gene therapy for different high-priority diseases where the platform is being targeted.Luxturna is approved for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss and may cause complete blindness in certain patients.

Hereditary retinal dystrophies are a broad group of genetic retinal disorders that are associated with progressive visual dysfunction and are caused by mutations in any one of more than 220 different genes. Biallelic RPE65 mutation-associated retinal dystrophy affects approximately 1,000 to 2,000 patients in the U.S. Biallelic mutation carriers have a mutation (not necessarily the same mutation) in both copies of a particular gene (a paternal and a maternal mutation). The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision. Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. Individuals with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. This loss of vision, often during childhood or adolescence, ultimately progresses to complete blindness.

Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina to restore patients vision loss. Luxturna uses a naturally occurring adeno-associated virus, which has been modified using recombinant DNA techniques, as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision.

The approval of Luxturna further opens the door to the potential of gene therapies, said Peter Marks, M.D., Ph.D., director of the FDAs Center for Biologics Evaluation and Research (CBER). Patients with biallelic RPE65 mutation-associated retinal dystrophy now have a chance for improved vision, where little hope previously existed.

Luxturna should be given only to patients who have viable retinal cells as determined by the treating physician(s). Treatment with Luxturna must be done separately in each eye on separate days, with at least six days between surgical procedures. It is administered via subretinal injection by a surgeon experienced in performing intraocular surgery. Patients should be treated with a short course of oral prednisone to limit the potential immune reaction to Luxturna.

The safety and efficacy of Luxturna were established in a clinical development program with a total of 41 patients between the ages of 4 and 44 years. All participants had confirmed biallelic RPE65 mutations. The primary evidence of efficacy of Luxturna was based on a Phase 3 study with 31 participants by measuring the change from baseline to one year in a subjects ability to navigate an obstacle course at various light levels. The group of patients that received Luxturna demonstrated significant improvements in their ability to complete the obstacle course at low light levels as compared to the control group.

The most common adverse reactions from treatment with Luxturna included eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear.

The FDA granted this application Priority Review and Breakthrough Therapy designations. Luxturna also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the 13th rare pediatric disease priority review voucher issued by the FDA since the program began.

To further evaluate the long-term safety, the manufacturer plans to conduct a post-marketing observational study involving patients treated with Luxturna.

The FDA granted approval of Luxturna to Spark Therapeutics Inc. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Luxturna is the first gene therapy approved in the U.S. to target a disease caused by mutations in a specific gene

Andrea Fischer301-796-0393

888-INFO-FDAOCOD@fda.hhs.gov

###

Read more from the original source:

FDA approves novel gene therapy to treat patients with a rare form of ...

Adeno-Associated Virus (AAV) as a Vector for Gene Therapy

BioDrugs. 2017; 31(4): 317334.

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

2BiStro Biotech Consulting, LLC, Bridgewater, NJ 08807 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

2BiStro Biotech Consulting, LLC, Bridgewater, NJ 08807 USA

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

There has been a resurgence in gene therapy efforts that is partly fueled by the identification and understanding of new gene delivery vectors. Adeno-associated virus (AAV) is a non-enveloped virus that can be engineered to deliver DNA to target cells, and has attracted a significant amount of attention in the field, especially in clinical-stage experimental therapeutic strategies. The ability to generate recombinant AAV particles lacking any viral genes and containing DNA sequences of interest for various therapeutic applications has thus far proven to be one of the safest strategies for gene therapies. This review will provide an overview of some important factors to consider in the use of AAV as a vector for gene therapy.

The discovery of DNA as the biomolecule of genetic inheritance and disease opened up the prospect of therapies in which mutant, damaged genes could be altered for the improvement of the human condition. The recent ability to rapidly and affordably perform human genetics on hundreds of thousands of people, and to sequence complete genomes, has resulted in an explosion of nucleic acid sequence information and has allowed us to identify the gene, or genes, that might be driving a particular disease state. If the mutant gene(s) could be fixed, or if the expression of overactive/underactive genes could be normalized, the disease could be treated at the molecular level, and, in best case scenarios, potentially be cured. This concept seems particularly true for the treatment of monogenic diseases, i.e. those diseases caused by mutations in a single gene. This seemingly simple premise has been the goal of gene therapy for over 40years.

Until relatively recently, that simple goal was very elusive as technologies to safely deliver nucleic acid cargo inside cells have lagged behind those used to identify disease-associated genes. One of the earliest approaches investigated was the use of viruses, naturally occurring biological agents that have evolved to do one thing, i.e. deliver their nucleic acid (DNA or RNA) into a host cell for replication. There are numerous viral agents that could be selected for this purpose, each with some unique attributes that would make them more or less suitable for the task, depending on the desired profile [1]. However, the undesired properties of some viral vectors, including their immunogenic profiles or their propensity to cause cancer have resulted in serious clinical adverse events and, until recently, limited their current use in the clinic to certain applications, for example, vaccines and oncolytic strategies [2]. More artificial delivery technologies, such as nanoparticles, i.e. chemical formulations meant to encapsulate the nucleic acid, protect it from degradation, and get through the cell membrane, have also achieved some levels of preclinical and clinical success. Not surprisingly, they also have encountered some unwanted safety signals that need to be better understood and controlled [3].

Adeno-associated virus (AAV) is one of the most actively investigated gene therapy vehicles. It was initially discovered as a contaminant of adenovirus preparations [4, 5], hence its name. Simply put, AAV is a protein shell surrounding and protecting a small, single-stranded DNA genome of approximately 4.8kilobases (kb). AAV belongs to the parvovirus family and is dependent on co-infection with other viruses, mainly adenoviruses, in order to replicate. Initially distinguished serologically, molecular cloning of AAV genes has identified hundreds of unique AAV strains in numerous species. Its single-stranded genome contains three genes, Rep (Replication), Cap (Capsid), and aap (Assembly). These three genes give rise to at least nine gene products through the use of three promoters, alternative translation start sites, and differential splicing. These coding sequences are flanked by inverted terminal repeats (ITRs) that are required for genome replication and packaging. The Rep gene encodes four proteins (Rep78, Rep68, Rep52, and Rep40), which are required for viral genome replication and packaging, while Cap expression gives rise to the viral capsid proteins (VP; VP1/VP2/VP3), which form the outer capsid shell that protects the viral genome, as well as being actively involved in cell binding and internalization [6]. It is estimated that the viral coat is comprised of 60 proteins arranged into an icosahedral structure with the capsid proteins in a molar ratio of 1:1:10 (VP1:VP2:VP3) [6]. The aap gene encodes the assembly-activating protein (AAP) in an alternate reading frame overlapping the cap gene. This nuclear protein is thought to provide a scaffolding function for capsid assembly [7]. While AAP is essential for nucleolar localization of VP proteins and capsid assembly in AAV2, the subnuclear localization of AAP varies among 11 other serotypes recently examined, and is nonessential in AAV4, AAV5, and AAV11 [8].

