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Gene Therapies Make it to Clinical Trials – Discover Magazine

After years of ethical debates and breakthroughs in the lab, CRISPR has finally made its way to clinical trials. Researchers are now looking at whether the DNA-editing tool, as well as more conventional gene therapies, can effectively treat a wide array of heritable disorders and even cancers.

Theres been a convergence of the science getting better, the manufacturing getting much better, and money being available for these kinds of studies, says Cynthia Dunbar, a senior investigator at the National Heart, Lung, and Blood Institute. Its truly come of age.

CRISPR formally known as CRISPR-Cas9 has been touted as an improvement over conventional gene therapy because of its potential precision. CRISPR (clustered regularly interspaced short palindromic repeats) is a genetic code that, contained in a strand of RNA and paired with the enzyme Cas9, acts like molecular scissors that can target and snip out specific genes. Add a template for a healthy gene, and CRISPRs cut can allow the cell to replace a defective gene with a healthy one.

In April, scientists at the University of Pennsylvania announced they had begun using CRISPR for cancer treatments. The first two patients one with multiple myeloma, the other with sarcoma had cells from their immune systems removed. Researchers used CRISPR to genetically edit the cells in the lab, and then returned them back into their bodies.

On the other side of the country, Mark Walters, a blood and bone marrow transplant specialist at the University of California, San Francisco, Benioff Childrens Hospital in Oakland, is gearing up for trials that will use CRISPR to repair the defective gene that causes sickle cell disease. With CRISPR, once youve made that type of correction, [that cell] is 100 percent healthy, says Walters.

Another team is tackling the same disease using a type of hemoglobin, a protein in red blood cells, thats normally made only in fetuses and newborn babies. Researchers found that some adults continue to produce these proteins throughout their lives, and when those adults also have sickle cell disease, their symptoms are mild. So the international team used CRISPR to disable the gene that interferes with production of this hemoglobin, resuming its production and protecting the adult patients against sickle cell disease.

Several other CRISPR studies are in the works to treat a range of inherited disorders, including hemophilia and SCID-X1 (also known as X-linked severe combined immunodeficiency, the so-called bubble boy disease in which babies are born without a functioning immune system).

At St. Jude Childrens Research Hospital, a gene therapy trial cured Gael Jesus Pino Alva (pictured with his mother, Giannina) of SCID-X1, the bubble boy disease. (Credit: St. Jude Children's Research Hospital/Peter Barta)

The past year also saw success in a handful of experiments on conventional gene therapy. Instead of using CRISPR to repair disease-causing genes, these treatments use hollowed-out viruses to ferry healthy versions of genes into cells. Millions of these altered cells are released into the bloodstream or bone marrow in hopes that enough will land in the right places. But because scientists cant predict where the circulating genes may end up, this shotgun approach has had unintended, sometimes fatal, consequences including, in an earlier study, inadvertently activating leukemia-causing genes in patients treated for SCID-X1.

But in 2019, researchers learned that using a different type of virus one related to HIV to transport the genes may prevent these side effects. In an April study, researchers at St. Jude Childrens Research Hospital in Memphis, Tennessee, and UCSF Benioff Childrens Hospital in Oakland collected bone marrow from eight newborns with SCID-X1. They loaded corrective genes into the disabled HIV-related virus, which carried them into the patients bone marrow stem cells. The infants also received low doses of busulfan, a chemotherapy that gave the doctored stem cells room to grow. So far, we havent seen anything worrisome, says Ewelina Mamcarz, a pediatric oncologist at St. Jude who led the research team. The study recently added its 12th patient.

Gene therapy does have its momentum [back], says Mamcarz, reflecting on the fields setback after the earlier studys leukemia side effects. Theres so much that still needs to be done, and so many questions, she says. [But] this is how medicine evolves. We always want to be better than we were a week ago.

In the future, the hope is that gene therapy technologies will move beyond mending simple genetic mistakes and be used to combat big killers like diabetes or heart disease. [Those diseases are] more challenging, but a lot of them would benefit from knocking out a bad gene, says Dunbar.

For now, though, researchers are optimistic about the progress thats already been made. All of this has been very encouraging, says Dunbar. [And] for sickle cell in the U.S. and hemophilia in the developed world, these diseases may soon be solved.

[This story originally appeared in print as "Gene Therapy Gets Clinical."]

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Gene Therapies Make it to Clinical Trials - Discover Magazine

Experimental Gene Therapy Shows Promise for Preventing and Treating Lou Gehrig’s Disease in Mice – BioSpace

Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrigs disease, is a neurodegenerative disease affecting nerve cells in the brain and spinal cord. Researchers at the University of California San Diego School of Medicine published research describing a new way to deliver a gene-silencing vector to mice with ALS. The therapy resulted in long-term suppression of the disease if the treatment was given before the disease started. It also blocked disease progression in the mice if symptoms already appeared.

The study was published in the journal Nature Medicine.

At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS, said senior author Martin Marsala, professor in the Department of Anesthesiology at UC San Diego School of Medicine. In addition, effective spinal cord delivery of AAV9 vector in adult animals suggests that the use of this new delivery method will likely be effective in treatment of other hereditary forms of ALS or other spinal neurodegenerative disorders that require spinal parenchymal delivery of therapeutic gene(s) or mutated-gene silencing machinery, such as in C9orf72 gene mutation-linked ALS or in some forms of lysosomal storage disease.

ALS appears in two forms, sporadic and familial. The most common form is sporadic, responsible for 90 to 95% of all cases. Familial ALS makes up 5 to 10% of all cases in the U.S., and as the name suggests, is inherited. Studies have shown that a least 200 mutations of the SOD1 gene are linked to ALS.

In healthy individuals, the SOD1 gene provides instructions for an enzyme called superoxide dismutase. This enzyme is used to break down superoxide radicals, which are toxic oxygen molecules that are a byproduct of normal cellular processes. It is believed that the mutations in the gene cause ineffective removal of superoxide radicals or potentially cause other toxicities resulting in motor neuron cell death.

The new research involves injecting shRNA, an artificial RNA molecule that can turn off, or silence, a targeted gene. This delivers shRNA to cells by way of a harmless adeno-associated virus (AAV). In the research, they injected the viruses carrying shRNA into two locations in the spinal cord of adult mice expressing an ALS-causing mutation of the SOD1 gene. They were performed just before disease onset or after the laboratory animals started showing symptoms.

The researchers have tested the approach in adult pigs, whose have spinal cord dimensions closer to those in humans. They found that by using an injector developed for adult humans, the procedure could be performed without surgical complications and in a reliable fashion.

The next step will be more safety studies with a large animal model.

While no detectable side effects related to treatment were seen in mice more than one year after treatment, the definition of safety in large animal specimens more similar to humans is a critical step in advancing this treatment approach toward clinical testing, Marsala said.

About 5,000 people are diagnosed with ALS in the U.S. each year, with about 30,000 people living with the disease. There are symptomatic treatments, but no cure. Most patients die from the disease two to five years after diagnosis.

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Experimental Gene Therapy Shows Promise for Preventing and Treating Lou Gehrig's Disease in Mice - BioSpace

2019: The year gene therapy came of age – INQUIRER.net

For decades, the DNA of living organisms such as corn and salmon has been modified, but Crispr, invented in 2012, made gene editing more widely accessible. Image: YinYang/IStock.com via AFP Relaxnews

In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old told AFP in an email.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as molecular scissors.

The genetically edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified.

But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Cures

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practicing the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not such as making normal red blood cells, in Victorias case, or making tumor-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the United States and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he told AFP from Paris.

It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said Carrie Wolinetz, NIHs associate director for science policy.

These therapies are exorbitantly expensive, however, costing up to $2 million meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Bioterrorism

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

Last year in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, Musunuru added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist weve been talking about bioterrorism for years, she said. Nothing has ever happened.IB/JB

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2019: The year gene therapy came of age - INQUIRER.net

BLA Submitted for Gene Therapy to Treat Hemophilia A – Monthly Prescribing Reference

Home News Drugs in the Pipeline

BioMarin has submitted a Biologics License Application (BLA) to the Food and Drug Administration (FDA) for valoctocogene roxaparvovec (BMN 270) for the treatment of hemophilia A in adults. This is the first marketing application submission for a gene therapy product for any type of hemophilia.

Valoctocogene roxaparvovec is an investigational adeno-associated virus (AAV) gene therapy that is administered as a single infusion to produce clotting factor VIII. The BLA submission is supported by interim analysis of a phase 3 study and 3-year phase 1/2 data. Results from the ongoing phase 1/2 study showed that bleed rate control and reduction in factor VIII usage was maintained for a third year following a single administration of valoctocogene roxaparvovec.

The FDA previously granted Breakthrough Therapy and Orphan Drug designations to valoctocogene roxaparvovec. The Company anticipates the BLA review to commence in February 2020.

We look forward to working with the FDA as we seek marketing authorization for the potential first gene therapy for hemophilia A, said Hank Fuchs, MD, President, Global Research and Development at BioMarin. Our hope is one day very soon to deliver a transformative treatment that has the potential to change the way hemophilia A is treated.

For more information visit biomarin.com.

