Gluconokinase IDNK Promotes Cell Proliferation and Inhibits Apoptosis | OTT – Dove Medical Press

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Xiao-Min Wu,1,* Cheng Jin,2,* Yuan-Long Gu,2 Wu-Qiang Chen,2 Mao-Qun Zhu,2 Shuo Zhang,2 Zhen Zhang1

1Department of Integrated Traditional Chinese and Western Medicine Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, Peoples Republic of China; 2Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214041, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Cheng JinDepartment of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, 585 Xingyuan Road, Wuxi, Peoples Republic of ChinaTel +8613338770679Email jingcheng1008@163.com

Purpose: Hepatocellular carcinoma (HCC) is one of the deadliest cancers globally with a poor prognosis. Breakthroughs in the treatment of HCC are urgently needed. This study explored the role of IDNK in the development and progression of HCC.Methods: IDNK expression was suppressed using short hairpin (shRNA) in BEL-7404 and Huh-7 cells. The expression of IDNK in HCC cells after IDNK knockdown was evaluated by real-time quantitative RT-PCR analysis and Western blot. After IDNK silencing, the proliferation and apoptosis of HCC cells were evaluated by Celigo cell counting, flow cytometry analysis, MTT assay, and caspase3/7 assay. Gene expressions in BEL-7404 cells transfected with IDNK shRNA lentivirus plasmid and blank control plasmid were evaluated by microarray analysis. The differentially expressed genes induced by deregulation of IDNKwere identified, followed by pathway analysis.Results: The expression of IDNK at the mRNA and protein levels was considerably reduced in shRNA IDNK transfected cells. Knockdown of IDNK significantly inhibited HCC cell proliferation and increased cell apoptosis. A total of 1196 genes (585 upregulated and 611 downregulated) were differentially expressed in IDNK knockdown BEL-7404 cells. The pathway of tRNA charging with Z-score = 3 was significantly inhibited in BEL-7404 cells with IDNK knockdown.Conclusion: IDNK plays a key role in the proliferation and apoptosis of HCC cells. IDNK may be a candidate therapeutic target for HCC.

Keywords: hepatocellular carcinoma cells, shRNA IDNK, cell proliferation, cell apoptosis, microarray, differentially expressed gene

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Gluconokinase IDNK Promotes Cell Proliferation and Inhibits Apoptosis | OTT - Dove Medical Press

The perfect virus: two gene tweaks that turned COVID-19 into a killer – Sydney Morning Herald

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But this virus infected only bats, not humans. The researchers named it RaTG13 and then promptly forgot about it.

At the same time, other research groups noted these bat coronaviruses regularly seemed to jump from animals to humans, and posed a significant pandemic threat.

In 2013, in the province of Yunnan, about 2000 kilometres west of Wuhan, a horseshoe bat was caught in a trap.

And then ... the world moved on. We had bigger things to worry about than Chinese bat coronaviruses.

It is now clear we made a mistake.

The virus that is causing the first pandemic in 100 years it will likely kill millions before this is all over, and mean that life may never be the same again shares 96 per cent of its genetic code with RaTG13.

We have been monitoring these coronaviruses. Theyve been jumping species boundaries, says Professor Edward Holmes. We knew this was going to happen.

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RaTG13, or another very similar bat virus, has managed to pick up two tiny genetic tweaks that turned it from a bat disease into a virus perfectly adapted to make humans sick.

Then it had the unbelievable misfortune to emerge in exactly the wrong place at exactly the wrong time.

Its got this beautifully adapted set of mutations, says Holmes. In his published work, he calls it a perfect epidemiological storm.

A crown of spikes

Holmes, a researcher based at the University of Sydney, is among the worlds leading experts on the genetics and evolution of SARS-CoV-2, the virus that causes COVID-19.

He was on the team that first sequenced the genes of the virus from one of the first patients in Wuhan. The

ir article on the possible origins of the virus is now the most-publicised Nature study in the history of that venerable journal.

He has visited the Huanan seafood and wildlife market where the Wuhan outbreak began. He has visited caves in China, searching for bats so he can survey the viruses they contain.

CoV-2 is a coronavirus, just like SARS and MERS. These viruses get their name from how they look under a microscope: a tiny bubble of fat surrounded by a crown of spikes which are used to penetrate cells.

An electron-microscope image of the COVID-19 virus, isolated from the first Australian coronavirus case.Note the bubble in the centre surrounded by spikes.Credit:CSIRO

Animals have many different types of viruses. But coronaviruses seem uniquely able to jump from animal to human. They just have this ability, says Holmes. We dont know why.

The emergence of SARS in 2003, killing 774 people, should have been a warning: these viruses jumped, and when they did lots of humans died.

We should have started building broad-based vaccines and antivirals that target all coronaviruses.

Instead, SARS was defeated largely by enhanced hygiene measures. Several drugs and vaccine candidates for SARS were developed and then largely abandoned.

CSIRO comparative immunologist Michelle Baker. Credit:CSIRO

We have been completely complacent, says Dr Michelle Baker, the CSIROs leading bat virus researcher.

It gets really difficult to get funding when there is not an outbreak. People feel a sense of security. They dont feel its relevant anymore.

Why this virus?

The virus pulled from bats in 2013 could not infect humans. SARS-CoV-2 can. Why?

It appears that two tiny tweaks to the virus genetic code have made a huge difference.

CoV-2 wants to do two things: bind to a human cell and then get inside it. The virus binds to a cellular receptor think of them as little antennae that stick off the side of human cells called ACE2.

ACE2 receptors are designed to listen for signals that change our blood pressure. Fine adjustments to blood pressure are really important in our lungs, so our lung cells are covered in ACE2 receptors.

SARS was able to bind to ACE2. But small genetic changes mean CoV-2 binds almost perfectly, at least 10 times more tightly than SARS. Its beautifully adapted to do that, says Holmes.

But thats not enough. Once CoV-2 is stuck on a cell, it needs to get in. Thats where the second tweak comes in.

CoV-2 is covered in spikes. They act like tiny harpoons. The virus needs to stick to the cell and then fire a harpoon. The harpoon pulls the surface of the cell and the virus together, allowing them to fuse. Thats how the virus gets inside.

A 3D map of the virus's spike protein, which it uses to 'harpoon' human cells. Credit:Science

But you dont want the harpoon firing off randomly, says Professor Stephen Turner, head of microbiology at Monash University. You only want it to fire when its ready to infect the cell. If its going off too early or too late, the virus would not be able to infect us.

To trigger the harpoon at just the right time, viruses rely on human enzymes, little proteins in our blood. Some enzymes trigger the harpoon too early, others trigger it too late. Among the best enzyme triggers the one that fires the harpoon at exactly the right time is an enzyme called furin. Our bodies produce heaps of furin.

Basically, you can work out if a virus is going to be highly pathogenic or not if it is activated by furin, says Turner.

Bird flu is triggered by furin. We got lucky, though, because it wasnt very good at sticking to our cells. CoV-2 is great at sticking to our cells. And its triggered by furin, among the best triggers a virus can have.

The combination is what makes it so infectious, says Turner.

The birth of a virus

How does a bat virus pick up these tricks?

Bats live essentially symbiotic relationships with their viruses. The viruses dont want to kill the bats, because then theyd have nowhere to live.