Although there is much more to the biology of wild-type AAV, much of which is not fully understood, this is not the form that is used to generate gene therapeutics. Recombinant AAV (rAAV), which lacks viral DNA, is essentially a protein-based nanoparticle engineered to traverse the cell membrane, where it can ultimately traffic and deliver its DNA cargo into the nucleus of a cell. In the absence of Rep proteins, ITR-flanked transgenes encoded within rAAV can form circular concatemers that persist as episomes in the nucleus of transduced cells [9]. Because recombinant episomal DNA does not integrate into host genomes, it will eventually be diluted over time as the cell undergoes repeated rounds of replication. This will eventually result in the loss of the transgene and transgene expression, with the rate of transgene loss dependent on the turnover rate of the transduced cell. These characteristics make rAAV ideal for certain gene therapy applications. Following is an overview of the practical considerations for the use of rAAV as a gene therapy agent, based on our current understanding of viral biology and the state of the platform. The final section provides an overview for how rAAV has been incorporated into clinical-stage gene therapy candidates, as well as the lessons learned from those studies that can be applied to future therapeutic opportunities.

The main point of consideration in the rational design of an rAAV vector is the packaging size of the expression cassette that will be placed between the two ITRs. As a starting point, it is generally accepted that anything under 5kb (including the viral ITRs) is sufficient [10]. Attempts at generating rAAV vectors exceeding packaging cassettes in excess of 5kb results in a considerable reduction in viral production yields or transgene recombination (truncations) [11]. As a result, large coding sequences, such as full-length dystrophin, will not be effectively packaged in AAV vectors. Therefore, the use of dual, overlapping vector strategies (reviewed by Chamberlain et al.) [12], should be considered in these cases. An additional consideration relates to the biology of the single-stranded AAV-delivered transgenes. After delivery to the nucleus, the single-stranded transgene needs to be converted into a double-stranded transgene, which is considered a limiting step in the onset of transgene expression [13]. An alternative is to use self-complementary AAV, in which the single-stranded packaged genome complements itself to form a double-stranded genome in the nucleus, thereby bypassing that process [13, 14]. Although the onset of expression is more rapid, the packaging capacity of the vector will be reduced to approximately 3.3kb [13, 14].

AAV2 was one of the first AAV serotypes identified and characterized, including the sequence of its genome. As a result of the detailed understanding of AAV2 biology from this early work, most rAAV vectors generated today utilize the AAV2 ITRs in their vector designs. The sequences placed between the ITRs will typically include a mammalian promoter, gene of interest, and a terminator (Fig.). In many cases, strong, constitutively active promoters are desired for high-level expression of the gene of interest. Commonly used promoters of this type include the CMV (cytomegalovirus) promoter/enhancer, EF1a (elongation factor 1a), SV40 (simian virus 40), chicken -actin and CAG (CMV, chicken -actin, rabbit -globin) [15]. All of these promoters provide constitutively active, high-level gene expression in most cell types. Some of these promoters are subject to silencing in certain cell types, therefore this consideration needs to be evaluated for each application [16]. For example, the CMV promoter has been shown to be silenced in the central nervous system (CNS) [16]. It has been observed that the chicken -actin and CAG promoters are the strongest of these constitutive promoters in most cell types; however, the CAG promoter is significantly larger than the others (1.7kb vs. 800bp for CMV), a consideration to take into account when packaging larger gene inserts [15].

Schematic representation of the basic components of a gene insert packaged inside recombinant AAV gene transfer vector. AAV adeno-associated virus, ITR inverted terminal repeat

Although many therapeutic strategies involve systemic delivery, it is often desirable to have cell- or tissue-specific expression. Likewise, for local delivery strategies, undesired systemic leakage of the AAV particle can result in transduction and expression of the gene of interest in unwanted cells or tissues. The muscle creatine kinase and desmin promoters have been used to achieve high levels of expression, specifically in skeletal muscle, whereas the -myosin heavy chain promoter can significantly restrict expression to cardiac muscle [15, 17]. Likewise, the neuron-specific enolase promoter can attain high levels of neuron-specific expression [18, 19]. Often is the case, systemic delivery of AAV results in a significant accumulation in the liver. While this may be desirable for some applications, AAV can also efficiently transduce other cells and tissues types. Thus, in order to restrict expression to only the liver, a common approach is to use the 1-antitrypsin promoter [20, 21]. Finally, there are now technologies that have the ability to generate novel, tissue-specific promoters, based on DNA regulatory element libraries [22].

Over the course of the past 1015years, much work has been done to understand the correlation between codon usage and protein expression levels. Although bacterial expression systems seem to be most affected by codon choice, there are now many examples of the effects of codon engineering on mammalian expression [23]. Many groups have developed their own codon optimization strategies, and there are many free services that can similarly provide support for codon choice. Codon usage has also been shown to contribute to tissue-specific expression, and play a role in the innate immune response to foreign DNA [24, 25]. With regard to the gene of interest, codon engineering to support maximal, tissue-specific expression should be performed.

Additionally, terminator/polyadenylation signal choices, the inclusion of post-transcriptional regulator elements and messenger RNA (mRNA) stability elements, and the presence of microRNA (miRNA) target sequence in the gene cassette can all have effects on gene expression [26]. The human factor IX 3 UTR, for example, was shown to dramatically increase factor IX expression in vivo, especially in the context of additional cis regulatory elements [27]. Likewise, synthetic miRNA target sequences have been engineered into the 3 UTR of AAV-delivered genes to make them susceptible to miRNA-122-driven suppression in the liver [28]. Although there is much known about these individual components that needs to be considered when designing an AAV vector, the final design will most likely need to be determined empirically. It is not yet possible to know how a particular design will function by just combining the best elements together based on published reports, therefore considerable trial and error will eventually be required for deciding on the final construct. In addition, one also needs to consider the differences between in vitro and in vivo activity. Although it is possible to model rAAV expression in rodents, there is still significant concern about the translatability to humans.

AAV has evolved to enter cells through initial interactions with carbohydrates present on the surface of target cells, typically sialic acid, galactose and heparin sulfate [29, 30]. Subtle differences in sugar-binding preferences, encoded in capsid sequence differences, can influence cell-type transduction preferences of the various AAV variants [3133]. For example, AAV9 has a preference for primary cell binding through galactose as a result of unique amino acid differences in its capsid sequence [34]. It has been postulated that this preferential galactose binding could confer AAV9 with the unique ability to cross the bloodbrain barrier (BBB) and infect cells of the CNS, including primary neurons [35, 36].

In addition to the primary carbohydrate interactions, secondary receptors have been identified that also play a role in viral transduction and contribute to cell and tissue selectivity of viral variants. AAV2 uses the fibroblast/hepatocyte growth factor receptor and the integrins V5 and 51; AAV6 utilizes the epidermal growth factor receptor; and AAV5 utilizes the platelet-derived growth factor receptor. Recently, an uncharacterized type I membrane protein, AAVR (KIAA0319L), was identified as a critical receptor for AAV cell binding and internalization [37].

As a result of these subtle variations in primary and secondary receptor interactions for the various AAV variants, one can choose a variant that possesses a particular tropism and preferentially infects one cell or tissue type over others (Table). For example, AAV8 has been shown to effectively transduce and deliver genes to the liver of rodents and non-human primates, and is currently being explored in clinical trials to deliver genes for hemoglobinopathies and other diseases [38]. Likewise, AAV1 and AAV9 have been shown to be very effective at delivering genes to skeletal and cardiac muscle in various animal models [3946]. Engineered AAV1 is currently being explored as the gene transfer factor in clinical trials for heart failure, and has been approved for the treatment of lipoprotein lipase deficiency [47]. However, although different AAV vectors have been identified that preferentially transduce many different cell types, there are still cell types for which AAV has proven difficult to transduce.