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BLA Submitted for Gene Therapy to Treat Hemophilia A - Monthly Prescribing Reference

First Alzheimer’s Disease Gene Therapy Human Study Provided by Maximum Life Foundation, Offers 10 Free Therapies for Qualifying Patients – Benzinga

Maximum Life Foundation ("MaxLife"), is rapidly transforming the way we treat aging diseases. MaxLife plans to use a promising gene therapy offered by Integrated Health Systems to give free access to ten (10) early to mid-stage Alzheimer's Disease (AD) patients. David Kekich, MaxLife's CEO, stated "MaxLife will grant 100% of the therapy costs to help bring pioneering gene therapy to cure this disease and make Alzheimer's Disease a thing of the past."

NEWPORT BEACH, Calif. (PRWEB) December 30, 2019

Cure Now Instead of Palliative Care

According to the Alzheimer's Association:

Alzheimer's costs Americans $277 billion a year and rising. Sharp increases in Alzheimer's disease cases, deaths and costs are stressing the U.S. healthcare system and caregivers. About 5.7 million Americans have Alzheimer's disease. To date, no one has survived it.

Improvements of AD symptoms and the recovery of normal brain functions have been demonstrated in-vivo in mouse experiments, and in-vitro in human cell experiments through the rejuvenation of microglia (the brain's first line of defense against infection) and neurons as well as stimulating mitochondrial function using the telomerase reverse transcriptase (TERT) protein.

One human patient received a lower dose therapy in August 2018 with no adverse side effects. To date, the patient's disease has not progressed. MaxLife hopes to see symptom reversals in the next patients.

"If we can prove a benefit to patients that have no other option now, we can potentially treat Alzheimer's Disease in people in early to mid-stage Alzheimer's, finally creating effective medicine at the cellular level," states Kekich. "If successful, this treatment could potentially be used on other diseases such as Parkinson's and ALS."

The unique difference is developing treatments against the cellular degeneration caused by aging as the root cause of most major diseases. Studies have proven aging is the leading risk factor for many life-threatening diseases, including Alzheimer's.

With a world class Scientific Advisory Board, MaxLife is ready to push forward into practical solutions. A gene therapy facilitator, Integrated Health Systems plans to treat other adult aging-related diseases with no previous cure such as Sarcopenia, Atherosclerosis, Chronic Kidney Disease (CKD) and even aging itself with gene therapies.

"This technology could halt many of the big age associated killers in industrialized countries'" states Kekich. "Compassionate care helps patients with no other option to get access to experimental therapies that may benefit both themselves and society as a whole."

MaxLife also seeks grants and donations for human gene therapy studies for atherosclerosis, sarcopenia and chronic kidney disease as well as for human aging. The protocols have already been developed. Please Click Here and scroll to the bottom of the page to see how to donate.

To apply for a free therapy or for more information, see http://www.maxlife.org/alzheimers-disease/ and https://maxlife.org/how-to-register-and-qualify-for-the-alzheimers-human-study/.

For Further Information, Contact: David Kekich, CEO Maximum Life Foundation.

Maximum Life Foundation is a 501(c)(3) Not-For-Profit corporation founded in 1999.

Tax I.D. #31-1656405. David A. Kekich Tel. #949-706-2468. Info@MaxLife.org

For the original version on PRWeb visit: https://www.prweb.com/releases/first_alzheimers_disease_gene_therapy_human_study_provided_by_maximum_life_foundation_offers_10_free_therapies_for_qualifying_patients/prweb16809113.htm

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First Alzheimer's Disease Gene Therapy Human Study Provided by Maximum Life Foundation, Offers 10 Free Therapies for Qualifying Patients - Benzinga

Year in Review: Gene Therapy Technology and a Milestone 2019 for Medical Research – News18

In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering -- by editing her genome. Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy. "I have hoped for a cure since I was about 11," the 34-year-old told AFP in an email.

"Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency." Over several weeks, Gray's blood was drawn so doctors could get to the cause of her illness -- stem cells from her bone marrow that were making deformed red blood cells. The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 -- pronounced "Crisper" -- a new tool informally known as molecular "scissors." The genetically edited cells were transfused back into Gray's veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured. "This is one patient. This is early results. We need to see how it works out in other patients," said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville. "But these results are really exciting." In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden. For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs. The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself. "It's all developing very quickly," said French geneticist Emmanuelle Charpentier, one of Crispr's inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Cures

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy. Scientists practising the technique insert a normal gene into cells containing a defective gene. It does the work the original could not -- such as making normal red blood cells, in Victoria's case, or making tumor-killing super white blood cells for a cancer patient. Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union. They join several other gene therapies -- bringing the total to eight -- approved in recent years to treat certain cancers and an inherited blindness. Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution. "Twenty-five, 30 years, that's the time it had to take," he told AFP from Paris.

"It took a generation for gene therapy to become a reality. Now, it's only going to go faster." Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a "breakthrough period." "We have hit an inflection point," said Carrie Wolinetz, NIH's associate director for science policy.These therapies are exorbitantly expensive, however, costing up to $2 million -- meaning patients face grueling negotiations with their insurance companies. They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion -- and fighting a general infection. "You cannot do this in a community hospital close to home," said her doctor. However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers. They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Bioterrorism

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who don't necessarily share the medical ethics of Western medicine. Last year in China, scientist He Jiankui triggered an international scandal -- and his excommunication from the scientific community -- when he used Crispr to create what he called the first gene-edited humans. The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process. "That technology is not safe," said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr "scissors" often cut next to the targeted gene, causing unexpected mutations. "It's very easy to do if you don't care about the consequences," Musunuru added. Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability. There is also the temptation to genetically edit entire animal species -- malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US. The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesn't believe in the more dystopian scenarios predicted for gene therapy, including American "biohackers" injecting themselves with Crispr technology bought online. "Not everyone is a biologist or scientist," she said. And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies' crops? Charpentier thinks that technology generally tends to be used for the better. "I'm a bacteriologist -- we've been talking about bioterrorism for years," she said. "Nothing has ever happened."

Get the best of News18 delivered to your inbox - subscribe to News18 Daybreak. Follow News18.com on Twitter, Instagram, Facebook, Telegram, TikTok and on YouTube, and stay in the know with what's happening in the world around you in real time.

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Year in Review: Gene Therapy Technology and a Milestone 2019 for Medical Research - News18

Gene therapy to conquering hepatitis C: A decade of medical breakthroughs – Business Standard

For all the flak the pharmaceutical industry has taken for its exorbitant pricing practices, there's no getting around the fact that it's been a pretty stunning decade for medical progress.

Multiple new categories of medicines have moved from dreams and lab benches into the market and peoples lives, and investors who came along for the ride often reaped extraordinary profits. The Nasdaq Biotech Index is up 360% over the last 10 years to the S&P 500's 190%. And thats without mentioning the hundreds of billions of dollars in takeovers that rewarded shareholders with windfalls.

As 2020 approaches, it's worth highlighting how far we've come in the past 10 years in developing new therapies and approaches to treating disease, even as politicians grapple with how to rein in health-care costs without breaking an ecosystem that incentivizes the search for new discoveries. Here are some of the decades biggest medical breakthroughs:

Cell therapies: First approved in the U.S. two years ago, these treatments still sound like science fiction. Drugmakers harvest immune cells from patients, engineer them to hunt tumors, grow them by the millions into a living drug, and reinfuse them. Yescarta from Gilead Siences Inc. and Novartis AGs Kymriah the two treatments approved so far can put patients with deadly blood cancers into remission in some cases. At the beginning of the decade, academics were just beginning early patient tests.

Its still early days for the technology, and some issues are holding these drugs back. There are significant side effects, and the bespoke manufacturing process is expensive and time-consuming. That has contributed to a bruising price tag: Both of the approved medicines cost over $350,000 for a single treatment. And for now, cell therapy is mostly limited to very sick patients who have exhausted all other alternatives.

Luckily, more options are on their way. Some drugmakers are focused on different types of blood cancers. Others hope to mitigate side effects or create treatments that can be grown from donor cells to reduce expenses and speed up treatment. In the longer run, companies are targeting trickier solid tumors. Scientists wouldn't be looking so far into the future without this decades extraordinary progress.

Gene therapies: Researchers have spent years trying to figure out how to replace faulty DNA to cure genetic diseases, potentially with as little as one treatment. Scientific slip-ups and safety issues derailed a wave of initial excitement about these therapies starting in the 1990s; the first two such treatments to be approved in Europe turned out to be commercial flops.

This decade, the technology has come of age. Luxturna, a treatment developed by Spark Therapeutics Inc. for a rare eye disease, became the first gene therapy to get U.S. approval in late 2017. Then in May came the approval of Novartis AGs Zolgensma for a deadly muscle-wasting disease. The drugs have the potential to stave off blindness and death or significant disability with a single dose, and, unsurprisingly, Big Pharma has given them a substantial financial endorsement. Roche Holding AG paid $4.7 billion to acquire Spark this year, while Novartis spent $8.7 billion in 2018 to buy Zolgensma developer Avexis Inc.

Dozens of additional therapies are in development for a variety of other conditions and should hit the market in the next few years. They offer the tantalizing potential not just to cure diseases, but to replace years of wildly expensive alternative treatment. If drugmakers can resist the temptation to squeeze out every ounce of value by doing things like charging $2.1 million for Zolgensma, theres potential for these treatments to save both lives and money.