When scientists test bats, they find lots of different viruses but at very low levels. Often its really difficult to find a virus in a bat, says Baker.

And these viruses are, in evolutionary terms, very stable. They dont change much. It is unlikely RaTG13 turned into SARS-CoV-2 within a bat, Baker says.

But things change when a bat virus jumps to another animal.

Heres one potential scenario.

RaTG13 has the ability to bind to ACE2. But it did not have the furin tweak which makes the virus so infectious.

It is possible RaTG13, or a similar virus, jumped from a bat into a pangolin a small, scaly anteater common to Asia and highly valued in traditional Chinese medicine.

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Pangolins also have the ACE2 receptor, as do other animals like ferrets.

Either of these animals, or many others, could have been the middle animal between bats and humans.But in this particular origin story, the pangolin was infected at the same time with another bat coronavirus. This virus possessed the furin tweak.

When two viruses infect the same host, they can recombine swapping their genes.

This may have created a virus that could both stick to ACE2 and use furin to quickly get inside human cells. That could have been how SARS-CoV-2 was born. Then it jumped to humans in the close confines of the Wuhan wet market.

An image of a bamboo rat caged on top of a deer allegedly sold at the Wuhan seafood market has circulated online. Credit:Weibo

And Wuhan is the perfect spot for a virus to jump. The city is home to millions. It is an international travel hub. The virus appeared just before the biggest travel period of the year: the Chinese Spring festival.

That story is neat. But it is no certainty. The first documented COVID-19 patient had no exposure to the wet market.

It is possible, although unlikely, this virus was circulating in humans for years before breaking out into a pandemic.

It could have spread silently, causing only mild cold-like symptoms, before suddenly acquiring a key mutation or two that made it much more contagious - and much more dangerous. You cannot rule that out, says Holmes.

Whether that market was involved or not, its really unclear at the moment. We may never answer that question.

We need to change the way we live

Holmes is shocked at how fast SARS-CoV-2 has spread. But hes not shocked it was a bat coronavirus that caused a worldwide pandemic.

Environmental damage, illegal wildlife trading (pangolins in particular are heavily traded), wet markets and the climate crisis are all combining to push humans and bats closer than ever before.

It is blindingly obvious that we as humans have to change the way we interact with the animal world. There is no doubt about that, he says. And its not the animals' fault.

Bats have been carrying these viruses for millennia. Its not them thats changed, its us the way we interact with them.

The whole world is now set up for a pandemic - we live in megacities, there is transport. Its an accident waiting to happen, and it happened.

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When the world eventually starts to recover from the pandemic, steps need to be put in place to widen the gap between bats and humans so this cannot happen again, Holmes says.

We have to cut our exposure. Those markets have to go, he says. The illegal trade in wildlife has to end. We have to cut our exposure. Thats very very clear.

Liam is The Age and Sydney Morning Herald's science reporter

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The perfect virus: two gene tweaks that turned COVID-19 into a killer - Sydney Morning Herald

Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA TUG1 to | DDDT – Dove Medical Press

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Ganhua You, 1, 2 Xiangshu Long, 3, 4 Fang Song, 3, 4 Jing Huang, 3, 4 Maobo Tian, 3, 4 Yan Xiao, 3, 4 Shiyan Deng, 3, 4 Qiang Wu 3, 4

1Guizhou University School of Medicine, Guiyang 550025, Peoples Republic of China; 2Guizhou Institute for Food and Drug Control, Guiyang 550004, Peoples Republic of China; 3Department of Cardiology, Guizhou Provincial Peoples Hospital, Guiyang 550002, Peoples Republic of China; 4Department of Cardiology, Peoples Hospital of Guizhou University, Guiyang 550002, Peoples Republic of China

Correspondence: Qiang WuDepartment of Cardiology, Guizhou Provincial Peoples Hospital, 83 Zhongshan East Road, Guiyang, Guizhou, Peoples Republic of ChinaTel +86-0851-85937194Fax +86-0851-85924943Email wqgz0851@126.com

Background: Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS.Methods: First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS.Results: qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS.Conclusion: Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1.

Keywords: metformin, taurine up-regulated gene 1, AMPK/mTOR, autophagy, atherosclerosis

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Decibel Therapeutics Announces Strategic Research Focus on Regenerative Medicine for the Inner Ear – Business Wire

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BOSTON--(BUSINESS WIRE)--Decibel Therapeutics, a development-stage biotechnology company developing novel therapeutics for hearing loss and balance disorders, today announced a new strategic research focus on regenerative medicine approaches for the inner ear. The company is also announcing a collaboration and option agreement that gives Decibel exclusive access to novel compounds targeting proteins in a critical regenerative pathway.

Decibels research focus on regeneration will be powered by the companys research and translation platform. The company has built one of the most sophisticated single cell genomics and bioinformatics platforms in the industry to identify and validate targets. Decibel has also developed unique insights into regulatory pathways and inner ear delivery mechanisms that together enable precise control over gene expression in the inner ear and differentiate its AAV-based gene therapy programs.

Our deep understanding of the biology of the inner ear and our advanced technological capabilities come together to create a powerful platform for regenerative medicine therapies for hearing and balance disorders, said Laurence Reid, Ph.D., acting CEO of Decibel. We see an exciting opportunity to leverage this platform to address a broad range of hearing and balance disorders that severely compromise quality of life for hundreds of millions of people around the world.

The first program in Decibels regeneration portfolio aims to restore balance function using an AAV-based gene therapy (DB-201), which utilizes a cell-specific promoter to selectively deliver a regeneration-promoting gene to target cells. In collaboration with Regeneron Pharmaceuticals, Decibel will initially evaluate DB-201 as a treatment for bilateral vestibulopathy, a debilitating condition that significantly impairs balance, mobility, and stability of vision. Ultimately, this program may have applicability in a broad range of age-related balance disorders. There are currently no approved medicines to restore balance. Decibel expects to initiate IND-enabling experiments for this program in the first half of 2020.

Decibel is also pursuing novel targets for the regeneration of critical cells in both the vestibule and cochlea of the inner ear; these targets may be addressable by gene therapy or other therapeutic modalities. As a key component of that program, Decibel today announced an exclusive worldwide option agreement with The Rockefeller University, which has discovered a novel series of small-molecule LATS inhibitors. LATS kinases are a core component of the Hippo signaling pathway, which plays a key role in regulating both tissue regeneration and the proliferation of cells in the inner ear that are crucial to hearing and balance. The agreement gives Decibel an exclusive option to license this series of compounds across all therapeutic areas.

The agreement also establishes a research collaboration between Decibel and A. James Hudspeth, M.D., Ph.D., the F.M. Kirby Professor at The Rockefeller University and the director of the F.M. Kirby Center for Sensory Neuroscience. Dr. Hudspeth is a world-renowned neuroscientist, a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and a Howard Hughes Medical Institute investigator. Dr. Hudspeth has been the recipient of numerous prestigious awards, including the 2018 Kavli Prize in Neuroscience.

Rockefeller scientists are at the leading edge of discovery, and we are excited to see the work of Dr. Hudspeth move forward in partnership with Decibel, said Jeanne Farrell, Ph.D., associate vice president for technology advancement at The Rockefeller University. The ambitious pursuit of harnessing the power of regenerative medicine to create a new option for patients with hearing loss could transform how we address this unmet medical need in the future.