Selected AAV vectors, known receptors, and known tropisms

With the strong desire to utilize AAV to deliver genes to very selective cell and tissue types, efforts to clone novel AAV variants from human and primate tissues have identified a number of unique capsid sequences that are now being studied for tropism specificities [48]. In addition, recombinant techniques involving capsid shuffling, directed evolution, and random peptide library insertions are being utilized to derive variants of known AAVs with unique attributes [4951]. In vivo-directed evolution has been successfully used to identify novel AAV variants that preferentially transduce the retinal cells of the eye, as well as other cell populations, including those in the CNS [50, 52, 53]. In addition, these techniques have been employed to identify novel AAV variants with reduced sensitivities to neutralizing antibodies (NAbs) [5457].

Alternatively, other investigators have inserted larger binding proteins into different regions of AAV capsid proteins to confer selectivity. For example, DARPins (designed ankyrin repeat proteins), portions of protein A, and cytokines, have all been engineered into the capsid of AAV for the purpose of greater cell specificity and targeting [58, 59]. Employing this concept, others have been able to selectively target AAV to tumors and CD4+ T cells, as examples of engineered tropism [60, 61].

As we continue to learn more about the biology of AAV with regard to the mechanisms involved in membrane translocation, endosomal escape, and nuclear entry, we will undoubtedly find opportunities to engineer unique properties into viral vectors through modulating one or more of these functions. For example, it has been hypothesized that surface-exposed serine and tyrosine residues could be phosphorylated upon viral cell entry, resulting in their ubiquitination and proteolytic degradation [6264]. Studies have shown that mutation of tyrosine to phenylalanine, which prevents this phosphorylation, results in dramatically improved transduction efficiencies [63]. Similar efforts have been made in attempts to limit the effects of NAbs, as discussed below.

The choice of a particular AAV to use as a gene transfer vector is heavily reliant on several critically important criteria: (1) which cell/tissue types are being targeted; (2) the safety profile associated with the delivered gene; (3) the choice of systemic versus local delivery; and (4) the use of tissue-specific or constitutively active promoters. As one gives careful consideration to these selection criteria, it is possible to narrow the choices of which AAVs (natural or engineered) to profile. Alternatively, one can begin the path of exploring fully engineered versions of AAV for truly selective cell targeting and optimized transduction. Because our understanding of AAV biology is in relative infancy, many of these efforts will remain empirical for quite some time as optimization for one activity could have a negative impact on another. Nonetheless, the future looks promising for this highly adaptable platform.

One of the appealing aspects of using rAAV as a gene transfer vector is that it is composed of biomolecules, i.e. proteins and nucleic acids. Fortunately, a full-package virus lacks engineered lipids or other chemical components that could contribute to unwanted toxicities or immunogenicities that may not be predictable or fully understood. In general, AAV has been shown to be less immunogenic than other viruses. Although not completely understood, one possible reason for this may hinge on the observation that certain AAVs do not efficiently transduce antigen-presenting cells (APCs) [65]. Additionally, unlike previous viral delivery strategies, rAAV does not contain any viral genes, therefore there will be no active viral gene expression to amplify the immune response [66]. Although AAV has been shown to be poorly immunogenic compared with other viruses (i.e. adenovirus), the capsid proteins, as well as the nucleic acid sequence delivered, can trigger the various components of our immune system. This is further complicated by the fact that most people have already been exposed to AAV and have already developed an immune response against the particular variants to which they had previously been exposed, resulting in a pre-existing adaptive response. This can include NAbs and T cells that could diminish the clinical efficacy of subsequent re-infections with AAV and/or the elimination of cells that have been transduced. It should be of no surprise that the formidable challenge is how to deliver a therapeutically efficacious dose of rAAV to a patient population that already contains a significant amount of circulating NAbs and immunological memory against the virus [67]. Whether administered locally or systemically, the virus will be seen as a foreign protein, hence the adaptive immune system will attempt to eliminate it.

The humoral response to AAV is driven by the uptake of the virus by professional APCs, and their presentation of AAV capsid peptides in the context of class II major histocompatibility proteins (MHCs) to B cells and CD4+ T cells [68, 69]. This leads to plasma cell and memory cell development that has the capacity to secrete antibodies to the AAV capsid. These antibodies can either be neutralizing, which has the potential to prevent subsequent AAV infection, or non-neutralizing. Non-NAbs are thought to opsonize the viral particles and facilitate their removal through the spleen [70].

Upon entry of the virus into target cells during the course of the natural infection process, the virus is internalized through clathrin-mediated uptake into endosomes [71]. After escape from the endosome, the virus is transported to the nucleus where the ITR-flanked transgene is uncoated from the capsid [72]. The pathway and mechanism of AAV intracellular transport and processing is not fully understood, and there are quite a few areas of debate with regard to current understanding. The most current hypothesis is that following endosomal escape, capsid breakdown and uncoating occurs after subsequent nuclear translocation. However, it is thought that cytosolic ubiquitination of the intact virus can occur during transport to the nucleus [73]. This would be a critical step in directing capsid proteins to the proteasome for proteolytic processing into peptides for class I MHC presentation. This hypothesis is supported by data in which proteasome inhibitors, or mutations in capsid residues that are sites for ubiquitination, can limit class I presentation and T-cell activation [7376]. However, apparent differences have been observed for T-cell activation to different AAV variants with significant sequence identity. At this time, it is unclear whether this is due to subtle capsid sequence differences and susceptibility to MHC I presentation or differential cellular processing that is innate to the different AAV variants, or simply due to contaminants in vector preparations [76].

In addition to an adaptive immunological reaction to the capsid of AAV, the transgene can elicit both an adaptive and an innate response. If the transgene encodes a protein that can be recognized as foreign, it too can generate a similar B- and T-cell response. For example, in replacement therapy applications in which the protein to be replaced is the consequence of a null genotype, the immune system will have never selected against precursor B and T cells to that protein [70, 77]. Likewise, if the transgene is an engineered variant, the engineered sequence can be recognized as foreign. Even the variable regions of antibodies can activate an adaptive response that can result in deletion of target cells that are expressing transgene as a result of AAV delivery. Finally, a transgene with a significant number of CpG dinucleotides can activate innate responses through toll-like receptor (TLR) molecular pattern receptors [78].

Pre-existing immunity to AAV, especially the presence of circulating NAb, can have a dramatic effect on AAV clinical efficacy. To date, this represents one of the biggest therapeutic challenges to the use of systemically delivered AAV, and is thought to be one of the factors in early clinical failures [79]. Pre-existing immunity to AAV can often be overcome by selecting a particular AAV variant that has not circulated throughout the human population, and, therefore, does not have any memory responses elicited against it, including NAbs and T cells [80]. Additionally, some of the AAV evolution technologies discussed above have been used to identify AAVs that are resistant to the effects of NAbs [50, 57]. Although not optimal, it is possible to prescreen subjects for the presence of NAbs to the particular AAV variant to be used. In addition, the impact of this immunological response can sometimes be minimized by the particular route of administration employed for the particular therapeutic strategy, as discussed in Sect. 6 [80].

Like most biotherapeutics, AAV needs to be produced in a living system (Fig.). The parallels with recombinant antibody production during the 1990s and 2000s, with regard to the upstream challenges of robust production levels, are important to understand where the industry currently is, and where we need to strive to be.