RNA revolution: The above treatments modify DNA; this group uses the bodys messaging system to turn a patients cells into a drug factory or interrupt a harmful process. Two scientists won a Nobel Prize in 2006 for discoveries related to RNA interference (RNAi), one approach to making this type of drug, showing its potential to treat difficult diseases. That prompted an enormous amount of hype and investment, but a series of clinical failures and safety issues led large drugmakers to give up on the approach. Sticking with it into this decade paid off.

Alnylam Inc. has been working since 2002 to figure out the thorny problems plaguing this class of treatments. It brought two RNAi drugs for rare diseases to the market in the past two years and has more on the way. The technology is also moving from small markets to larger ones: Novartis just paid $9.7 billion to acquire Medicines Co. for its Alnylam-developed drug that can substantially lower cholesterol with two annual treatments.

Ionis Pharmaceuticals Inc. and Biogen Inc. collaborated on Spinraza, a so-called antisense drug that became the first effective treatment for a deadly rare disease. It was approved in late 2016 and had one of the most impressive drug launches of the decade. And Moderna Therapeutics rode a wave of promising messenger RNA-based medicines to the most lucrative biotechnology IPO of all time in 2018. From pharma abandonment to multiple approvals and blockbuster sales potential in under 10 years. Not bad!

Cancer immunotherapy: Scientists had been working on ways to unleash the human immune system on cancers well before the 2010s without much luck. Checkpoint inhibitors drugs that release the brakes on the body's defense mechanisms have since produced outstanding results in a variety of cancers and are the decades most lucrative turnaround story.

Merck got a hold of Keytruda via its 2009 acquisition of Schering-Plough, but it was far from the focus of that deal. Once Bristol-Myers Squibb & Co. produced promising results for its similar drug, Opdivo, Merck started a smart development plan that has turned Keytruda into the worlds most valuable cancer medicine. Its now available to treat more than 10 types of the disease, and has five direct competitors in the U.S. alone. Analysts expect the category to exceed $25 billion in sales next year.

If anything, the drugs may have been too successful. Copycat efforts are pulling money that could fund more innovative research. There are thousands of trials underway attempting to extend the reach of these medicines by combining them with other drugs. Some are based more on wishful thinking than firm scientific footing. Still, the ability to shrink some previously intractable tumors is a considerable advance. If drugmakers finally figure out the right combinations and competition creates pricing pressure that boosts access, these medicines will do even more in the years to come.

Conquering hepatitis C: From a combined economic and public-health standpoint, a new group of highly effective hepatitis C medicines may outstrip just about anything else on this list so far. Cure rates for earlier treatments werent especially high; they took some time to work and had nasty side effects. The approval of Gileads Sovaldi in 2013, followed in time by successor drugs such as AbbVie Inc.s Mavyret, have made hepatitis C pretty easily curable in a matter of weeks. For Gilead, getting to market rapidly with its drug proved enormously profitable; it raked in over $40 billion in revenue in just three years.

Hepatitis C causes liver damage over time that can lead to transplants or cancer. The existence of a rapid cure is a significant long-term boon even if the initial pricing on the drugs made them, in some cases, prohibitively expensive. Sovaldi notoriously cost $1,000 per pill at launch and over $80,000 for a course of treatment. The good new is, treatments have become a lot more affordable, which should allow this class of drugs to have a broad and lasting positive health impact.

Hepatitis C is one of the relatively few markets where the drug-pricing system has worked well. As competing medicines hit the market, the effective cost of these treatments plummeted. That, in turn, made the drugs more accessible to state Medicaid programs and prison systems, which operate on tight budgets and care for populations with higher rates of hepatitis C infection. Louisiana has pioneered the use of a Netflix model, under which the state paid an upfront fee for unlimited access to the drug. Its an arrangement that will help cure thousands of patients, and other states are likely to follow its lead.

Many of the medicines highlighted in this column have list prices in the six figures, a trend thats helped drive up Americas drug spending by more than $100 billion since 2009. Building on this decades medical advances is going to lead to even more effective medicines that will likely come with steeper prices. Id like to hope that policymakers will come up with a solution that better balances the need to reward innovation with the need to keep medicines accessible. That would really be a breakthrough.

Max Nisen at mnisen@bloomberg.net

@2019Bloomberg

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Gene therapy to conquering hepatitis C: A decade of medical breakthroughs - Business Standard

What were the biggest biopharma stories of 2019? – MedCity News

Like any reporting beat, biopharma has its slow news days. But its rare to find a whole year when few events of note occur, and 2019 was no exception. Indeed, the last year of the 21st centurys second decade saw its fair share of major mergers and acquisitions, controversies and historical milestones across the medical biotechnology and pharmaceutical industries.

The year kicked off with a mega-merger, when on Jan. 3, New York-based Bristol-Myers Squibb said it would acquire Summit, New Jersey-based Celgene for $74 billion. A wave of mergers and acquisitions across the biopharma industry soon followed. This was a decade after another wave of biopharma consolidation, when 2009 kicked off with Pfizers acquisition of Wyeth, followed by Merck & Co. buying Schering-Plough and Roche buying Genentech. The next large-scale deal happened in June, when Chicago-based AbbVie said it would spend $63 billion to acquire Allergan.

Other than the two aforementioned large deals, however, most M&A activity this year has taken the form of large biotechnology and pharmaceutical companies buying much smaller, but still large-cap players. Earlier this month, Roche concluded its $4.3 billion acquisition of gene therapy maker Spark Therapeutics, originally announced in February. That deal was dogged by a 10-month investigation by U.S. and U.K. regulators into the question of whether the Roche might have a disincentive to develop Sparks Phase III gene therapy candidate for hemophilia A, given that the Swiss drugmaker already makes a drug for the disease. Indianapolis-based Eli Lilly & Co.s $8 billion acquisition of Loxo Oncology days after the BMS-Celgene deal did not face such hurdles, though Loxo handed off its one approved product, the cancer drug Vitrakvi (larotrectinib), to development partner Bayer. Numerous other deals have followed, including Novartis deal to acquire The Medicines Co. for $9.7 billion, Astellas announcement that it would buy Audentes Therapeutics for $3 billion, Mercks move to buy ArQule for $2.7 billion, among others.

While dwarfed by its counterpart in 2009, the current M&A wave has not been without controversy. In September, a group of eight Democratic senators and one independent several of whom are or had been running for president wrote to the Federal Trade Commission urging greater scrutiny over such deals amid concerns about competition and high drug prices. While its uncertain if the FTC was responding to their concerns, the agency said Dec. 17 that it would seek to block genomic sequencing company Illumina from buying a smaller firm, Pacific Biosciences of California, in a previously announced $1.2 billion deal.

Another controversy that arose in 2019 was on the regulatory front. In August, the Food and Drug Administration said it was looking into a disclosure from Novartis subsidiary AveXis that mouse data from a disused assay used in its application for the gene therapy Zolgensma (onasemnogene abeparvovec-xioi) in spinal muscular atrophy which the FDA approved in May had been manipulated. The scandal, which predated Novartis acquisition of AveXis in 2018, led to two of the gene therapy developers executives being fired and created a publicity crisis for the drugmaker.

Yet, while the Zolgensma scandal did not affect the FDAs overall position on the product itself, another FDA decision still raised eyebrows. The approval of Karyopharm Therapeutics Xpovio (selinexor) in highly refractory multiple myeloma patients attracted significant criticism from physicians, who pointed both to what some called a low response rate in the Phase IIa study on which the approval was based and the FDA using Phase III data that were not disclosed to the public. The approval also happened despite the FDAs Oncologic Drugs Advisory Committee voting not to recommend it.

2019 also saw some important milestones on the regulatory front. Nine months after Scott Gottliebs resignation as commissioner of the FDA, the Senate confirmed Dr. Stephen Hahn, a radiation oncologist and chief medical executive at The University of Texas MD Anderson Cancer Center, to take his place. And the agency approved the first ever drug to tackle the root cause of sickle cell disease and its first vaccine against the Ebola virus.

In addition to specific events, many trends that have garnered increasing public and political attention moved to front and center in 2019 as well. The national conversation about drug pricing showed no signs of quieting down, as the Trump administration rolled out various programs designed to tackle high drug prices, and the House fired a shot across the bow with a bill this month that would require the Centers for Medicare and Medicaid Services to negotiate prices for some drugs.

Many of these events will continue to play out in 2020, as a new FDA commissioner takes the helm of the agency and large companies see their acquisitions bear fruit, for good or ill. And the conversation about drug pricing will only get louder amid the 2020 presidential election, which in turn could lead to greater scrutiny over biopharma industry consolidation.

Photo: klenger, Getty Images

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What were the biggest biopharma stories of 2019? - MedCity News

Global Gene Therapy Market 2019 Revenue, Opportunity, Forecast and Value Chain 2025 – Market Research Sheets

GlobalGene TherapyMarketcovers all the aspects of market factors. The report involves detailed specifications about theGene Therapymarket size with respect to sales, revenue, value, and volume. The research study furnishes crucial information along with the market size and share of the global market. The report then highlights factors affecting the development of market such as drivers, restraints, threats, and opportunities, technology advances, the latest market scenarios, etc. It also includes detailed segmentation by types and applications and the forecasting about the market status in the coming future from 2019 to2025. The report analyzes important financial conditions such as costs, stocks, price structure, and profits in terms of key regions.