In parallel with its new research focus on regenerative strategies, Decibel will continue to advance key priority preclinical and clinical programs. DB-020, the companys clinical-stage candidate designed to prevent hearing damage in people receiving cisplatin chemotherapy, is in an ongoing Phase 1b trial. Decibel will also continue to progress DB-OTO, a gene therapy for the treatment of genetic congenital deafness, which is being developed in partnership with Regeneron Pharmaceuticals. The DB-OTO program aims to restore hearing to people born with profound hearing loss due to a mutation in the otoferlin gene and is expected to progress to clinical trials in 2021.

To support the new research focus, Decibel is restructuring its employee base and discontinuing some early-stage discovery programs.

About Decibel Therapeutics, Inc.Decibel Therapeutics, a development-stage biotechnology company, has established the worlds first comprehensive drug discovery, development, and translational research platform for hearing loss and balance disorders. Decibel is advancing a portfolio of discovery-stage programs aimed at restoring hearing and balance function to further our vision of a world in which the benefits and joys of hearing are available to all. Decibels lead therapeutic candidate, DB-020, is being investigated for the prevention of ototoxicity associated with cisplatin chemotherapy. For more information about Decibel Therapeutics, please visit decibeltx.com or follow @DecibelTx.

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Largest-Ever Genetic Study of Autism Yields New Insights – The Southern Maryland Chronicle

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By: Dr. Francis Collins , National Institutes of Health

Anyone whos spent time with people affected by autism spectrum disorder (ASD) can tell you that its a very complex puzzle. The wide variability seen among individuals with this group of developmental brain disorders, which can disrupt communication, behavior control, and social skills, has also posed a huge challenge for researchers trying to identify underlying genetic and environmental factors. So, its no surprise that theres been considerable interest in the recent findings of the largest-ever genetic study of ASD.

In a landmark study that analyzed the DNA of more than 35,000 people from around the world, the NIH-funded international Autism Sequencing Consortium (ASC) identified variants in 102 genes associated with increased risk of developing ASD, up from 65 identified previously. Of the 102 genes, 60 had not been previously linked to ASD and 53 appeared to be primarily connected to ASD as opposed to other types of intellectual disability or developmental delay. It is expected that this newfound genetic knowledge will serve to improve understanding of the complex biological mechanisms involved in ASD, ultimately paving the way for new approaches to diagnosis and treatment.

The study reported in the journalCellwas led by Joseph Buxbaum, Icahn School of Medicine at Mount Sinai, New York; Stephan Sanders, University of California, San Francisco; Kathryn Roeder, Carnegie Mellon University, Pittsburgh, PA; and Mark Daly, Massachusetts General Hospital, Boston, MA and the Broad Institute of MIT and Harvard, Cambridge, MA. These researchers and their teams faced what might seem like a rather daunting task.

While common genetic variants collectively are known to contribute substantially to ASD, rare variants have been recognized individually as more major contributors to a persons risk of developing ASD. The challenge was how to find such rare variantswhether inherited or newly arising.

To do so, the researchers needed to analyze an enormous amount of DNA data. Fortunately, they and their ASC colleagues already had assembled a vast trove of data. Over the last decade, the ASC had collected DNA samples with full consent from thousands of people with and without ASD, including unaffected siblings and parents. All were aggregated with other studies, and, at the time of this investigation, they had gathered 35,584 unique samples. Those included more than 21,000 family-based samples and almost 12,000 samples from people diagnosed with ASD.

In search of rare genetic alterations, they sequenced whole exomes, the approximately 1.5 percent of the genome that codes for proteins. Their search produced a list of 102 ASD-associated genes, including 30 that had never been implicated in any developmental brain disorder previously.

But that was just the beginning. Next, the ASC team dug deeper into this list. The researchers knew from previous work that up to half of the people with ASD also have an intellectual disability or developmental delay. Many of the associated genes overlap, meaning they play roles in both outcomes. So, in one set of analyses, the team compared the list to the results of another genetic study of people diagnosed with developmental delays, including problems with learning or gross motor skills such as delayed walking.

The detailed comparison allowed them to discern genes that are more associated with features of ASD, as opposed to those that are more specific to these developmental delays. It turns out that 49 of the 102 autism-associated genes were altered more often in people with developmental delays than in those diagnosed with ASD. The other 53 were altered more often in ASD, suggesting that they may be more closely linked to this conditions unique features.

Further study also showed that people who carried alterations in genes found predominantly in ASD also had a better intellectual function. They also were more likely to have learned to walk without a developmental delay.

The 102 new genes fell primarily into one of two categories. Many play a role in the brains neural connections. The rest are involved primarily in switching other genes on and off in brain development. Interestingly, they are expressed both in excitatory neurons, which are active in sending signals in the brain and in inhibitory neurons that squelch such activity. Many of these genes are also commonly expressed in the brains cerebral cortex, the outermost part of the brain that is responsible for many complex behaviors.

Overall, these findings underscore that ASD truly does exist on a spectrum. Indeed, there are many molecular paths to this disorder. The ASC researchers continue to collect samples, so we can expect this list of 102 genes will continue to expand in the future.

With these gene discoveries in hand, the researchers will now also turn their attention to unraveling additional details about how these genes function in the brain. The hope is that this growing list of genes will converge on a smaller number of important molecular pathways, pointing the way to new and more precise ways of treating ASD in all its complexity.

Reference:

[1]Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, Peng M, Collins R, Grove J, Klei L, Stevens C, Reichert J, Mulhern MS, Artomov M, Gerges S, Sheppard B, Xu X, Bhaduri A, Norman U, Brand H, Schwartz G, Nguyen R, Guerrero EE, Dias C; Autism Sequencing Consortium; iPSYCH-Broad Consortium, Betancur C, Cook EH, Gallagher L, Gill M, Sutcliffe JS, Thurm A, Zwick ME, Brglum AD, State MW, Cicek AE, Talkowski ME, Cutler DJ, Devlin B, Sanders SJ, Roeder K, Daly MJ, Buxbaum JD.Cell. 2020 Jan 23. {Epub ahead of print]

Links:

NIH Support: National Institute Mental Health; National Human Genome Research Institute

The Southern Maryland Chronicle is a local, small business entrusted to provide factual, unbiased reporting to the Southern Maryland Community.While we look to local businesses for advertising, we hope to keep that cost as low as possible in order to attract even the smallest of local businesses and help them get out to the public. We must also be able to pay employees(part-time and full-time), along with equipment, and website related things. We never want to make the Chronicle a pay-wall style news site.

To that end, we are looking to the community to offer donations. Whether its a one-time donation or you set up a reoccurring monthly donation. It is all appreciated. All donations at this time will be going to furthering the Chronicle through hiring individuals that have the same goals of providing fair, and unbiased news to the community. For now, donations will be going to a business PayPal account I have set-up for the Southern Maryland Chronicle, KDC Designs. All business transactions currently occur within this PayPal account. If you have any questions regarding this you can email me at davidhiggins@southernmarylandchronicle.com

Thank you for all of your support and I hope to continue bringing Southern Maryland the best news possible for a very long time. David M. Higgins II

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Here’s Why Editas Medicine Jumped 45.3% in November – The Motley Fool

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What happened

Shares of Editas Medicine (NASDAQ:EDIT) rose more than 45% last month, according to data fromS&P Global Market Intelligence. The gene editing pioneer rose for reasons both internal and external.