Overview of AAV production/purification. Cell platform: HEK-293T, Sf9, or other suitable cell system can be grown on a small scale on 150mm tissue culture-treated culture dish, hyperflasks, or shake flasks. Cells are then transfected with adenovirus helper virus, rep/cap, and ITR-transgene plasmids for 293T, or infected with baculovirus for Sf9. Producer lines with integrated expression of rep/cap and ITR-transgene can be infected with adenovirus and grown to scale. Scale-up: For larger-scale culture volumes, virus can be produced in roller bottles, continuous perfusion, or WAVE Bioreactor systems. Purification/polishing: Affinity or heparin chromatography are optimal for isolation of virus from culture supernatants with or without cell pellet harvesting. Benzonase/DNAse treatment of eluted virus is required for removal of extraviral DNA contamination, followed by anion-exchange chromatography to fractionate empty vs. full AAV particles. QC/release: Upper left of far right panel: image depicts a silver stain analysis of culture FT next to affinity/anion exchange purified AAV (pure). The three bands represent the viral capsid proteins VP1, VP2, and VP3. Upper right of far right panel: Dynamic light scattering analysis of purified AAV1 indicates a uniform particle distribution of approximately 2530nM. Bottom half of far right panel: Analytical ultracentrifugation can resolve the proportion of empty vs, full particles of purified material. Additional assays that should be employed are digital drop polymerase chain reaction for determining titer in GC/mL, cryo or transmission electron microscopy for visual representation of purified particles, endotoxin testing, and other assays to evaluate the presence of residual host-cell protein contamination. AAV adeno-associated virus, FT flow-through, GC genome copies, rep/cap replication/capsid, QC quality control

Current methods to produce rAAV are still expensive despite years of research (Table). The most widely used platform for producing rAAV involves transfecting HEK293 cells with either two or three plasmids; one encoding the gene of interest, one carrying the AAV rep/cap genes, and another containing helper genes provided by either adeno or herpes viruses [6]. While most robust production rates have been achieved with adherent cells in either roller bottles or cell stacks, similar rates are now achievable in suspension-adapted HEK293 cells (Table). Production rates of approximately 105 genome copies (GC)/cell are now common, resulting in 1014 GC/L [81]. While this has proven to be sufficient to support early clinical trials, and could supply marketed product for small patient population indications, the deficiencies in scalability with this platform are a significant limitation [82, 83]. As one could surmise, successfully delivering three plasmids to one cell is a relatively inefficient process. For larger-scale manufacturing efforts, transient delivery of plasmid requires excess quantities of DNA, adding to the overall cost of production and purification. Moreover, transient delivery of rep/cap genes in the presence of helper genes can also contribute to product heterogeneity, including AAV vectors lacking a transgene. These empty capsids represent a significant proportion of virus produced in transient transfection assays. Thus, it is critically important to develop robust analytical quality control (QC) methods that are able to distinguish between these viral variants in order to ensure similarities between production lots [82, 83].

Current manufacturing platforms being employed to generate rAAV for clinical use

In three other AAV manufacturing platforms, one or more genetic components for the AAV manufacturing has been integrated into the genome of mammalian or insect production cell lines. While most viral helper genes needed for AAV production cannot be stably transfected, the adenoviral E1a and E1b genes are exceptions. These genes have been used to transform HEK293 cells, however they induce expression of the AAV rep gene, which is toxic to mammalian and insect cells [84, 85]. Hence, two different approaches have been used to develop mammalian cell lines. The first uses co-infection of BHK cells with two replication-defective HSVs engineered to encode the ITR-flanked transgene and the rep/cap genes. The second is based on stable producer cell lines in HeLa cells carrying the ITR-flanked transgene and the rep/cap genes. Rep proteins are not expressed in these cells since HeLa carries no adenoviral genes. However, infection with wild-type adenovirus is required for AAV production. The inclusion of replication-competent viral agents into a production process is a concern that needs to be addressed and also requires additional steps during the downstream processing [82, 83].

More recently, the Sf9 insect cell system in combination with baculovirus infection has been utilized to produce bulk quantities of rAAV. In this system, two or three baculovirus particles may be used to infect the Sf9 cells and initiate AAV production. In one example, one virus contains the rep gene, a second contains the cap gene, and the final virus carries the ITR-flanked gene of interest. In an alternative system, the Sf9 cells can be engineered to have the ITR-flanked gene of interest integrated into their genome, upon which production is initiated with only two baculovirus preps [81, 82]. A further improvement has recently been shown whereby the rep/cap genes are stably integrated into the Sf9 cell line genome, but are under the control of a promoter/enhancer that is induced by subsequent baculovirus infection. In this system, infection can occur, with only one baculovirus containing the ITR-flanked gene of interest, simplifying the system significantly [86, 87].

Production levels of approximately 105 GC/cell and 1015 GC/L have routinely been achieved with these Sf9 systems. Because of their ease of manipulation and their ability to grow to very high cell densities, the Sf9 system is rapidly becoming the platform of choice for AAV manufacturing. Concerns regarding baculovirus instability and differences in post-translational modifications between mammalian and insect cell systems are now beginning to be understood and controlled. These concerns are offset by the fact that baculovirus cannot efficiently infect mammalian cells which makes it inherently safer then other viral-based production systems [8183, 86, 87].

Unlike antibody manufacturing that relied on a single protein A-based purification platform early in the development of the downstream process, AAV is still rapidly evolving in that area. The products of an AAV production run will contain not only cellular debris (protein/lipids/nucleic acids) but also two main populations of AAV particles: particles that contain (full capsids) or those lacking (empty capsids) the ITR-flanked transgene. Although still widely debated in the field, the presence of empty capsids represents another contaminant that must be removed or controlled. Initial attempts to separate these two populations originally relied on the cumbersome and non-scalable method of density ultracentrifugation. In addition to the scalability issue, there are also concerns about the physiochemical effects of this method on the particles. Regardless, this method is still employed by many organizations as either a primary or secondary step in AAV purification [83].

Current technologies utilizing various affinity resins and/or ion exchange chromatography are being adopted by the industry. As mentioned above, AAV uses cell membrane-associated carbohydrates as the primary cell receptor for transduction. This affinity for carbohydrates can be exploited as an initial capture step in AAV purification. Indeed, heparin columns are frequently used in many downstream processing steps for AAV [88]. However, because of the lack of specificity, alternative affinity columns based on AAV-specific binding proteins such as scFvs and antibody single domains from llamas (camelids) have started to dominate the field. Improvements in generating these AAV-specific resins confers many advantages in downstream purification. These resins have the ability to bind to more than one AAV variant, have very high binding capacities (>1014GC/mL resin), and are stable against harsh clean-in-place and regeneration methods, making them suitable for use multiple times. Some of these commercial resins are already Good Manufacturing Practice (GMP) compliant, making them ideal for downstream manufacturing at commercial scales. Polishing steps using anion exchange chromatography are now routinely included after affinity capture steps, and can efficiently separate full capsids from empty capsids [8992].

As with any new therapeutic platform, and, again, similar to antibody-based therapeutic evolution, details on product specification and regulatory requirements are still evolving. With still very limited clinical experience, the impact of empty particles, host-cell impurities, post-translational modifications from different production platforms, fidelity of the packaged transgene, capsid ratio integrity, and probably many other specifications are still not known. However, over time, and as more clinical experience is gained, the field will be able to better relate these details to product performance and safety [83].