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The study profiles and examines leading companies and other prominent companies operating in the industry, covering:Spark Therapeutics LLC, Bluebird Bio, UniQure N.V., Juno Therapeutics, GlaxoSmithKline, Chiesi Farmaceutici S.p.A., Bristol Myers Squibb, Celgene Corporation, Human Stem Cell Institute, Voyager Therapeutics, Shire Plc, Sangamo Biosciences, Dimension Therapeutics and others.

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Manufacturing: the next breakthrough in gene therapy – STAT

I never thought Id see the day when words like process, scale, and automation would make news in the biopharma industry. Yet as the race heats up to bring more first-of-their-kind gene therapies to market, breakthroughs in manufacturing are often the key or break down the barrier to delivering these therapies to patients.

In my career, which has largely focused on drug manufacturing, Ive been lucky to be directly involved in the approval of six new medicines. My current work, as head of technical operations at Spark Therapeutics, is offering the biggest challenge: bringing Luxturna, the first gene therapy for a genetic disease, to patients and families in the U.S. Getting here has been no small task.

With no precedent to guide us, we had to forge new clinical, regulatory, and manufacturing pathways. Working through the unknown meant developing a robust set of assays to test various aspects of the gene therapy product just so we could better understand it. We also built, from scratch, the only in-house manufacturing facility for a licensed gene therapy that is approved by both the U.S. Food and Drug Administration and the European Medicines Agency. This facility is located on the 13th floor of a high-rise in West Philadelphia.

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Gene therapy, as others in this space know, is not a one-size-fits-all approach. That means there isnt a gene therapy manufacturing playbook yet to guide the development of gene therapies, as there is for well-established therapeutic categories. And at least for now, every gene therapy is different. Each relies on a different delivery mechanism (vector) to transport functional copies of a gene into the patient.

Even if one day we have a platform that is flexible enough to accommodate multiple vector types, well still need to consider the fact that individual therapies require different dosing and modes of administration, both dependent on the patients cells and disease. While we certainly seek to standardize processes through enhanced analytics, automation, and even artificial intelligence, manufacturing each therapy will still require custom processes.

And time is of the essence, because patients and their families are waiting for these therapies. Given that many of these diseases have limited or no treatment options, regulatory authorities are rightly granting expedited approval pathways for investigational gene therapies. The tight timelines in these pathways narrow the window for manufacturing teams to plan and implement strategies to create gene therapies at scale for commercial use.

Here are three aspects I see as unique to the gene therapy manufacturing process:

Get comfortable with the uncomfortable. Given the shortened clinical development timelines and limited precedent to guide them, gene therapy manufacturers must make decisions about investing in Phase 3 manufacturing processes far in advance of knowing the clinical outcome of their therapy. Its important to trust your expertise and invest in well informed good risk. We saw the success of this at Spark with the first gene therapy, which is helping create a clearer road map for future ones.

Develop capability for capacity. Manufacturing a gene therapy is only half the battle. The other half is making enough of it, doing that as efficiently as possible, and getting it to the patients who need it. These challenges become even more urgent to tackle as the industry shifts to the next chapter in gene therapy development, from treatments made in small batches for small patient populations to bigger volumes for larger rare-disease populations and commercial scale.

Spark, for example, is optimizing the way it produces viral vectors, shifting from adherent cell lines, which attach cells to the sides of roller bottles, to a suspension process that is more efficient and scalable. In this process, bioreactors grow cells unattached, in a liquid or suspended environment. This alternate way of manufacturing uses well-established unit operations commonly employed in the biotechnology industry, making efficiency at scale more easily achievable. Less manual manipulation provides for more process consistency and higher success rates. Each of these elements aids in our ability to scale more easily.

Dont let perfection be the enemy of progress. Versions of this phrase have been attributed to Voltaire, Shakespeare, and Winston Churchill, among others, but the point here is that when it comes to manufacturing, the process is never perfect and can always be better. Our gene therapy manufacturing processes are constantly evolving based on what we learn from them and from new best practices. What matters most today is that we can manufacture gene therapies safely and effectively. The speed will continue to improve.

Manufacturers are accustomed to setting up highly repeatable processes for making and delivering medicines. But when it comes to gene therapies, we understand that the ingenuity for manufacturing needs to be as unique and cutting-edge as the therapies themselves.

While its exciting to see gene therapy manufacturing in the limelight today, I hope that the progress we are making will soon make these challenges old news.

Diane Blumenthal is the head of technical operations at Spark Therapeutics, where her responsibilities include manufacturing, quality control, and more.

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Novartis in talks with patients upset about lottery-like gene therapy giveaway – Reuters

NEW YORK (Reuters) - Novartis is in discussion with patient groups over its lottery-style free drug program for its multi-million-dollar gene therapy for spinal muscular atrophy (SMA) after criticism that the process could be unfair to some babies with the deadly disease.

FILE PHOTO: The company's logo is seen at the new cell and gene therapy factory of Swiss drugmaker Novartis in Stein, Switzerland, November 28, 2019. REUTERS/Arnd Wiegmann

The company said on Friday that it will be open to refining the process in the future, but it is not making any changes at this time. The program is for patients in countries where the medicine, called Zolgensma, is not yet approved for the rare genetic disorder, which can lead to death and profound physical disabilities.

At $2.1 million per patient, Zolgensma is the worlds costliest single-dose treatment.

Novartis said the program will open for submission on Jan. 2 and the first allocation of drugs would begin in February. Novartiss AveXis unit, which developed the drug, will give out 50 doses of the treatment through June for babies under 2 years old, it said on Thursday, with up to 100 total doses to be distributed through 2020.

Patient advocacy group SMA Europe had a conference call with the company on Friday, according to Kacper Rucinski, a board member of the patient and research group who was on the call.

There are a lot of ethical questions, a lot of design questions that need to be addresses. We will be trying to address them in January, Rucinski said. He said the program has no method of prioritizing who needs the treatment most, calling it a Russian roulette.

The company said it developed the plan with the help of bioethicists with an eye toward fairness.

This may feel like youre blindly passing it out, but it may be the best we can do, said Alan Regenberg, who is on the faculty at Johns Hopkins Berman Institute of Bioethics and was not among the bioethicists Novartis consulted with on the decision. It may be impossible to separate people on the basis of prognosis out of the pool of kids under 2, he said.

According to Rucinski, the parties will continue their discussion in January to see what can be improved in the design of the program.

Novartis said on Thursday that because of manufacturing constraints it is focused on providing treatment to countries where the medicine is approved or pending approval. It has one licensed U.S. facility, with two plants due to come on line in 2020.

Zolgensma, hit by turmoil including data manipulation allegations and suspension of a trial over safety concerns, is the second SMA treatment, after Biogens Spinraza.

Not all of the SMA community are opposed to Novartis program.

Rajdeep Patgiri moved from the United Kingdom to the United States in April so his daughter could receive Zolgensma. She has responded well to the treatment, and Patgiri worries that negative attention to the program could keep patients from receiving the drug.

The best outcome for all patients would be if everybody could get the treatment. Given all the constraints, a lottery is probably the fairest way to determine who receives the treatment, he said.

Reporting by Michael Erman; Additional reporting by John Miller in Zurich; Editing by Leslie Adler

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Novartis in talks with patients upset about lottery-like gene therapy giveaway - Reuters

Ring Therapeutics Launches to Expand Gene Therapy Viral Vector Options – Xconomy

XconomyBoston

Ring Therapeutics, a Flagship Pioneering spinout, launched Thursday with ambitious plans to expand the universe of vectors available for gene therapy delivery.

Gene therapy, treatments intended to treat disease by inserting a gene instead of using drugs or surgery, has had a banner year, with the second ever such therapy approved this year in the US.

Ring want to use itsresearch into viruses that exist in the human body without apparent negative effects to provide more and better options to fuel the rise of gene therapy treatments.

For the past two years, Flagship Pioneering partner and Rings founding CEO Avak Kahvejian says the company has been exploring the human commensal viromebasically, a group of viruses that exist within humans without negative effectsfor its potential to address limitations of the vectors currently used.

The sector relies heavily on adeno-associated viruses (AAVs), which naturally infect humans but arent known to cause disease, to deliver the DNA. Previous exposure, however, can spark an immune response.

A lot of the workhouses in gene therapy have either been pathogenic viruses or viruses that have been taken from other species or viruses that are highly immunogenic, or all of the above, Kahvejian tells Xconomy. That leads to a certain number of limitations, despite the successes and advances weve made to date.

A number of issues stymie widespread use of AAVs, Kahvejian says, including the fact that 10 percent to 20 percent of people have at one time or another been infected with such a virus, thereby building up an immune response to it. Another concern is where such gene therapies end up, because viruses tend to gravitate toward certain types of tissues, and to go elsewhere, require special tweaking.

The Cambridge, MA-based startup believes the viruses it has found are unlikely to cause an immune response or prove pathogenic, given their ubiquity in the body.