The business announced an amended collaboration with Celgene (NASDAQ:CELG) for developing engineered immune cells and will receive an upfront payment of $70 million as a result of the new agreement. The company also enjoyed a bump from peer CRISPR Therapeutics, which reported promising results for the first two patients dosed with its lead drug candidate, CTX001. Investors took that as evidence that CRISPR-based medicines might be the real deal, although that's a mighty big leap.

The gene editing company also reported a business update and operating results for the third quarter of 2019, but there wasn't much to report for the pre-commercial entity.

Image source: Getty Images.

Editas Medicine started working with Juno Therapeutics, now owned by Celgene, in 2015. The idea was to combine the gene-editing platform of the former with the immunotherapy leadership of the latter. That's still the case, but the amended agreement scales back the specific types of engineered T cells that will be developed in the collaboration. It's a subtle, but potentially important, detail with (beneficial) ramifications for the long-term future of Editas Medicine.

It appears that the $70 million upfront payment was made in part to compensate Editas Medicine for the difference. After all, the company had already received $70 million in upfront, milestone, and execution payments under the original collaboration agreement. It's not immediately clear how the financial terms have changed, if they did at all, but the gene editing pioneer originally stood to receive up to $920 million in milestone payments.

Beyond that, there were several other updates provided in November:

The gene-editing landscape is still in the earliest stages of development. While CRISPR Therapeutics has taken an early lead as the top gene editing company, Editas Medicine is hoping to prove that its direct delivery approach will prove equally effective. The trial results the company will present in the coming years will become crucial tests for the future of CRISPR-gene editing, especially with competing techniques on the horizon.

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Here's Why Editas Medicine Jumped 45.3% in November - The Motley Fool

Gene fragment could explain link between autism and cognitive difficulties: U of T study – News@UofT

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Autism is associated with brilliance as well as cognitive difficulty, but how either scenario plays out in the brain is not clear. Now a study by University of Toronto researchers has found that a tiny gene fragment impacts the brain in a way that could explain swathes of autism cases that come with mental health challenges.

Researchers led byBenjamin Blencowe, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research and Faculty of Medicine, andSabine Cordes, a senior investigator at Sinai Health Systems Lunenfeld-Tanenbaum Research Institute (LTRI), have identified a short gene segment that is crucial for brain development and information processing. Writing in the journalMolecular Cell, the researchersdescribe how an absence of this segment is sufficient to induce altered social behaviour a hallmark of autism in mice, as well as learning and memory deficits, which are seen in a subset of autism cases.

Best known for causing difficulties in social interaction and communication, autism is thought to arise from mishaps in brain wiring during development. It can strike in various ways. Those who experience it can have superior mental ability or need full-time care. Where on the autism spectrum a person falls depends in large part on their genetics, but most cases are idiopathic, or of unknown genetic origin.

Its very important to understand the mechanisms that underlie autism, especially in idiopathic forms where it is not clear what the underlying causes are, saysThomas Gonatopoulos-Pournatzis, a research associate in Blencowes lab and lead author of the study. Not only have we identified a new mechanism that contributes to this disorder, but our work may also offer a more rational development of therapeutic strategies.

Blencowes team had previously uncovered a link between autism and short gene segments, known as microexons, that are predominantly expressed in the brain. Through a process known as alternative splicing, microexons are either spliced in or left out from the final gene transcript before it is translated into a protein. Although small, microexons can have dramatic effects by impacting a proteins ability to bind its partners as required during brain development. However, how individual microexons contribute to autism is not clear.

The team focused on a specific microexon located in a gene known as eIF4G, which is critical for protein synthesis in the cell. They found that this microexon is overwhelmingly excluded from eIF4G gene transcripts in the brains of autistic individuals.

Hippocampal neurons from a normal mouse (above) and a mouse bred to lack the eIF4G microexon (below). The latter contains fewer particles that represent paused protein synthesis machineries. In these mice, higher levels of protein synthesis in neurons lead to disrupted brain waves and autistic-like behaviors as well as cognitive deficits down the line.

To test if the eIF4G microexon is important for brain function, Gonatopoulos-Pournatzis, together with Cordess team, bred mice that lack it. These mice showed social behaviour deficits, such as avoiding social interaction with other mice, establishing a link between the eIFG4 microexon and autistic-like behaviours.

A surprise came when the researchers found that these mice also performed poorly in a learning and memory test, which measures the animals ability to associate an environment with a stimulus.

We could not have imagined that a single microexon would have such an important impact not only on social behaviour but also on learning and memory, says Gonatopoulos-Pournatzis.

Further analysis revealed that the microexon encodes a part of eIF4G that allows it to associate with the Fragile X mental retardation protein, or FMRP, which is missing from people affected with Fragile X syndrome, a type of intellectual disability. About a third of individuals with Fragile X have features of autism but the link between the two remained unclear until now.

FMRPandeIF4G work together to act as a brake to hold off protein synthesis until new experience comes along, as the brake is removed by neural activity, the researchers also found.

Its important to control brain responses to experience, says Gonatopoulos-Pournatzis. This brake in protein synthesis is removed upon experience and we think it allows formation of new memories.

Without the microexon, however, this brake is weakened and what follows is increased protein production. The newly made proteins, identified in experiments performed withAnne-Claude Gingras, a senior investigator at LTRI and a professor in the department of molecular genetics, form ion channels, receptors and other signaling molecules needed to build synapses and for them to function properly.

However, making too many of these proteins is not a good thing because it leads to the disruption of the type of brain waves involved in synaptic plasticity and memory formation. This is revealed by electrode recordings of mouse brain slicesin experiments performed by the teams ofGraham Collingridge, a senior investigator at LTRI and a professor in the department of physiology, andMelanie Woodin, a professor of cell and systems biology at U of T and the dean of the Faculty of Arts & Science.

Moreover, an excess of similar kinds of proteins occurs in the absence of FMRP, suggesting a common molecular mechanism for Fragile X and idiopathic autism.

Researchers believe that their findings could help explain a substantial proportion of autism cases for which no other genetic clues are known. The findings also open the door to the development of new therapeutic approaches. One possibility is to increase the splicing of the eIF4G microexon in affected individuals using small molecules as a way to improve their social and cognitive deficits, Blencowe said.

The study would not have been possible without a close collaboration among multiple teams contributing diverse expertise. Blencowe and Gonatopoulos-Pournatzis also worked closely withJulie Forman-Kay, a professor of biochemistry and program head and senior scientist in the molecular medicine program at the Hospital for Sick Children, andNahum Sonenberg, a professor of biochemistry at McGill University.

The research was made possible by grants from the Canadian Institutes of Health Research, Simons Foundation and theCanada First Research Excellence Fund Medicine by Design program, among others.

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Gene fragment could explain link between autism and cognitive difficulties: U of T study - News@UofT

‘Beethoven mice’ prevent deafness: Medicine’s next big thing? – WNDU-TV

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Researchers at Harvard Medical School and Boston Children's Hospital have found a potential treatment for hereditary deafness, the same condition thought to have caused Ludwig van Beethoven to lose his hearing.

The scientists are using a new gene-editing approach that they say could someday prevent profound hearing loss.