The use of rAAV as a delivery vector for gene therapies has been rapidly gaining interest over the past 35years. As approvals begin to increase (see Sect.6), efforts to optimize and maximize clinical manufacturing technologies will see a burst of activity. This will most likely mirror what occurred with antibody therapeutics in the 1990s and 2000s, in which early technologies were quickly overcome by next-generation technologies, resulting in significant cost savings and increased clinical supplies.

AAV has been shown to be a very stable vector able to withstand wide temperature and pH changes with little to no loss in activity [93]. To date, the only limitation seems to be the concentration with which it can be formulated, currently maximized around 51013 particles per milliliter [83]. With the resurgence in clinical use, this formulation limit will most likely be overcome in the near future. However, the robust stability of these vectors provides ample opportunities to attempt different routes of administration and specialized delivery strategies (Table).

Selected examples of more than 50 clinical candidates employing rAAV

Other than the European Medicines Agency (EMA)-approved AAV-based product alipogene tiparvovec (Glybera), the most advanced current clinical trial using AAV is sponsored by Spark Therapeutics and utilizes local injection of AAV2 into the eye for inherited retinal diseases (voretigene neparvovec-RPE65) (Table) [94]. Phase III studies have just been completed on this candidate and a Biologics License Application (BLA) submission is expected this year. This type of local delivery has proven to be safe and efficacious, but requires specialized surgical techniques and/or devices to deliver the vector [94, 95]. Similar strategies are being conducted by Applied Genetic Technologies Corporation (AGTC), targeting X-linked retinoschisis and achromatopsia, X-linked retinitis pigmentosa, and age-related macular degeneration. These programs are at various stages of development, with the most advanced for X-linked retinoschisis and achromatopsia in phase I safety studies (http://www.AGTC.com) (Table).

Several clinical trials are being run in which systemic administration is being used to target the liver, a tissue that is readily accessible through this route of administration and a tissue type that is readily transduced by many well-understood AAV variants [96]. These trials are mostly for monogenic, inherited diseases, in which the goal is gene replacement for defective genes, including those mutated in hemophilia A and B. Currently, these trials are in phase I/II, and are sponsored by academic groups, as well as biopharmaceutical companies such as Spark Therapeutics (SPK-9001, SPK-8011), Sangamo Therapeutics (SB-525), UniQure (AMT-060), Dimension Therapeutics (DTX101, DTX201), and Biomarin (BMN 270) (Table) [97]. Unlike local administration to the eye, which is considered an immune-privileged site that might not be affected by the existence of NAbs, systemic administration will require patient stratification for patient NAb levels. In addition, the possibility for re-administration becomes very difficult, should the need arise [80]. Although rare, there have been reports of rAAV vector integration into animal model genomes with subsequent genotoxicities [98, 99]. In addition, AAV genome sequences have been found in human hepatocellular carcinoma samples near known cancer driver genes, although at a low frequency [100]. There is an ongoing debate on these findings regarding cause and effect, and mouse/human translation. Regardless, hepatocellular, as well as other tissue genotoxicity, will need to be monitored in the course of AAV clinical development.

Another common delivery strategy is direct intramuscular injections. The only approved AAV gene therapy in Europe (Glybera) is an AAV1 encoding the gene for lipoprotein lipase deficiency [47, 101]. Skeletal muscle has been shown to be a target tissue type that is efficiently transduced by many AAV variants [39]. Once transduced, the muscle cells serve as a production site for protein products that can act locally or systemically, as is the case with Glybera. As a result of the low cellular turnover rate of the muscle cells, the transduced AAV gene product will be maintained in these cells as an episome for years, as has been shown in many studies in non-human primates [39]. Consequently, a single-dose regimen of an intramuscularly-delivered product may never need to be readministered unless there is significant damage or immune clearance of the transduced cells. This strategy is also being employed by Adverum and AGTC for 1-antitrypsin deficiency, as well as for certain muscular dystrophies (Table) [97].

Direct CNS administration is being utilized for Parkinsons disease, as well as various inherited diseases such as Batten disease, Canavan disease, and mucopolysaccharidosis (MPS) IIA and IIB, as well as MPS IIIa and MPS IIIb (Sanfilippo syndromes type A and type B, respectively). Phase I/II studies for these diseases using a variety of AAV variants, including AAV2, AAVrh10, and AAV9, are currently ongoing by various academic groups and biopharmaceutical companies, such as Abeona Therapeutics (ABO-101, ABO-102, ABO-201, ABO-202) [97, 102, 103]. Delivery strategies range from direct intraparenchymal administration into particular areas of the brain, intracerebroventricular, and cisternal and lumbar intrathecal routes [102]. The decision on the best route of administration is intimately related to the disease and affected areas. For example, for Parkinsons disease, according to our current understanding of disease pathogenesis and therapeutic strategies, direct injection into the putamen, substantia nigra or striatum is thought to be required. Similarly, for diseases that affect larger areas of the brain, such as Canavan disease or MPS, direct injection into the cerebellum is thought to be most beneficial [102, 103].

Alternatively, administration directly into the cerebrospinal fluid through an intrathecal route can result in wide CNS biodistribution, which is thought to be necessary for diseases such as spinal muscular atrophy (SMA) and Alzheimers disease [102106]. An alternative to cerebral spinal fluid (CSF)-based routes is the use of systemic administration of AAV variants that have been shown to cross the BBB. AAV9 has been shown to transcytosis across the BBB and transduce large sections of the CNS [36, 104, 107, 108]. This approach is currently being explored in the clinic for the treatment of SMA by AveXis (AVXS-101).

Neurodegenerative diseases represent a particular devastating health problem for which there is significant unmet medical need. These diseases of the CNS have proven to be very difficult to treat as a result of our poor understanding of their etiology and difficulty getting efficacious agents across the BBB. With regard to Alzheimers disease, although there is still some disagreement in the field, idiopathic amyloid plaque formation or generation of neurofibrillary tau tangles (NFTs), both of which are thought to be neurotoxic, are still the prevailing hypotheses behind the mechanism of many of these neuropathologies. Attempts to clear these plaques with plaque-specific antibodies have shown signs of limiting this process in animals and early-stage clinical trials [109, 110]; However, larger studies have all shown to be inconclusive at best, or failures at worst. It is unclear if these failures were because the plaque hypothesis is wrong, or if there was inefficient CNS exposure to the antibody therapeutic [110, 111]. Alternative strategies taking advantage of the safety and persistence of AAV would utilize either local administration of antibody-encoding AAVs directly to the CNS, or systemic delivery of AAVs that can cross the BBB, resulting in significantly higher CNS exposure levels of the antibody [112].

Local delivery of AAV to cardiac muscle for heart failure has been attempted in various clinical trials. In one case, Celladon failed in their attempt to deliver SERCA2A directly to the heart, and, in a second case, there is an ongoing program sponsored by UniQure to deliver S100A directly to the heart that is currently still in preclinical development [46, 113115]. Although it is not thoroughly clear why Celladon failed in the clinic, and why one would expect UniQure/BMS to succeed, there are significant differences in the delivery methods used by the two programs and the target gene delivered. Celladon used intracoronary infusion to deliver their AAV1 SERCA2A gene product, whereas UniQure is using retroinfusion and left anterior descending (LAD) coronary occlusion [41, 115]. This procedure is thought to better localize and restrict the delivered AAV9 S100A gene product to better target the heart tissue of interest. The reality of this suspected benefit will be realized in the clinic in the coming years.