Like extrachromosomal DNAa new discovery at least one company is exploring for its potential as a target in cancer treatmentsthe viral sequencing Ring is studying are circular pieces of DNA that exist outside the 23 chromosomes of the human genome.

Ring says it has found thousands of these viruses that coexist with our immune system. It aims to use those to develop vectors that can facilitate gene replacement throughout the bodymultiple times, if necessary. While gene therapy is thought of as a one-time fix, cell turnover means whatever the fix engendered by the inserted gene could falter over time, necessitating a re-up.

Kahvejian wouldnt share a timeline for Rings plan to develop re-dosable, tissue-targeted treatments.

Were looking at the unique features and activities of these viruses in different tissues to establish the various vectors were going to pursue, he said.

Flagship, which pursues scientific questions in-house and builds and funds companies around the answershas put $50 million toward Ring, which has about 30 employees.

Rings president is Rahul Singhvi, an operating partner at Flagship. Most recently he was chief operating officer of Takedas global vaccine business unit. Its head of R&D is Roger Hajjar, who has led gene therapy trials in patients with heart failure.

Ring is the second startup Flagship has spun out this month. Cellarity launched last week.

Sarah de Crescenzo is an Xconomy editor based in San Diego. You can reach her at sdecrescenzo@xconomy.com.

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Gene Therapy for Sickle-Cell Anemia Looks Promisingbut It’s Riddled With Controversy – Singularity Hub

Gene therapy is fighting to enter mainstream medicine. With sickle cell disease, the fight is heating up.

Roughly two years ago, the FDA made the historic decision to approve the first gene therapy in the US, finally realizing the therapeutic potential of hacking our biological base code after decades of cycles of hope and despair. Other approvals soon followed, including Luxturna to target inherited blindness and Zolgensma, a single injection that could save children with a degenerative disease from their muscles wasting away and dying before the age of two.

Yet despite their transformative potential, gene therapy has only targeted relatively rareand often fataldisorders. Thats about to change.

This year, a handful of companies deployed gene therapy against sickle-cell anemia, a condition that affects over 20 million people worldwide and 100,000 Americans. With over a dozen therapies in the run, sickle-cell disease could be the indication that allows gene therapy to enter the mainstream. Yet because of its unique nature, sickle-cell could also be the indication that shines an unflinching spotlight on challenges to the nascent breakthrough, both ethically and technologically.

You see, sickle-cell anemia, while being one of the worlds best-known genetic diseases, and one of the best understood, also predominantly affects third-world countries and marginalized people of color in the US. So far, gene therapy has come with a hefty bill exceeding millions; few people afflicted by the condition can carry that amount. The potential treatments are enormously complex, further upping costs to include lengthy hospital stays, and increasing potential side effects. To muddy the waters even more, the disorder, though causing tremendous pain and risk of stroke, already has approved pharmaceutical treatments and isnt necessarily considered life-threatening.

How we handle gene therapies for sickle-cell could inform many other similar therapies to come. With nearly 400 clinical trials in the making and two dozen nearing approval, theres no doubt that hacking our genes will become one of the most transformative medical wonders of the new decade. The question is: will it ever be available for everyone in need?

Even those uninterested in biology have likely heard of the disorder. Sickle-cell anemia holds the crown as the first genetic disorder to be traced to its molecular roots nearly a hundred years ago.

The root of the disorder is a single genetic mutation that drastically changes the structure of the oxygen-carrying protein, beta-globin, in red blood cells. The result is that the cells, rather than forming their usual slick disc-shape, turn into jagged, sickle-shaped daggers that damage blood vessels or block them altogether. The symptoms arent always uniform; rather, they come in crisis episodes during which the pain becomes nearly intolerable.

Kids with sickle-cell disorder usually die before the age of five; those who survive suffer a lifetime of debilitating pain and increased risk of stroke and infection. The symptoms can be managed to a degree with a cocktail of drugsantibiotics, painkillers, and a drug that reduces crisis episodes but ups infection risksand frequent blood transfusions or bone marrow transplants. More recently, the FDA approved a drug that helps prevent sickled-shaped cells from forming clumps in the vessels to further combat the disorder.

To Dr. David Williams at Boston Childrens Hospital in Massachusetts, the availability of these treatmentshowever inadequatesuggests that gene therapy remains too risky for sickle-cell disease. Its not an immediately lethal diseaseit wouldnt be ethical to treat those patients with a highly risky experimental approach, he said to Nature.

Others disagree. Freeing patients from a lifetime of risks and pain seems worthy, regardless of the price tag. Inspired by recent FDA approvals, companies have jumped onto three different treatments in a bitter fight to be the first to win approval.

The complexity of sickle-cell disease also opens the door to competing ideas about how to best treat it.

The most direct approach, backed by Bluebird Bio in Cambridge, Massachusetts, uses a virus to insert a functional copy of the broken beta-globin gene into blood cells. This approach seems to be on track for winning the first FDA approval for the disorder.

The second idea is to add a beneficial oxygen-carrying protein, rather than fixing the broken one. Here, viruses carry gamma-globin, which is a variant mostly present in fetal blood cells, but shuts off production soon after birth. Gamma-globin acts as a repellent that prevents clotting, a main trigger for strokes and other dangerous vascular diseases.

Yet another idea also focuses on gamma-globin, the good guy oxygen-carrier. Here, rather than inserting genes to produce the protein, the key is to remove the breaks that halt its production after birth. Both Bluebird Bio and Sangamo Therapeutics, based in Richmond, California, are pursing this approach. The rise of CRISPR-oriented companies is especially giving the idea new promise, in which CRISPR can theoretically shut off the break without too many side effects.

But there are complications. All three approaches also tap into cell therapy: blood-producing cells are removed from the body through chemotherapy, genetically edited, and re-infused into the bone marrow to reconstruct the entire blood system.

Its a risky, costly, and lengthy solution. Nevertheless, there have already been signs of success in the US. One person in a Bluebird Bio trial remained symptom-free for a year; another, using a CRISPR-based approach, hasnt experienced a crisis in four months since leaving the hospital. For about a year, Bluebird Bio has monitored a dozen treated patients. So far, according to the company, none has reported episodes of severe pain.

Despite these early successes, advocates worry about the actual impact of a genetic approach to sickle-cell disease.

Similar to other gene therapies, the treatment is considered a last-line, hail Mary solution for the most difficult cases of sickle cell disease because of its inherent risks and costly nature. Yet end-of-the-line patients often suffer from kidney, liver, and heart damages that make chemotherapy far too dangerous.

Then theres the problem of global access. Some developing countries, where sickle-cell disease is more prevalent, dont even have consistent access to safe blood transfusions, not to mention the laboratory equipment needed for altering blood-producing stem cells. Recent efforts in education, early screening, and prevention have also allowed people to live longer and reduce the stigma of the disorder.

Is a $1 million price tag ever attainable? To combat exhorbitant costs, Bluebird Bio is offering an installment payment plan for five years, which can be terminated anytime the treatment stops working. Yet for patients in South Africa, India, or Cambodia, the costs far exceed the $3 per month price tag for standard treatment. Even hydroxyurea, the newly-approved FDA drug to reduce crisis pain episodes, is just a fraction of the price tag that comes with gene therapy.

As gene therapy technologies are further refined and their base cost reduced, its possible that overall costs will drop. Yet whether these treatments will be affordable in the long run remains questionable. Even as scientists focus on efficacy rather than price tag, NIH director Dr. Francis Collins believes not thinking about global access is almost unethical. There are historical examples for optimism: vaccines, once rather fringe, now touch almost every corner of our world with the help of scientific knowledge, advocacy groups, andfundamentallyproven efficacy.

With the rise of gene therapy, were now in an age of personalized medicine beyond imagination. Its true that perhaps sickle-cell disease genetic therapies arent quite there yet in terms of safety and efficacy; but without tackling access issues, the therapy will be stymied in its impact for global good. As genetic editing tools become more powerful, gene therapy has the potential to save even more livesif its made accessible to those who need it most.

Image Credit: Image by Narupon Promvichai from Pixabay

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Gene Therapy for Sickle-Cell Anemia Looks Promisingbut It's Riddled With Controversy - Singularity Hub

Making advanced therapies takes industrializing personalization – STAT

Whats the best way to measure the real rate of progress in personalized cell therapies, gene therapies, and other advanced therapies?

Ive been tracking the ever-growing flow of reports about these therapies in scientific journals and press releases for 15 years, ever since I co-led the passage of Californias $3 billion Stem Cell Research and Cures Act in 2004.

But to truly gauge who will benefit from todays innovations, Ive learned I also need to study the stream of business and technology announcements that runs in parallel. That might seem more mundane but to veterans of advanced therapies, making the science work actually signals success for these gene-, tissue-, and cell-based advanced therapies.

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The reason is simple. My experience working with advanced therapies has taught me, time and again, that true next-generation medicine requires the industrialization of personalization. That sounds like an oxymoron, but it isnt. To create individualized therapeutics in a sustainable way, we need to deliver even if it seems counterintuitive mass customization.

Breakthroughs such as CAR-T cell therapies are inspiring. They are also unsustainably expensive, difficult to manufacture, and complicated to deliver. We can change this by creating a more focused cross-collaborative production and delivery ecosystem.