Beethoven's Symphony No. 5 is a cornerstone of classical music. It is hard to believe the composer was almost completely deaf from a genetic condition when he finished it.

"These children are born fairly normal, but then over 10 or 20 years, they lose their hearing," Harvard neurobiology professor Dr. David Corey.

Aptly named "Beethoven mice" might hold the key to a potential cure. Scientists believe the animals have a defect in the same gene that may have caused Beethoven's deafness.

"Our genome is composed of about 3 billion letters of DNA that together make up 20,000 genes," Corey explained. "For the disease we're studying, one mistake in the DNA in one of the genes causes deafness."

Researchers identified that hearing gene called TMC1. It's a gene that comes in pairs.

Using a newly refined gene-editing system, they disabled the defective copy of the TMC1 gene, leaving the good gene in place.

"By eliminating just the bad copy, that would be sufficient to preserve hearing," Corey said.

The scientists then delivered the edited DNA back into the cells of the mice and tested their hearing.

"We put little scalp electrodes on the back of the head, play sounds into the ear and can measure the brain activity in response," Boston Children's Hospital professor of otolaryngology Dr. Jeffrey Holt said.

Researchers say the mice were able to hear sounds as low as 45 decibels, the level of a quiet conversation.

"This could be life-changing," Holt said.

A famed composer, his namesake mice and a team of scientists are using cutting-edge medicine to help people who would otherwise go deaf.

The scientists say this research paves the way for using the new editing system to treat as many as 3,500 other genetic diseases that are caused by one defective copy of a gene.

It's important to note that Holt holds patents on TMC1 gene therapy.

MEDICAL BREAKTHROUGHSRESEARCH SUMMARYTOPIC: BEETHOVEN MICE PREVENT DEAFNESS: MEDICINE'S NEXT BIG THING?REPORT: MB #4689

BACKGROUND: In the United States, hearing loss affects 48 million people and can occur at birth or develop at any age. One out of three people over the age 65 have some degree of hearing loss, and two out of three people over the age 75 have a hearing loss. Children in the United States are estimated at 3 million in having a hearing loss, and of those, 1.3 million are under the age of three. One of the leading causes of hearing loss is noise, and while preventable, can be permanent. Listening to a noisy subway for just 15 minutes a day over time can cause permanent damage to one's hearing. Listening to music on a smartphone at high volumes over time can cause permanent damage to one's hearing as well. The number of people with hearing loss is more than those living with Parkinson's, epilepsy, Alzheimer's, and diabetes combined. (Source: https://chchearing.org/facts-about-hearing-loss/ and https://hearinghealthfoundation.org/hearing-loss-tinnitus-statistics/)

TREATMENTS: The treatment you receive will depend on the cause and severity of the hearing loss. A reversible cause of hearing loss is earwax blockage where your doctor may remove earwax using suction or a small tool with a loop on the end. Some types of hearing loss can be treated with surgery, including abnormalities of the ear drum or bones of hearing (ossicles). Repeated infections with persistent fluid may result in your doctor inserting small tubes to help your ears drain. If your hearing loss is due to damage to your inner ear, a hearing aid can be helpful. With more severe hearing loss and limited benefit from conventional hearing aids, a cochlear implant may be an option. Unlike a hearing aid that amplifies sound and directs it into your ear canal, a cochlear implant bypasses damaged or nonworking parts of your inner ear and directly stimulates the hearing nerve. (Source: https://www.mayoclinic.org/diseases-conditions/hearing-loss/diagnosis-treatment/drc-20373077)

GENE EDITING WITH CRISPR: Scientists at Harvard Medical School and Boston Children's Hospital have used a newly tailored gene-editing approach in mice thought to have the same genetic defect that caused famed composer Beethoven to go deaf in adulthood. CRISPR-Cas9 gene editing works by using a molecule to identify the mutant DNA sequence. Once the system pinpoints the mutated DNA, the cutting enzyme, or Cas9, "snips" it; however, the gene editors are not always accurate. Sometimes, the guide RNA that leads the enzyme to the target site and the Cas9 enzyme are not precise and could cut the wrong DNA. The Harvard and Boston Children's scientists are using a modified Cas9 enzyme derived from Staphylococcus aureus bacteria that they are finding is significantly more accurate. (Source: https://hms.harvard.edu/news/saving-beethoven)

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JAK2 gene – Genetics Home Reference – NIH

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Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations in the JAK2 gene are associated with essential thrombocythemia, a disorder characterized by an increased number of platelets, the blood cell fragments involved in normal blood clotting. The most common mutation (written as Val617Phe or V617F) replaces the protein building block (amino acid) valine with the amino acid phenylalanine at position 617 in the protein. This particular mutation is found in approximately half of people with essential thrombocythemia. A small number of affected individuals have a somatic mutation in another part of the JAK2 gene known as exon 12.

The V617F JAK2 gene mutation results in the production of a JAK2 protein that is constantly turned on (constitutively activated), which, in essential thrombocythemia, leads to the overproduction of abnormal blood cells called megakaryocytes. Because platelets are formed from megakaryocytes, the overproduction of megakaryocytes results in an increased number of platelets. Excess platelets can cause abnormal blood clotting (thrombosis), which leads to many signs and symptoms of essential thrombocythemia.

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$125 million for Inscripta may usher in the next wave of genetic engineering – Yahoo Tech

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In these waning days of the second decade of the twenty-first century, technologists and investors are beginning to lay the foundations for new, truly transformational technologies that have the potential to reshape entire industries and rewrite the rules of human understanding.

It may sound lofty, but new achievements from businesses and research institutions in areas like machine learning, quantum computing and genetic engineering mean that the futures imagined in science fiction are simply becoming science.

And among the technologies that could potentially have the biggest effect on the way we live, nothing looms larger than genetic engineering.

Investors and entrepreneurs are deploying hundreds of millions of dollars to create the tools that researchers, scientists and industry will use to re-engineer the building blocks of life to perform different functions in agriculture, manufacturing and medicine.

One of these companies, 10X Genomics, which gives users hardware and software to determine the functionality of different genetic code, has already proven how lucrative this early market can be. The company, which had its initial public offering earlier this year, is now worth $6 billion.

Another, the still-private company Inscripta, is helmed by a former 10X Genomics executive. The Boulder, Colo.-based startup is commercializing a machine that can let researchers design and manufacture small quantities of new organisms. If 10X Genomics is giving scientists and businesses a better way to read and understand the genome, then Inscripta is giving those same users a new way to write their own genetic code and make their own organisms.

It's a technology that investors are falling over themselves to finance. The company, which closed on $105 million in financing earlier in the year (through several tranches, which began in late 2018), has just raised another $125 million on the heels of launching its first commercial product. Investors in the round include new and previous investors like Paladin Capital Group, JS Capital Management, Oak HC/FT and Venrock.

"Biology has unlimited potential to positively change this world," says Kevin Ness, the chief executive of Inscripta . "It's one of the most important new technology forces that will be a major player in the global economy."

Ness sees Inscripta as breaking down one of the biggest barriers to the commercialization of genetic engineering, which is access to the technology.

While genome centers and biology foundries can manufacture massive quantities of new biological material for industrial uses, it's too costly and centralized for most researchers. "We can put the biofoundry capabilities into a box that can be pushed to a global researcher," says Ness.