Aerosolized AAV for inhaled pulmonary delivery was utilized in some of the earliest trials for cystic fibrosis (CF). Although none of these trials resulted in significant benefit or showed much of a pharmacodynamic response, they did help to show the safety of AAV when administered via this route [116118]. More importantly, the pathophysiology of CF, molecular biology of the CF transmembrane conductance regulator (CFTR) gene, and the target cell population for this type of indication exposed some key considerations when using AAV [117]. Congestion of the airways in these patients can limit AAV biodistribution after delivery, thus attenuating robust transduction [118]. In addition, the CFTR gene is over 4kb in size, putting it at the upper limit of the packaging capacity of AAV after also considering a required promoter and terminator. Finally, CFTR is expressed by the submucosal glands, which may be difficult to target efficiently [116, 117]. Nonetheless, these early efforts proved that AAV can safely deliver genes to the lung, which might be an ideal strategy for other diseases, such as influenza and other infectious diseases of the lung [119].

The field is just beginning to explore localized delivery of AAV for gene therapy applications. The stability of the virus and broad tropism for many different cell and tissue types make them ideal for most applications. There appears to be at least one AAV variant option for every tissue type of interest, with engineering and novel AAV discovery efforts sure to identify and create AAV variants with very specialized functions on demand. These efforts will undoubtedly result in new therapeutic strategies for many new indications.

The transfer of genes and other nucleic acids into cells has been a research tool in the laboratory for more than four decades. However, it was our growing understanding of the genetic components underlying certain diseases that has driven the search for true gene therapies. Progressively, research in other areas have identified other potential opportunities in which gene delivery could be applied therapeutically. In addition, limitations with current small molecule and protein therapeutic platforms have also driven the search for alternative therapeutic platforms that accommodate those limitations [120, 121]. Gene therapies accommodate all of those limitations, especially around target accessibility. As a result, the search for safe and effective gene delivery technologies has been a major focus in pharmaceutical research and development, and will hopefully represent a paradigm shift in how we approach disease-state intervention.

AAV was discovered over 50years ago and has since become one of the leading gene delivery vectors in clinical development. As a result of its unique biology, simple structure, and no known disease associations, AAV could become the vector of choice for most gene therapy applications. Gene therapy using rAAV has been demonstrated to be safe and well-tolerated in virtually every clinical setting in which it has been used. These studies, along with basic research on its biology, have revealed many facets of this vector that can be applied to future efforts.

Among the critical parameters to be considered are vector design, capsid selection, desired target cell and tissue type, and route of administration. The transgene to be delivered optimized for expression, the right AAV variant with an appropriate capsid for target cell transduction and immunoreactivity profile, and the appropriate delivery approach to maximize target tissue exposure while limiting off-tissue exposure are key focal points for AAV-based therapies.

All of these variables will be dictated by the overall therapeutic strategy which will be influenced by our understanding of the pathobiology of the disease to be treated. Will the transgene have the desired effect? Is the target cell driving the disease state? Is the turnover rate of the target cell high, requiring repeat dosing? This cannot be emphasized enough; without a strong understanding of the mechanisms driving the disease state, it will not be possible to design, discover, and develop the right gene therapeutic. Better designed trials, optimized vector construction, and novel AAV variants will certainly result in future regulatory approvals and improvements on patient outcomes and health.

Michael F. Naso, Brian Tomkowicz, and William L. Perry III are employees of Janssen Research and Development. William R. Strohl has no conflicts of interest to declare.

No funding was received for the preparation of this review.

View original post here:

Adeno-Associated Virus (AAV) as a Vector for Gene Therapy

Gene therapy: Where the action is for retinal diseases – Modern Retina

Foundation Fighting Blindness is a driving force in advancing retinal gene therapies into clinical trials.

Growth in the clinical and commercial development of gene therapies for retinal degenerative diseases has been explosive over the past decade. The rapid expansion of the field has been led by dramatic vision restoration for virtually blind patients made possible by voretigene neparvovec-rzyl(Luxturna; Spark Therapeutics), which the FDA approved in December 2017. It is the first gene therapy for the eye or any inherited retinal disease to cross the regulatory finish line in the United States. Developed by gene therapy pioneer Jean Bennett, MD, PHD, for children and adults with Leber congenital amaurosis (LCA) or retinitis pigmentosa (RP) caused by biallelic RPE65 mutations, the therapy provided immediate and impressive vision improvements in a phase 1/2 clinical trial at Childrens Hospital of Philadelphia. Those initial results, reported in 2008, sent a strong signal to investigators and biotechnology companies that gene therapy could be a powerful modality for treating retinal diseases.

Now, dozens of companies are in the retinal gene therapy development space and more than 20 clinical trials for genetic therapies are underway for patients with a broad range of retinal degenerative diseases. These include RP, LCA, choroideremia, achromatopsia, and the dry and wet forms of age-related macular degeneration (AMD).

The Foundation Fighting Blindness, the worlds leading private funder of retinal degenerative research, has played a pivotal role in advancing retinal gene therapies into clinical development. As an early funder of the modality for myriad retinal diseases, the foundation began investing in RPE65 gene therapy research back in the mid-1990s and ultimately invested $10 million in the research that eventually led to voretigene neparvovec.

We were very early adopters, recognizing that the retina was an ideal gene therapy target. Its a small, accessible piece of tissue, and many conditions that affect the retina are monogenic. We knew that if we could directly address the patients mutated gene by augmenting or modifying its activity, we had an excellent opportunity to save and restore vision, said Benjamin Yerxa, PhD, chief executive officer at the foundation. Furthermore, we see gene therapys potential for gene-agnostic applications such as neuroprotection and optogenetics to help a broad range of patients, regardless of the mutated gene causing their vision loss.

The foundation currently funds a broad range of gene therapies and other treatment modalities at both early and late stages of development. Its RD (Retinal Degeneration) Fund, a venture philanthropy fund with nearly $120 million in commitments, was launched in 2018 to help investigators and start-up companies move their emerging therapies into and through early-stage clinical trials. The funds goal is to attract additional investments from pharmaceutical and biotechnology companies to fund the more expensive, late-stage trial phases. Furthermore, all returns on the funds investments are put back into the foundation to support additional research and investments.

The ultimate goal of the RD Fund is to get more treatments across the finish line and out to patients. We cant afford to fund late-stage clinical research, which often costs a hundredmillion dollars or more, but we can afford the earlier-stage research to attract those major investments from biotechs and big pharma, said Yerxa.

In fall 2021, the RD Fund took the bold step of launching its own company, Opus Genetics, to develop gene therapies for orphan retinal diseases, those rare conditions that werent being addressed by other companies. Opus $19 million in seed financing included investments from the Manning Family Foundation and Bios Partners. Its first 3 targets are for LCA caused by mutations in LCA5, RDH12, and NMNAT1. The LCA5 and RDH12 therapies were developed preclinically by Opus cofounder Bennett and licensed from the University of Pennsylvania. The NMNAT1 treatment was developed in the laboratory by cofounder Eric A. Pierce, MD, PhD, and licensed from Harvard Medical Schools Massachusetts Eye and Ear. Opus plans to launch a clinical trial for LCA5 by the end of 2022. In April 2022, the company signed a collaboration agreement with Resilience to provide manufacturing services for its gene therapy pipeline.