The Food and Drug Administration anticipates that it will approve 10 to 20 advanced therapies a year beginning in 2025. It also expects to receive up to 200 clinical trial applications for cell and gene therapies per year, starting now. The more than 1,000 advanced therapy clinical trials now underway worldwide could enroll almost 60,000 patients, according to the Alliance for Regenerative Medicine. That pace wont be possible without new systems and networks that reduce cost, simplify manufacturing, and streamline delivery.

I can see some of these on the horizon when I read the biotech and pharma partnerships reported in BioSpace and BioCentury. Of the 100 most recent, almost 10% were dedicated to cell- and gene-therapy companies and organizations. These partnership announcements are typically viewed as opportunities to highlight new business deals or contract wins. But they are also daily snapshots of the infrastructure of an evolving next-generation health care system forming from within. Here are just a few examples from 2019:

Its encouraging to see biopharma manufacturing, logistics, transport, and other partners in the cell- and gene-therapy ecosystem coming together in new ways to ensure the successful and reliable delivery of advanced therapies for individual patients. But much more evolution is needed to provide sustainable patient access to advanced therapies.

We need even more industry collaboration to overhaul and connect existing health care systems, so production and delivery of cell- and gene-based therapies can be more automated and affordable. According to estimates from credible industry colleagues and leaders, end-to-end automation can shave costs by at least 20% to 30%, and at the same time greatly improve predictability and patient safety.

We must also make this new world simpler for health care providers. Doctors and nurses must not only understand how advanced therapies work medically, but be able to order and deliver them safely with a minimum of delay or hassle. As noted in the New Yorker, CAR-T requires bringing a manufacturing lens to medicine. Supporting health care providers means creating true collaboration between digital technology providers, hospitals, logistics providers, biotech and pharma companies, and manufacturing, like the Boston initiative I described earlier.

Standardization is often decried as cookie-cutter medicine. In this space, however, it is the wave of the future.

While patient biology is unique, and each patients cells may produce a one-of-a-kind manufacturing batch, essential parts of the production and delivery process should be as predictable and easy as possible. One key place to start is in-process drug labeling. When patients cells become the raw material for advanced therapies, these labels become more complex and more necessary: When a patient is about to receive a cell therapy infusion, its essential that the name on the bag of genetically re-engineered cells is his or hers. The Standards Coordinating Body, an FDA-funded but independent nonprofit, is now leading an industry-wide labeling initiative for cell and gene therapies.

There are other clear signs that the advanced therapies field gets it when it comes to infrastructure needs, such as the inclusion of digital health and handling of patient data as categories of focus in the federal Cures 2.0 initiative currently circulating in Washington. But much remains to be done.

In centers caring for individuals with cancer and rare diseases, thousands of patients are today receiving advanced therapies that are transforming their lives. We need to make that possible for many, many more by working together to industrialize and personalize in parallel.

Amy DuRoss is the CEO and co-founder of Vineti, a digital technology company that provides next-generation software platforms for advanced therapies. Before that she was managing director for new business creation for GE Ventures, chief business officer at Navigenics, the co-founder and executive director of Proposition 71, Californias $3 billion stem cell research initiative that passed in 2004, and chief of staff at the resulting California Institute for Regenerative Medicine.

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Making advanced therapies takes industrializing personalization - STAT

Dyno Therapeutics Launches to Improve Viral Vectors for Gene Therapy – BioSpace

Gene therapy is a way of delivering healthy genes or genetic material to cells in order to treat genetic disorders. The most common way to do this is using adeno-associated viruses (AAVs). The outer part of the virus, called the capsid, is generally retained, but the viral genes are replaced with the therapeutic genes. Attempts have been made to improve the capsid or shell of the virus, but usually fail. George Church and his team at Harvard Medical School with the original researchers at the Karolinska Institute and Lund University in Sweden, have developed a technique to modify the capsid. They have also launched a company, Dyno Therapeutics, to develop the approach.

The groups research, by senior author Tomas Bjrklund, with Lund, was published in PNAS, the Proceedings of the National Academy of Sciences of the United States of America.

The technique allows the researchers to engineer the virus shell to deliver the gene package to the exact cell type in the body they intend to treat. The process leverages computer simulations and modeling with gene and sequencing technology.

Thanks to this technology, we can study millions of new virus variants in cell culture and animal models simultaneously, Bjorklund said. From this, we can subsequently create a computer simulation that constructs the most suitable virus shell for the chosen applicationin this case, the dopamine-producing nerve cells for the treatment of Parkinsons disease.

The technique also dramatically decreases the need for laboratory animals. The millions of variations on the same therapy can be studied in the same individual.

The authors wrote, A challenge with the available synthetic viruses used for the treatment of genetic disorders is that they originate from wild-type viruses. These viruses benefit form infecting as many cells as possible in the body, while therapies should most often target a particular cell type, for example, dopamine neurons in the brain.

Current approaches to finding the most advantageous viruses for gene therapy use random screening, enrichment and, the authors say, serendipity. Their technique is dubbed BRAVE (barcoded rational AAV vector evolution). In BRAVE, each virus displays a peptide derived from a protein. That peptide as a known function on the AAV shell surface and what they call a unique molecular barcode in the packaged genome.

By sequencing the RNA-expressed barcodes, they can map the binding sequences from hundreds of proteins simultaneously. They liken the technique to accelerating evolution from millions of years to just weeks.

Bjorklund said The reason we can do this is that we study each generation of the virus in parallel with all the others in the same nerve cells. Unlike evolution, where only the best suited live on to the next generation, we can also learn what makes the virus work less well through this process. This is crucial when building computer models that interpret all the information.

The study showed the potential for using machine learning for AAV design, although the research fell short of actually designing an improved AAV that could be used in clinical testing. Thats where Dyno Therapeutics comes in, working to improve and develop the technique.

Luk Vandenberghe, director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear, told C&EN, Chemical & Engineering News, What theyve done here is truly a remarkable tour de force.

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Dyno Therapeutics Launches to Improve Viral Vectors for Gene Therapy - BioSpace

Pharma’s gene and cell therapy ambitions will kick into high gear in 2020despite some major hurdles – FiercePharma

In January 2019, then-FDA commissioner Scott Gottlieb ushered in the new year with a bold prediction: The agency, he said, would be approving between 10 and 20 gene and cell therapies per year by 2025. At the time, there were a whopping 800 such therapies in the biopharma pipeline and the FDA was aiming to hire 50 new clinical reviewers to handle the development of the products.

That momentum will no doubt start to pick up in 2020, as several companies in late-stage development of their gene and cell therapies achieve key milestones or FDA approval. Among the companies expected to make major strides in gene and cell therapies next year are Biomarin, with valoctocogene roxaparvovec to treat hemophilia A, Sarepta and its gene therapy for Duchenne muscular dystrophy, plus multiple players developing CAR-T treatments for cancer, including Bristol-Myers Squibb and Gilead.

But with such explosive growth comes challenges. Gene and cell therapies require enormous up-front investing in complex manufacturing processes, as well asinnovative approaches to securing insurance coverage for products that come with eye-popping price tagssuch as Novartis $2 million gene therapy Zolgensma to treat spinal muscular atrophy. Those are just a few of the obstacles that will be front-and-center in 2020 as more gene and cell therapies make their way towardthe finish line.

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Pharma companies will face challenges figuring out how to incorporate gene and cell therapies into their overall business, said Michael Choy, partner and managing director at Boston Consulting Group, in an interview with FiercePharma. They dont fit well into the normal paradigms of budgeting and decision-making. They require a different pace of evolution and specialized expertise. For now, companies are shoe-horning gene therapies into their current model, but over the long-term there will have to be changes.

That will become increasingly clear in 2020 as both Big Pharma and small up-and-comers move towardthe clinic with their gene and cell therapies. John Zaia, M.D., director of the Center for Gene Therapy at City of Hope, predicts there will be at least three gene and cell therapy FDA approvals in 2020. He also expects to see momentum among companies seeking to improve on the technology to address unmet needs in medicine.

For example, Zaia believes off-the-shelf CAR-T cancer treatments will show promise in early studiesand will be met with enthusiasm in the cancer community, he told FiercePharma in an email. The first generation of FDA-approved CAR-T treatments, Novartis Kymriah and Gileads Yescarta, take several weeks to make because they require removing T cells from patients and engineering them to recognize and attack the patients'cancers. Several companies are advancing off-the-shelf CAR-T treatments, including Precision BioSciences, which has been building out a manufacturing plant equipped to make 10,000 doses per year.

RELATED: Biotech building facility to make genome-edited, off-the-shelf CAR-T therapies

Gene therapies for inherited diseases will make strides in 2020, too, Zaia predicts. City of Hope is one of the participants in a phase 1 study of CSL Behrings gene therapy to treat adults with sickle cell disease. CSL will be racing against several companies working on the disease, including Bluebird Bio, which is testing its beta thalassemia gene therapy Zynteglo in sickle cell. There is a big push from many research centers to cure sickle cell diseaseand early results with the use of gene therapy look very promising, Zaia said. Years of research is finally coming to realization.