Earlier this year, the company announced that it was taking orders for its first bio-manufacturing product; the new capital is designed to pay for expanding its manufacturing capabilities.

That wasn't the only barrier that Inscripta felt that it needed to break down. The company also developed a proprietary biochemistry for gene editing, hoping to avoid having to pay fees to one of the two laboratories that were engaged in a pitched legal battle over who owned the CRISPR technology (the Broad Institute and the University of California both had claims to the technology).

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Type 1 diabetes cured in mice using gene therapy – Medical News … – Medical News Today

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Researchers from the University of Texas Health Science Center in San Antonio have found a way to cure type 1 diabetes in mice. It is hoped that the novel technique - which boosts insulin secretion in the pancreas - will reach human clinical trials in the next 3 years.

Study co-author Dr. Bruno Doiron, Ph.D., of the Division of Diabetes, and colleagues recently reported their findings in the journal Current Pharmaceutical Biotechnology.

Type 1 diabetes is estimated to affect around 1.25 million children and adults in the United States. Onset of the condition is most common in childhood, but it can arise at any age.

In type 1 diabetes, the immune system destroys the insulin-producing beta cells of the pancreas. Insulin is the hormone that regulates blood glucose levels. As a result, blood glucose levels become too high.

There is currently no cure for type 1 diabetes; the condition is managed through diet and insulin therapy. However, in recent years, researchers have investigated replacing beta cells as a means of eradicating type 1 diabetes once and for all.

Dr. Doiron and colleagues have taken a different approach with their new study. The team reveals how they used a method called gene transfer to coax other pancreatic cells into producing insulin.

Using this technique, the researchers have managed to cure type 1 diabetes in mice, bringing us one step closer to curing the condition in humans.

The gene transfer technique - called Cellular Networking, Integration and Processing - involves introducing specific genes into the pancreas using a virus as a vector.

The team notes that beta cells are rejected in patients with type 1 diabetes. With the gene transfer method, the newly introduced genes encourage non-beta cells to produce insulin, without any side effects.

"The pancreas has many other cell types besides beta cells, and our approach is to alter these cells so that they start to secrete insulin, but only in response to glucose [sugar]," says study co-author Dr. Ralph DeFronzo, chief of the Division of Diabetes. "This is basically just like beta cells."

Upon testing their technique on mouse models of type 1 diabetes, the researchers found that they were able to induce long-term insulin secretion and blood glucose regulation, with no adverse side effects.

"It worked perfectly. We cured mice for 1 year without any side effects. That's never been seen. But it's a mouse model, so caution is needed. We want to bring this to large animals that are closer to humans in physiology of the endocrine system."

Dr. Bruno Doiron, Ph.D.

Importantly, the researchers point out that the gene transfer therapy only releases insulin in response to blood sugar, so it has the potential to transform current treatments for type 1 diabetes.

"A major problem we have in the field of type 1 diabetes is hypoglycemia (low blood sugar)," says Dr. Doiron. "The gene transfer we propose is remarkable because the altered cells match the characteristics of beta cells. Insulin is only released in response to glucose."

Not only could the novel strategy yield a cure for type 1 diabetes, but the researchers say that it may also eliminate the need for insulin therapy in patients with type 2 diabetes, which arises when the body is unable to use insulin effectively.

It will cost around $5 million to test their technique in large animal models, but the researchers are confident that this can be achieved. They hope to reach human clinical trials within the next 3 years.

Learn how maternal omega-3 intake may influence the risk of type 1 diabetes in infants.

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Sangamo Therapeutics And Pfizer Announce Collaboration For Hemophilia A Gene Therapy – PR Newswire (press release)

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"With a long-standing heritage in rare disease, including hemophilia, Pfizer is an ideal partner for our Hemophilia A program," said Dr. Sandy Macrae, Sangamo's Chief Executive Officer. "We believe Pfizer's end-to-end gene therapy capabilities will enable comprehensive development and commercialization of SB-525, which could potentially benefit Hemophilia A patients around the world. This collaboration also marks an important milestone for Sangamo as we continue to make progress in the translation of our ground-breaking research into new genomic therapies to treat serious, genetically tractable diseases."

Under the terms of the collaboration agreement, Sangamo will receive a $70 million upfront payment from Pfizer. Sangamo will be responsible for conducting the SB-525 Phase 1/2 clinical study and certain manufacturing activities. Pfizer will be operationally and financially responsible for subsequent research, development, manufacturing and commercialization activities for SB-525 and additional products, if any. Sangamo is eligible to receive potential milestone payments of up to $475 million, including up to $300 million for the development and commercialization of SB-525 and up to $175 million for additional Hemophilia A gene therapy product candidates that may be developed under the collaboration. Sangamo will also receive tiered double-digit royalties on net sales. Additionally, Sangamo will be collaborating with Pfizer on manufacturing and technical operations utilizing viral delivery vectors.

Gene therapy is a potentially transformational technology for patients, focused on highly specialized, one-time, treatments that address the root cause of diseases caused by genetic mutation. The technology involves introducing genetic material into the body to deliver a correct copy of a gene to a patient's cells to compensate for a defective one. The genetic material can be delivered to the cells by a variety of means, most frequently using a viral vector such as rAAV. There have been no gene therapy products approved in the U.S. to date.

Hemophilia A is a rare blood disorder caused by a genetic mutation resulting in insufficient activity of Factor VIII, a blood clotting protein the body uses to stop bleeding. There are approximately 16,000 patients in the U.S. and more than 150,000 worldwide with Hemophilia A. SB-525 is comprised of a rAAV vector carrying a Factor VIII gene construct driven by a proprietary, synthetic, liver-specific promoter. The U.S. Food and Drug Administration has cleared initiation of human clinical trials for SB-525, which also has been granted orphan drug designation. Sangamo is on track this quarter to start a Phase 1/2 clinical trial to evaluate safety and to measure blood levels of Factor VIII protein and other efficacy endpoints.

Conference CallSangamo will host a conference call today, May 10, 2017 at 5:00 p.m. ET, which will be open to the public, to discuss the details of the collaboration and the Company's first quarter business and financial results. The call will also be webcast live and can be accessed via a link the Sangamo Therapeutics website in the Investors and Media section under Events and Presentations. A replay of the webcast will also be available for one week after the call.

The conference call dial-in numbers are (877) 377-7553 for domestic callers and (678) 894-3968 for international callers. The conference ID number for the call is 15225000. For those unable to listen in at the designated time, a conference call replay will be available for one week following the conference call, from approximately 8:00 p.m. ET on May 10, 2017 to 11:59 p.m. ET on May 17, 2017. The conference call replay numbers for domestic and international callers are (855) 859-2056 and (404) 537-3406, respectively. The conference ID number for the replay is 15225000.

About Sangamo Therapeutics Sangamo Therapeutics, Inc. is focused on translating ground-breaking science into genomic therapies that transform patients' lives using the company's industry leading platform technologies in genome editing, gene therapy, gene regulation and cell therapy. The Company is advancing Phase 1/2 clinical programs in Hemophilia A and Hemophilia B, and lysosomal storage disorders MPS I and MPS II. Sangamo has a strategic collaboration with Pfizer for Hemophilia A, with Bioverativ Inc. for hemoglobinopathies, including beta thalassemia and sickle cell disease, and with Shire International GmbH to develop therapeutics for Huntington's disease. In addition, it has established strategic partnerships with companies in non-therapeutic applications of its technology, including Sigma-Aldrich Corporation and Dow AgroSciences. For more information about Sangamo, visit the Company's website at http://www.sangamo.com.