In October 2020, the RD Fund realized its first financial win when Novartis acquired Vedere Bio for around $280 million. In 2019, the fund had helped launch Vedere Bio to advance an optogenetic therapy developed by its scientific cofounders John G. Flannery, PhD, and Ehud Isacoff, PhD, from the University of California, Berkeley. The investigators approacha gene-agnostic gene therapyprovides potential vision restoration for patients who have lost all their photoreceptors to a condition such as RP by delivering a gene that expresses a light-sensing green cone opsin in surviving ganglion cells. In essence, the treatment enables ganglion cells to work like a back-up system for lost photoreceptors. The approach holds promise for restoring vision for patients who are completely or nearly blind, regardless of the mutation causing their disease. A new incarnation of the company, Vedere Bio II, was subsequently launched after the Novartis acquisition to continue development of other retinal gene therapies.

Also in 2020, the RD Fund invested in the gene therapy start-up Atsena Therapeutics, which reported early, encouraging vision improvements for 3 patients in a phase 1/2 clinical trial for its LCA (GUCY2D mutations) gene therapy. Cofounded by Shannon E. Boye, PhD, and Sanford L. Boye, MS, both of the University of Florida in Gainesville, Atsena also has preclinical gene therapy programs for X-linked retinoschisis and Usher syndrome type 1B.

SparingVision, another RD Fund investment, is planning to launch a clinical trial in 2022 for its gene-agnostic, cone-preserving therapy for patients with RP, Usher syndrome, and related conditions. Nearly 2 decades ago, Jos-Alain Sahel, MD, and Thierry Lveillard, PhD, investigators from the Institut de la Vision in Paris, France, identified a protein secreted by rod photoreceptors that is critical to the survival of cones. Aptly named rod-derived cone-viability factor, it is the protein expressed by SparingVisions cone-preserving gene therapy. The company is also developing a gene therapy that restores light sensitivity to cones that have lost their ability to process light due to advanced forms of RP, Usher syndrome, and related diseases.

The RD Funds other gene-related therapy investments include SalioGen Therapeutics, whose Saliogase technology seamlessly inserts new DNA of any size (eg, the Stargardt disease gene ABCA4) into precise, defined genomic locations. The fund also invests in ProQR Therapeutics, which has an RNA therapy in a phase 2/3 clinical trial for individuals with Usher syndrome 2A and nonsyndromic RP caused by mutations in exon 13 of the USH2A gene.

We are off to a great start with our investments and working to continue to expand our portfolio with the strategy of investing in strong science being developed by well-managed companies, said Yerxa. I think our coinvestors recognize and appreciate our commitment to making every shot on goal really count.

View original post here:

Gene therapy: Where the action is for retinal diseases - Modern Retina

Adverum cuts jobs, restructures to give eye gene therapy another shot – BioPharma Dive

Dive Brief:

Despite significant setbacks that have left the fate of its eye gene therapy in doubt and shares trading near all-time lows, Adverum hasnt given up.

The company is one of a few gene therapy makers aiming to develop a one-time treatment for diabetic macular edema and age-related macular degeneration, two common forms of vision loss that are treated with chronic injections of biologic medicines. But those drugs, like Eylea and Lucentis, are highly effective and considered safe, making the bar much higher for a gene therapy whose main goal is to improve convenience.

Adverums program was also beset by side effects the company once described as not seen before in ocular gene therapy, a combination of inflammation, vision loss and decrease in eye pressure observed in five trial participants.

Adverum stopped that trial, in diabetic macular edema, in 2021. At the time, some analysts suggested the company should attempt a reverse merger, a way for struggling biotechs to bring in new assets by combining with a privately held company seeking fast access to the public markets.

The company instead vowed to press on. Executives suggested testing a lower dose than previously planned with a different regimen of protective drugs could lead to better results in AMD. In 2021, the company noted that no cases of severe inflammation were observed in DME patients treated with a lower dose or in participants with AMD in another trial.

Adverum has since gained clearance from U.S. regulators for its new plan, a Phase 2 trial in AMD thatll test both the lowest dose evaluated in previous studies as well as one more than three-times lower. With shares trading at just over $1 apiece and equity harder to raise during the sectors downturn, Adverum has turned to cost-cutting to save money and fund the work. The savings could enable the company to get to one-year results from that trial, in 2023, without needing to raise more cash, wrote RBC analyst Luca Issi.

Yet Adverums odds remain long. A rival gene therapy from Regenxbio is already in Phase 3 testing in AMD, and pending positive results, could lead to an approval filing in 2024. The company remains a show-me story given its history, Issi wrote. Additionally, Adverums decision to turn to layoffs, rather than a partnership, may also signal limited strategic interest in the platform, he added.

Excerpt from:

Adverum cuts jobs, restructures to give eye gene therapy another shot - BioPharma Dive

EditForce and Mitsubishi Tanabi Pharma to work on gene therapy for CNS – Labiotech.eu

EditForce, Inc. has entered into a license agreement with Mitsubishi Tanabe Pharma Corporation (MTPC) to research, develop and commercialize potential gene therapy products for a specific target disease related to the central nervous system (CNS) by utilizing EditForces pentatricopeptide repeat (PPR) protein platform technology.

MTPC and EditForce aim to create potential novel pharmaceuticals for the specific CNS disease by utilizing the drug R&D know-how and global business experience of MTPC and the novel biotechnology of EditForce.

MTPC will acquire the exclusive right to conduct the selection of drug candidate molecules, preclinical and clinical development, manufacturing, and commercialization worldwide.

Under the terms of the agreement, EditForce will receive an upfront payment and milestone payments amounting to more than 20 billion yen ($147.3 million), depending on the development stage and commercialization progress, and royalties based on worldwide sales after the launch.

I am so delighted to reach the agreement with MTPC, which has an interest in our proprietary PPR protein platform technology, said Takashi Ono, president and CEO of EditForce.

We look forward to working closely with MTPC to develop and deliver breakthrough pharmaceutical products with our technology to patients suffering from diseases.

PPR is a protein discovered in plants that regulates gene expression by binding to DNA and RNA in a sequence-specific manner. The PPR proteins are also found in humans and yeasts, and they have similar functions.

Takahiro Nakamura and Yusuke Yagi, CTO of EditForce, have focused on the PPR proteins and elucidated the mechanism that determines sequence specificity, and established a technology for creating various PPR proteins, each of which binds to a specific target DNA or RNA sequence.

It is possible to manipulate and modify the target genome and RNA both inside and outside the cell by fusion with effector proteins.

Follow this link:

EditForce and Mitsubishi Tanabi Pharma to work on gene therapy for CNS - Labiotech.eu

Lysogene Provides Additional Update on AAVance Phase 2/3 Gene Therapy Clinical Trial with LYS-SAF302 in children with MPS IIIA – Business Wire

PARIS--(BUSINESS WIRE)--Regulatory News:

Lysogene (Paris:LYS)(FR0013233475 LYS), a phase 3 gene therapy platform Company targeting central nervous system (CNS) diseases, today communicates additional preliminary data from the AAVance Phase 2/3 gene therapy trial in MPS IIIA (NCT03612869). Data will be presented at the ADVANCE 2022 Sanfilippo Community Conference held on July 7-8, 2022, and at the 3rd Annual Gene Therapy for Neurological Disorders Europe held on July 11-13, 2022.