With such robust R&D underway in gene and cell therapies, its no surprise several players are stepping up their investments in manufacturing. In October, Sanofi said it would retrofit a vaccine plant in France so it couldbe used for gene therapy manufacturing. Pfizer shelled out $19 million for a North Carolina facility that will serve as its manufacturing hub for gene therapies. Even Harvard University is getting into the game, working with a consortium of contract manufacturers to build a $50 million facility dedicated to making cell therapies and viral vectors for gene therapies.

But how will the healthcare system pay for all of these complex therapies? Its a question that will continue to dog the industry, BCGs Choy said. Theres a lot of interest in outcomes-based payments and payments over time, but the issue is theyre very difficult to implementbecause the infrastructure to track outcomes over time doesnt really exist, he said.

Still, payers and pharma companies are hinting at their willingness to put that infrastructure in place. Pfizer, which is developing DMD and hemophilia gene therapies, said recently its brainstorming with payers on innovative strategies for reimbursement. Novartis and Spark have already pioneered payment strategies that deviate from the standard pay-everything-up-front system. Novartis has some pay-for-performance contracts in place for the $475,000 Kymriah. And in September, Cigna agreed to cover Novartis Zolgensma and Sparks Luxturna on a per-month, per-member schedule.

RELATED: Novartis, Spark gene therapies win a boost with soup-to-nuts Cigna coverage

Despite the many challenges in cell and gene therapy, some players are showing theres likely to be a robust market for these innovative treatments. In its first quarter on the market, Zolgensma brought in $160 million in salesfar surpassing analysts expectations.

The promise of huge returns on gene and cell therapies will likely drive acquisitions in 2020, Choy predicted. These treatments are so transformative for patients, and as the clinical proof of effectiveness continues to grow, youre going to see a lot more deal-making in this area, he said.

Buyers will likely show a willingness to invest in early-stage gene and cell therapies, especially if they come with technology platforms that allow for the development of many follow-up products, Choy added. For these types of therapies, the lifecycles will be much shorter than they are for traditional pharmaceuticals, particularly for rare diseases, he said. If you administer a one-time therapy, that revenue peaks quite quickly and then drops off. So to have a sustainable revenue from a gene therapy business, you need to replace that, which requires managing a pipeline.

Judging from recent events in the burgeoning gene and cell therapy industry, the news flow in 2020 will be generated not just by the industrys largest players, but also by its upstarts. In December, Ferring Pharmaceuticals spinout FerGene turned heads with data showing that its gene therapy to treat non-muscle invasive bladder cancer eliminated tumors in more than half of participants in a phase 3 trial. And Gileads Kite Pharma just applied for FDA approval for its mantle cell lymphoma CAR-T, KTE-X19, based on a 93% overall response rate in a phase 2 trial.

There were 75 gene therapy clinical trials initiated in 2018, nearly doubling the trial starts of 2016momentum thats likely to continue next year, BCG said in a recent report. The scientific foundation is in place, BCG analysts concluded, but there is still much to do to deliver the full benefit of gene therapy to patients."

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Pharma's gene and cell therapy ambitions will kick into high gear in 2020despite some major hurdles - FiercePharma

New Gene Therapy Method May Open BRAVE New World in Parkinson’s – Parkinson’s News Today

A new method allows researchers to develop adeno-associated virus (AVV) commonly used as the vehicle for gene therapies that accurately target and deliver genes to specific cells in the body.

This new technology may be suitable to target dopaminergic neurons that are damaged in Parkinsons disease.

We believe that the new synthetic [lab-made] virus we succeeded in creating would be very well suited for gene therapy for Parkinsons disease, for example, and we have high hopes that these virus vectors will be able to be put into clinical use, Tomas Bjrklund, PhD,Lund University, Sweden, said in a press release.

Bjrklund is lead author of the studyA systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism, which was published in the journal Proceedings of the National Academy of Sciences.

The adeno-associated virus (AAV)is a common, naturally-occurring virus, which has been shown to work as an effective gene therapy delivery vehicle for genetic diseases, such asspinal muscular atrophy. In gene therapy, scientists deliver a working version of a faulty gene using a harmless AAV that was modified and inactivated in the lab. This way the virus functions only as a delivery vehicle and does not have the capacity to damage tissues and cause disease.

While AAVs have a natural ability to penetrate any cell of the body and infect as many cells as possible, their usefulness as a potential therapy requires the capacity to specifically deliver a working gene to a particular cell type, such as dopamine producing-nerve cells. Those are the ones hose responsible for releasing the neurotransmitter dopamine and that are gradually lost during Parkinsons disease.

A team of Swedish researchers have developed a new method called barcoded rational AAV vector evolution, or BRAVE that combines powerful computational analysis with the latest gene and sequencing technology to produce AAVs that can specifically target neurons.

To make AAVs neuron specific, the team selected 131 proteins known to specifically interact with synapses (the junctions between two nerve cells that allow them to communicate).

They then divided the proteins into small sequences, called peptides, and created a large library where each peptide could be identified by a specific pool of genetic barcodes (a short sequence of DNA that is unique and easily identified).

The peptide is then displayed on the surface of the AAV capsid, allowing researchers to test the simultaneous delivery of many cell-specific AAVs in a single experiment.

The team then injected these AAVs into the forebrain of adult rats and observed that around 13% of the peptides successfully homed to the brain. Moreover, 4% of the peptides were transported effectively through axons (long neuronal projections that conduct electrical impulses) toward the nerve cells body.

Researchers then selected 23 of these unique AAV capsids and injected them into rats striatum, a brain region involved in voluntary movement control and affected in Parkinsons disease. Twenty-one of the new AAV capsids had an improved transport capacity within nerve cells than in standard AAVs.

One particular capsid, called MNM008, showed a high affinity for rat dopaminergic neurons. Researchers then tested whether this viral vector also could target human dopaminergic neurons.

The team transplanted neurons generated from human embryonic stem cells into rats striatum. Six months later, they injected either MNM008 or a control AAV capsid and found that MNM008 was able to target these specific cells and be transported into dopaminergic neuronal cell bodies through axons.

Thanks to this technology, we can study millions of new virus variants in cell culture and animal models simultaneously. From this, we can subsequently create a computer simulation that constructs the most suitable virus shell for the chosen application in this case, the dopamine-producing nerve cells for the treatment of Parkinsons disease, Bjrklund said.

Overall, researchers believe the BRAVE method opens up the design and development of synthetic AAV vectors expressing capsid structures with unique properties and broad potential for clinical applications and brain connectivity studies.

The team has established a collaboration with a biotech company, Dyno Therapeutics, to use the BRAVE method in the design of new AAVs.

Together with researchers at Harvard University, we have established a new biotechnology company in Boston, Dyno Therapeutics, to further develop the virus engineering technology, using artificial intelligence, for future treatments, Bjrklund said.

Patricia holds a Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She has also served as a PhD student research assistant at the Department of Microbiology & Immunology, Columbia University, New York.

Total Posts: 208

Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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New Gene Therapy Method May Open BRAVE New World in Parkinson's - Parkinson's News Today

Viewpoint: EU should take a lead in enforcing the corporate social responsibility of gene therapy manufacturers – Science Business

Gene therapy is providing unprecedented hope for growing numbers of patients and families. This game changer in medicine restores vision in babies born with congenital blindness, reconstitutes defences against infection in inherited immunodeficiencies and offers the perspective of curing the devastating neuromuscular disease, spinal muscular atrophy.

Gene therapy is also removing the need for repeat blood transfusions in adolescents with the inherited blood disorder, beta-thalassemia. Meanwhile, in oncology, CAR-T therapies, involving genetic modifications of a patients own immune cells, are proving life-saving for children or adults with certain types of blood cancers.

All these revolutionary treatments are now approved by regulatory agencies in Europe or the US. Unfortunately, they carry astronomical price tags which prevent their effective delivery to patients. As one case in point, Bluebird Bios Zynteglo for treating beta-thalassemia, has a list price of 1.57 million.

Can high prices be justified?

Gene therapy manufacturers defend their prices by pointing to high development and manufacturing costs, small markets, and unique therapeutic effectiveness as compared to the current standard of care. However, R&D costs are kept secret, and higher numbers of patients eligible for a given therapy do not translate into lower prices.

Indeed, several arguments the manufacturers put forward are dubious or even far-fetched. As of today, claims that a single administration of a gene therapy product will ensure a lifelong cure are simply not supported by the scientific evidence.

Likewise, value-based pricing is often misconceived. As stated by the US Institute for Clinical and Economic Review in its 2017 white paper on gene therapy, the established value of a treatment reflects the maximum price society might be prepared to pay for it - but should not dictate the price that is actually paid. In an ideal world, actual prices should provide market-consistent returns for shareholders and sufficient incentive to innovate.

The EU, a pioneer in gene therapy

European scientists, institutions and charities have been central to the development of gene therapy. The world's first successful clinical trial was reported in 2000 by Alain Fischer and his team at Necker Hospital in Paris, while the first authorisation of a gene therapy product in a regulated market was granted by the European Medicines Agency in 2012.

According to the Cordis database of EU-supported research, 86 gene therapy projects for rare diseases had funding from the European Commission during the FP7 (2007-2013) and Horizon 2020 (2014-2020) research programmes. One can estimate that overall more than 1 billion has been invested in this area by the EU Commission, member states and not-for-profit organisations.