Forward Looking Statements This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation references relating to the collaboration agreement with Pfizer, potential milestone payments and royalties under the collaboration agreement, ability of the collaboration to advance and commercialize SB-525 as a treatment for Hemophilia A, research and development of therapeutic applications of Sangamo's genomic therapy platforms, the expected timing of clinical trials of lead programs, including SB-525 and the release of data from these trials, the impact of Sangamo's clinical trials on the field of genetic medicine and the benefit of orphan drug status. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to substantial dependence on the clinical success of lead therapeutic programs, the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo Therapeutics, Inc. assumes no obligation to update the forward-looking information contained in this press release.

Pfizer and Rare DiseaseRare disease includes some of the most serious of all illnesses and impacts millions of patients worldwide,i representing an opportunity to apply our knowledge and expertise to help make a significant impact on addressing unmet medical needs. The Pfizer focus on rare disease builds on more than two decades of experience, a dedicated research unit focusing on rare disease, and a global portfolio of multiple medicines within a number of disease areas of focus, including hematology, neuroscience, and inherited metabolic disorders.ii

Pfizer Rare Disease combines pioneering science and deep understanding of how diseases work with insights from innovative strategic collaborations with academic researchers, patients, and other companies to deliver transformative treatments and solutions. We innovate every day leveraging our global footprint to accelerate the development and delivery of groundbreaking medicines and the hope of cures.

Click here to learn more about our Rare Disease portfolio and how we empower patients, engage communities in our clinical development programs, and support programs that heighten disease awareness and meet the needs of patient families.

Pfizer Inc: Working together for a healthier worldAt Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. For more information, please visit us at http://www.pfizer.com. In addition, to learn more, follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.

Pfizer Disclosure Notice: The information contained in this release is as of May 10, 2017. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about an investigational Hemophilia A agent, SB-525, including its potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical study commencement and completion dates as well as the possibility of unfavorable study results, including unfavorable new clinical data and additional analyses of existing clinical data; risks associated with initial data, including the risk that the final results of the Phase I/2 study for SB-525 and/or additional clinical trials may be different from (including less favorable than) the initial data results and may not support further clinical development; whether and when any applications may be filed with regulatory authorities for SB-525; whether and when regulatory authorities may approve any such applications, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted; decisions by regulatory authorities regarding labeling and other matters that could affect the availability or commercial potential of SB-525; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned "Risk Factors" and "Forward-Looking Information and Factors That May Affect Future Results", as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at http://www.sec.gov and http://www.pfizer.com.

i Rare Disease: Facts and Statistics. http://globalgenes.org/rare-diseases-facts-statistics. Accessed September 7, 2016. ii Pfizer Inc. Rare Disease. http://www.pfizer.com/health-and-wellness/health-topics/rare-diseases/areas-of-focus. Accessed December 20, 2016.

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/sangamo-therapeutics-and-pfizer-announce-collaboration-for-hemophilia-a-gene-therapy-300455555.html

SOURCE Sangamo Therapeutics, Inc.

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Genetic test for anal cancer could identify those at high risk – Medical Xpress

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May 25, 2017

A new test, based on a patient's epigenetics, could be an accurate and inexpensive way to find and treat those at highest risk of anal cancer - a disease with growing incidence in women, men who have sex with men (MSM) and people with HIV.

The early research by Queen Mary University of London (QMUL), which was funded by Cancer Research UK, finds that the test could lead to a reduction in painful procedures and minimise the over-treatment of people at low risk.

Anal cancer is mostly caused by human papillomavirus (HPV) - the same virus that causes cervical cancer. In 2014, the UK had around 1,300 new cases of anal cancer and 360 deaths. In addition to rising levels in women and MSM, anal cancer is more common in HIV-positive MSM with around 100 cases per 100,000, compared to 25 in HIV-negative MSM, and only 1.5 in men in general.

Diagnosis presents many challenges. Full biopsies are painful, and taking a small sample of cells ('cytology') is problematic because lesions can be hidden and clinicians give varying interpretations of results. High-resolution anoscopy, where the anal canal is examined with a high resolution magnifying instrument, is often used as the primary screening tool for high-risk populations but is uncomfortable for the patient, expensive, complex and generates subjective results.

Lead researcher Professor Attila Lorincz from QMUL said: "The widespread over-treatment of anal precancerous lesions is necessary today because we don't know which ones will progress to cancer. But this creates a large burden on anoscopy clinics in the UK and the procedures can be detrimental to people's quality of life. Many people are undergoing these procedures unnecessarily, so what we really need is precision medicine to identify those who do need treatment."

The research, published in the journal Oncotarget, involved studying anal biopsy specimens from 148 patients in London, including 116 men (mostly MSM). The specimens were analysed to look for genetic markers that may be associated with the presence of anal cancer.

The team specifically looked at the patients' epigenetics and found that all of the anal cancers showed the presence of specific epigenetic methylation markers on the patients' EPB41L3 gene (a tumour suppressor gene) and also on certain regions of their viral HPV genome.

The results suggests that epigenetic testing may be an accurate and thorough method to indicate whether a patient's lesions are destined to progress to anal cancer. This could reduce the costs, pain and anxiety from other methods of diagnosis, and minimise over-treatment of low risk people.

Professor Lorincz added: "We thought this would require a complicated genomic signature involving hundreds of genes, so we were surprised that we could get such an accurate prediction from just two biomarker genes. That's important because the expected cost of the test will be fairly low.

"Now that we can identify those at risk, and conversely, those not at risk, we hope to see a big improvement, by making sure that anoscopies and laser or chemical surgery are only given to those who need it."

Once developed, the test would involve taking a small sample of cells from the anal canal via a swab and then sending the sample off to a laboratory for epigenetic analysis.

While a test could be developed within five years, the researchers caution that the results first need to be confirmed in a much larger study across the UK, and repeated using swab samples rather than the biopsies which were used in the current study.

Dr Rachel Orritt, Cancer Research UK's health information officer, said: "This study builds on what we already know about the link between changes to cell DNA and cervical cancer, and shows that similar changes to the DNA in anal cells could suggest anal cancer.

"If other studies confirm and build upon these findings, this promising research could be used to develop a less invasive method to help doctors identify people who are at a higher risk of anal cancer and avoid unnecessary procedures for those who are at a lower risk."

The researchers say that these types of biomarker - epigenetic methylation biomarkers - are important in a large number of other diseases, and could lead to a completely new approach to diagnostics and drug therapy.

Professor Lorincz explained: "These could be the early stages of a discovery of a universal set of biomarkers for any cancer. And there may be implications on therapies, as there are new techniques where the epigenetic pathway can be targeted by drugs. This is going to be the hot new area going forward in the next 15 years, so people need to be paying attention to this space."

Explore further: Most anal lesions don't cause cancer in men, research shows

More information: 'Methylation of HPV and a tumor suppressor gene reveals anal cancer and precursor lesions'. Attila T Lorincz, Mayura Nathan, Caroline Reuter, Rhian Warman, Mohamed A Thaha, Michael Sheaff, Natasa Vasiljevic, Amar Ahmad, Jack Cuzick, Peter Sasieni. Oncotarget, 2017.