A positive effect of LYS-SAF302 on the MPS IIIA disease biomarker heparan sulfate (HS) in the cerebrospinal fluid (CSF) was confirmed in additional subjects and at additional timepoints relative to previously communicated partial data. Statistically significant decreases of about 20% in average levels of total HS-derived oligosaccharides in the CSF relative to baseline levels were observed at 6, 12 and 24 months after dosing with LYS-SAF302. HS levels at 24 months after dosing with LYS-SAF302 (1654 497 ng/ml, mean SD, n=15) were decreased by 22% relative to baseline levels (2159 589 ng/ml, mean SD, n=16), p=0.015 by Student's t test (preliminary analysis). No statistically significant effect on serum HS levels was observed at 6, 12 or 24 months after dosing with LYS-SAF302. These results confirm the biological activity of LYS-SAF302 gene therapy treatment. They are consistent with the intraparenchymal mode of administration of LYS-SAF302, which is expected to lead to a specific decrease of HS in the brain, but not in the systemic circulation nor in other tissues, including the spinal cord.

The previous observation that treatment with LYS-SAF302 led to a transient increase in serum neurofilament light (NFL) levels, likely due to transient axonal damage caused by brain surgery, followed by a decrease below baseline levels, was confirmed in additional subjects and at additional timepoints. Moreover, a similar effect was demonstrated in the CSF. In the serum, NFL levels decreased by 33% (n=12, p=0.026) and 41% (n=16, p=0.0075) below baseline levels (113 50 pg/ml, mean SD, n=19), 18 and 24 months after dosing with LYS-SAF302, respectively. In the CSF, NFL levels decreased by 33% (n=15, p=0.025) below baseline levels (3.7 1.5 ng/ml, mean SD, n=17) 24 months after dosing with LYS-SAF302. All statistical analyses were done by Students t test and are preliminary. These results suggest that treatment with LYS-SAF302 led to a decrease in neuronal damage relative to baseline at 18 and 24 months after drug administration.

Three subjects in AAVance, treated at 10, 13 and 31 months of age, present continuous increase of cognitive, language and motor functions 24 months after dosing with LYS-SAF302, as assessed by the BSID-III (Bayleys Scales of Infant Development, Third edition). Two of these subjects have a cognitive developmental age (DA) at 24 months after dosing with LYS-SAF302 that is 5-6 months higher (41 and 42, respectively) than the highest cognitive DA (35) observed in natural history studies of MPS IIIA (Shapiro et al, 2016; Wijburg et al 2022). Remarkably, one of these subjects is homozygous for a severe mutation (deletion) and the other subject is compound heterozygous for two severe mutations (a duplication and a deletion). The third subject with continuously increasing DA at 24 months after dosing with LYS-SAF302 is a compound heterozygote for a severe mutation and a S298P mutation, which may give rise to either a classical severe or an intermediate phenotype. Longer follow-up is warranted to confirm positive evolution of development in this patient. Three other subjects, treated at 24, 30 and 31 months of age, have stable cognitive DA relative to baseline, as assessed by the BSID-III scale, and stable or continuously increasing BSID-III language and motor development scores at 24 months after dosing with LYS-SAF302. Two of these subjects have SGSH missense mutations associated with the classical severe phenotype of MPS IIIA. One subject has a severe mutation on one allele and a mutation with unknown effect on disease severity on the second allele. The fact that developmental progression or stabilization is seen in subjects with mutations associated with the classical severe disease phenotype suggests that early therapeutic intervention with LYS-SAF302 can protect children with MPS IIIA from decline of cognitive, language, and motor functions.

The AAVance trial Month 24 database lock took place as planned on 1st of July 2022. Full study results are expected by mid-September 2022, along with results from the PROVide patient reported outcome videos study. Based on this comprehensive clinical data package, the company plans to initiate discussions with regulatory authorities in the US and in Europe to determine next steps.

Preliminary data for AAVance indicates that subjects with MPS IIIA treated prior to 31 months of age not only continued with increasing developmental age, but exceeded developmental ages of any MPS IIIA subjects within the natural history cohorts. This data is highly suggestive of LYS-SAF302 efficacy in this treatment population, marking an important milestone as no treatment is currently available to slow the progression of MPS IIIA, said Raymond Wang, M.D., Director, Foundation of Caring Multidisciplinary Lysosomal Disorder Program at CHOC Childrens Specialists, Orange, CA, USA, and one of the principal investigators for the AAVance trial.

We are very pleased to confirm on a larger scale the encouraging data already observed earlier, notably stabilization or improvement in cognitive, language and motor functions in the younger patient population, even in those presenting with severe forms of the disease. We have recently locked the database of the 24-month post-treatment follow-up data. Full statistical analyses are underway with results expected in September this year. This represents a very exciting milestone as it completes years of efforts by the Lysogene team to bring a treatment to patients with MPSIIIA, a disease with a high unmet medical need. By Q3 2022, we should have the necessary elements to discuss the next steps with the regulatory authorities, said Marie Trad, M.D. Chief Medical Officer of Lysogene.

About Lysogene

Lysogene is a gene therapy Company focused on the treatment of orphan diseases of the central nervous system (CNS). The Company has built a unique capability to enable delivery of gene therapies to the CNS to treat lysosomal diseases and other disorders of the CNS. A phase 2/3 clinical trial in MPS IIIA is ongoing. An adaptive clinical trial in GM1 gangliosidosis is also ongoing. Lysogene is also developing an innovative AAV gene therapy approach for the treatment of Fragile X syndrome, a genetic disease related to autism. The Company also entered into an exclusive worldwide license agreement with Yeda, the commercial arm of the Weizmann Institute of Science, for a novel gene therapy candidate for neuronopathic Gaucher disease and Parkinson disease with GBA1 mutations. http://www.lysogene.com.

Forward Looking Statement

This press release may contain certain forward-looking statements, especially on the Companys progress of its clinical trials and cash runway. Although the Company believes its expectations are based on reasonable assumptions, all statements other than statements of historical fact included in this press release about future events are subject to (i) change without notice, (ii) factors beyond the Companys control, (iii) clinical trial results, (iv) increased manufacturing costs, (v) potential claims on its products. These statements may include, without limitation, any statements preceded by, followed by or including words such as target, believe, expect, aim, intend, may, anticipate, estimate, plan, objective, project, will, can have, likely, should, would, could and other words and terms of similar meaning or the negative thereof. Forward-looking statements are subject to inherent risks and uncertainties beyond the Companys control that could cause the Companys actual results, performance or achievements to be materially different from the expected results, performance or achievements expressed or implied by such forward-looking statements. A further list and description of these risks, uncertainties and other risks can be found in the Companys regulatory filings with the French Autorit des Marchs Financiers, including in the 2021 universal registration document, registered with the French Markets Authorities on April 19, 2022, and future filings and reports by the Company. Furthermore, these forward-looking statements are only as of the date of this press release. Readers are cautioned not to place undue reliance on these forward-looking statements. Except as required by law, the Company assumes no obligation to update these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future. If the Company updates one or more forward-looking statements, no inference should be drawn that it will or will not make additional updates with respect to those or other forward-looking statements.

This press release has been prepared in both French and English. In the event of any differences between the two texts, the French language version shall supersede.

Continue reading here:

Lysogene Provides Additional Update on AAVance Phase 2/3 Gene Therapy Clinical Trial with LYS-SAF302 in children with MPS IIIA - Business Wire