To ensure European patients benefit from these achievements and investments, it is essential to ensure reasonable pricing of gene therapies. Laudable efforts are currently being made by the World Health Organization to increase transparency, and by some member states to join forces in negotiating prices, but such initiatives are unlikely to solve the current crisis as they do not address its root, namely that the sole objective of most gene therapy companies is to maximise the return on investment and shareholder value.

A way forward: enforcing the corporate social responsibility of gene therapy manufacturers

As I recently argued with Alain Fischer and the economist Mathias Dewatripont in the journal Nature Medicine (November 25, 2019), now is the time to reflect on how to enforce the corporate social responsibility of gene therapy companies.

Among the measures we would like to see considered are the insertion of clauses into technology transfer agreements made between academic organisations receiving grants from the European Commission and for-profit companies to make reasonable pricing compulsory.

We also propose to make reimbursement of gene therapies by EU healthcare payers conditional on the companies which are commercialising these products being certified for their corporate social responsibility. This is in line with several commitments made recently by pharma companies. For example, in August 2019, the CEOs of US-based pharma companies signed the Business Roundtable Statement, affirming their commitment to generate value for all their stakeholders not just their shareholders.

Also in August, Novartis announced it had joined the Value Balancing Alliance, a body whose goal is to increase transparency around business decisions, work with external bodies to develop accounting frameworks, and shift priority from profit maximisation to optimising value creation.

Earlier this year, the pharmaceutical company Chiesi was certified as a Benefit Corporation, meaning its legally defined goals include positive social impact in addition to profit.

Of course, the effective implementation of such commitments and their translation into reasonable pricing policies will require both incentives and regulatory controls. The starting point should be a renewed multi-stakeholder conversation with industry, investors, regulators, payers and, of course, patients.

Professor Michel Goldman is Co-director of the I3h Institute at the Universit Libre de Bruxelles and former Executive Director of the EU Innovative Medicines Initiative.

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Viewpoint: EU should take a lead in enforcing the corporate social responsibility of gene therapy manufacturers - Science Business

Takeda Presents Data for Hemophilia A and B Gene Therapy Optimization – Hemophilia News Today

Takedahas presented early data on the prevalence of and a possible solution for one of gene therapys main hurdles: the development of an immune reaction against the viral-based delivery vectors used in such therapies.

The findings, presented at the 61stAmerican Society of Hematology (ASH) Annual Meeting Dec. 710 in Orlando, Florida, may inform the development of investigational gene therapies forhemophilia A and B.

Takedas gene therapy pipeline for hemophilia includes TAK-754 for hemophilia A, which is currently in a Phase 1 clinical study, and TAK-748 for hemophilia B, still in pre-clinical development.

Gene therapy involves the use of a modified viral vector, which does not cause an infection, to deliver a copy of the gene that provides instructions for making the clotting factor missing in hemophilia patients. The goal is to allow patients to produce their own clotting factor at normal levels, and in a durable manner, to limit the need for regular infusions of factor concentrates.

Most gene therapies being developed for hemophilia use protein shells, or capsids, based on adeno-associated virus (AAV), particularly AAV5 and AAV8, for packing and delivering a working copy of the clotting factor gene. Takedas gene therapy candidates for hemophilia A and B both use recombinant (lab-made) versions of AAV8.

The vector delivers the gene into a patients liver cells, where most clotting factors are produced naturally.

One of the major challenges with this approach is the fact that some patients have been exposed in the past to naturally-occurring AAVs and have become immune to these vectors.

While natural exposure to AAVs does not result in any known disease, people develop antibodies (called neutralizing antibodies, or NAbs) and cell-mediated immune responses that recognize and attack AAV capsids. That blocks gene therapy delivery and compromises its safety and effectiveness. These antibodies are known as anti-AAV.

The presence of neutralizing antibodies against AAVs is one of the major limitations for the successful use of gene therapies, and one of the reasons why patients are excluded from gene therapy trials.

At the ASH meeting, one of the posters presented by Takeda, titled Co-Prevalence of Pre-Existing Immunity to Different Serotypes of Adeno-Associated Virus (AAV) in Adults with Hemophilia, reported a study of the prevalence of pre-existing natural immunity against AAVs in adults with hemophilia A and B.

The study enrolled 194 patients with hemophilia A and 48 with hemophilia B, in the U.S. and Europe (NCT03185897). Results showed that approximately 50% of them have neutralizing antibodies to AAV2 (the most common in natural infections), to AAV5 or to AAV8. (Notably, 40% of patients carried antibodies against all three vector types.)

Such patients probably will not respond to AAV-based gene therapies and will be excluded from trials. These data will add to our appreciation of preexisting AAV immunity that prevent patient participation in gene therapy trials, the abstract concluded.

Another study conducted by Takeda focused on a potential strategy to overcome this problem.

The data were presented in a poster titled AAV8-Specific Immune Adsorption Column: A Treatment Option for Patients with Pre-Existing Anti-AAV8 Neutralizing Antibodies.

Researchers developed an immune adsorption column (IAC) specifially designed to remove anti-AAV8 antibodies from patients plasma using apheresis. In this process, blood is drawn from the patient and separated in plasma and its other components, outside the patients body. The plasma is then run through a platform which could be the IAC column to remove anti-AAV8 antibodies. After this process, the plasma is given back to the patient.

The column under development has a coat of AAV8 capsids that serve as bait to specifically fish out AAV8-targeted antibodies.

Early laboratory tests showed that the column effectively eliminated anti-AAV8 antibodies from human plasma samples, a result further supported by animal studies.

IAC is an enabler for treatment of patients with pre-existing immunity against AAV8 and would also facilitate re-administration. IAC is intended to be applied in combination with Takedas AAV8 based hemophilia programs, researchers wrote.

As we continue to advance our hemophilia A and hemophilia B investigational gene therapy programs, Takeda is also investigating approaches to overcome the challenges of current AAV gene therapies that could potentially be applied to hemophilia and other rare monogenic [a single gene] diseases, Dan Curran, MD, head of Rare Diseases Therapeutic Area Unit at Takeda, said in a press release.

Developing new gene therapy approaches including those capable of treating pre-existing immunity to AAV, enabling re-dosing, lowering doses, enhancing biodistribution and developing alternative gene delivery vehicles are critical to one day providing functional cures to patients, Curran said.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.

Total Posts: 121

Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Tcnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.

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Takeda Presents Data for Hemophilia A and B Gene Therapy Optimization - Hemophilia News Today

GenScript Biotech to Host Global Forum on Cell and Gene Therapy and the Booming China Market During JPM Week – PRNewswire

NANJING, China, Dec. 16, 2019 /PRNewswire/ -- GenScript Biotech Corp., one of the leadingbiotechnology companies inChina, today announcedits inaugural GenScript Biotech Global Forum on Jan. 14 in San Francisco, coinciding with the JP Morgan Healthcare Conference week. The Forum, exploring the theme "Cell and Gene Therapy and the Booming China Market," will feature gene and cell therapy leaders in industry, academia and the investment community and is expected to draw several hundred attendees.

"Advancements in cell and gene therapy have attracted global attention in recent years, as the promise of bringing life-changing treatments to cancer patients and others comes closer to reality," said Frank Zhang, PhD., founder and CEO of GenScript. "GenScript's Global Forum aims to foster closer collaborations among scientists, regulators, and industry, not just in the booming China market but around the globe. We hope that by working together we can advance the industry and accelerate drug development."

GenScript's Global Forum, will take place from 1:30 p.m. to 5:30 p.m. at the Grand Hyatt San Francisco. Highlights of the agenda include:

For more information about the Forum and to register for the event please visit hereor https://www.genscript.com/biotech-global-forum-2020.html.

About GenScript Biotechnology

GenScript Biotech Corporation (Stock Code: 1548.HK) is a global biotechnology group. GenScript's businesses encompass four major categories based on its leading gene synthesis technology, including operation as a Life Science CRO, enzyme and synthetic biology products, biologics development and manufacturing, as well as cell therapy.

Founded in 2002 and listed on the Hong Kong Stock Exchange in 2015, GenScript has an established global presence across Greater China, North America, the EU, and Asia Pacific. Today, over 300,000 customers from over 160 countries and regions around the world have used GenScript's premier, convenient, and reliable products and services.

GenScript currently has more than 2900 employees globally, 34% of whom hold master's and/or Ph.D. degrees. In addition, GenScript has a number of leading commercial technologies, including more than 100 patents and over 270 patent applications. As of June 2019, GenScript's products and services have been cited by 40,300 scientific papers worldwide.

GenScript is committed to striving towards its vision of being the most reliable biotech company in the world to make humans and nature healthier through biotechnology.

For more information, please visit https://www.genscript.com/

Contact:

Corporate:Fiona CheCorporate Communication Manager, GenScript+86 -025-58897288-6321Fiona.che@genscript.com

Media Susan ThomasPrincipal, Endpoint Communications(619) 540-9195susan@endpointcommunications.net

SOURCE GenScript Biotech Corp.

https://www.genscript.com

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GenScript Biotech to Host Global Forum on Cell and Gene Therapy and the Booming China Market During JPM Week - PRNewswire


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