(HealthDay) -- Anal human papillomavirus (HPV) infection and precancerous lesions are common among gay and bisexual men, but most of these cases will not progress to anal cancer, a new analysis of earlier research shows.

(HealthDay) -- Women with HIV are at increased risk for anal cancer, a new study finds.

Researchers at Women & Infants Hospital, a Care New England hospital, recently published the results of a study demonstrating a connection between anal cancer and human papillomavirus (HPV) infection.

The increase in anal cancer incidence in the U.S. between 1980 and 2005 was greatly influenced by HIV infections in males, but not females, according to a study published October 5 in the Journal of the National Cancer Institute.

(HealthDay)Anal cancer rates are on the rise in many countries. But vaccination against human papillomavirus (HPV)a virus linked to the development of anal cancermay help curb rates of the disease, a new study suggests.

A vaccine routinely used to shield against cervical cancer caused by the human papillomavirus also reduces women's risk of anal cancer, a study published by the journal The Lancet Oncology on Tuesday says.

Cancer is an extremely complex disease, but its definition is quite simple: the abnormal and uncontrollable growth of cells. Researchers from the University of Rochester's Center for RNA Biology have identified a new way ...

All cancer tumors have one thing in common - they must feed themselves to grow and spread, a difficult feat since they are usually in a tumor microenvironment with limited nutrients and oxygen. A study at The University of ...

A first-of-a-kind neural stem cell therapy that works with a common cold virus to seek out and attack a lethal and aggressive brain cancer is being tested at Northwestern Medicine in a Phase I clinical trial for patients ...

Scientists say they've developed a new blood test for identifying pancreatic cancera step that might eventually allow earlier diagnosis.

While target therapies directed toward genetic mutations that drive a tumor's growth have significantly improved the outlook for many patients, they have not been as successful in controlling brain metastases in several types ...

Cancers can be viewed as complex dynamic systems because they have many interacting parts that can change over time and space. Perhaps the most well-known complex dynamic system is the weather and, similar to weather forecasting, ...

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All women should get tested for cancer gene, says scientist who led discovery – Champaign/Urbana News-Gazette

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URBANA The scientist who led the discovery of genes responsible for 15 percent of all breast cancers says every woman age 30 and over should be tested for those genetic mutations, regardless of family history.

And women with a family history of reproductive cancer not linked to the BRCA1 or BRCA2 genes should get more extensive genetic testing, says Mary-Claire King, professor of genome sciences and medicine at the University of Washington School of Medicine.

King spoke at the University of Illinois on Monday afternoon at a talk marking the 10th anniversary of the Institute of Genomic Biology.

King said genetic testing is important for cancer prevention and treatment and for families themselves, and should be part of every woman's complete medical care. More than 40,000 women die of breast cancer, and 14,000 from ovarian cancer, each year.

"It's technically easy to do. It's not expensive to do," King said. "The major cost is not the testing itself. The major cost is how to care for women who turn out to have mutations, because they have to be cared for."

But preventive surgery is much less expensive than caring for a cancer patient, she said.

King and her colleagues spent 17 years finding and mapping the BRCA1 gene, which can cause both breast and ovarian cancer. In 1994, the gene was successfully cloned, and the closely related BRCA2 gene was cloned the following year. The discovery revolutionized genetics and cancer treatment.

Mutations in the gene interfere with the repair of DNA, deoxyribonucleic acid, the hereditary material in every human cell.

Women, or men, who carry the mutation have a higher risk of developing cancer. One study showed 80 percent of women with the mutation developed breast or ovarian cancer by age 80. In some families, there's also an increased risk of pancreatic or prostate cancer with the genetic mutations, though not as large, she said.

The mutation can be inherited through a father, not just a mother. One big challenge is getting physicians to ask patients about a history of breast or ovarian cancer in their father's family, not just their mother's, King said.

Because families are smaller than in the past, a history of breast or ovarian cancer might not be as obvious as it was in the 19th or early 20th centuries, when multiple family members may have gotten the disease, she said.

"In about 50 percent of the women in whom we identify inherited mutations of these genes, there's no immediate family history of breast or ovarian cancer that would have triggered concern," she said.

Before the work of King and other geneticists, scientists had different theories about the causes of breast cancer, from diet and stress to the use of contraceptives to a possible genetic link.

King started by identifying hundreds of families with long histories of breast and ovarian cancer.

She was able to show linkages across multiple generations and eventually narrowed the gene to a specific chromosome, then went on to isolate the gene in the lab.

There are more than 1,000 different mutations within the BRCA1 and BRCA2 genes, and more left to discover, she said.

King and her colleagues have now studied more than 5,000 families, including some "mystery families" where no common genetic mutation has been found. Researchers are sequencing the entire genome for women in those families, she said.

The cost of genetic sequencing has dropped precipitously since the Supreme Court ruled in 2013 that human genes cannot be patented, she said. The cost, around $250, is well within the budget of middle-class women, but "DNA repair does not care if you are middle class or not," she said.

It should be considered a public health issue, similar to vaccinations for contagious diseases, so every women has access to screening, she said.

The disease is an important public health problem, the risk of disease due to genetic mutation is high, the mutations responsible for the disease can be accurately identified, and effective treatments exist for women identified at risk, she said.

"They are not pretty, but they exist, and they work," she said.

Preventive surgery, such as a mastectomy or the removal of the ovaries and fallopian tubes between the ages of 35 and 40, has proven to drastically reduce cancer risk, she said.

And the study of how the BRCA1 and BRCA2 genes work has led to chemotherapy treatments that effectively target the tumors, she said.

Studies of women with the genetic mutation show that those born more recently have a higher risk of developing breast cancer, even if it's the same mutation in the same family, King said.

"This difference cannot be genetics. The difference must be changes in lifestyle," she said.

Research has shown that the earlier a girl starts her period, and the later she has her first child, her cancer risk increases. At the start of the 20th century, the average girl started menstruating at age 16 and had her first child by age 21. Today, the average start is about age 11, and more women are postponing childbirth until after age 30, King said.

Other than the genetic mutations, much of the increase in breast cancer worldwide can be pinned on those factors, she said.

UI Professor Gene Robinson, director of the Institute for Genomic Biology, said King's work has "changed the way we think of the role of genes in diseases that have both genetic and environmental causes," and how genetic therapy can help cancer patients make decisions about their health.

King has also used genetic science for humanitarian causes, to identify victims of human rights abuses in Rwanda, Serbia, the Philippines and South America, he said.

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All women should get tested for cancer gene, says scientist who led discovery - Champaign/Urbana News-Gazette

Ambry Genetics Recruits Patient Cohorts to Discover New Links between Genes and Autism – Yahoo Finance

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ALISO VIEJO, Calif.--(BUSINESS WIRE)--

Ambry Genetics Corporation (Ambry) is calling on psychiatrists, psychologists and behavioral specialists to encourage their patients with autism, along with their family members, to sign up for a new study conducted through Ambrys data sharing program, AmbryShare. With this program, Ambry is taking a step towards discovering possible associations between genes and autism, so clinicians can provide their patients with targeted treatments and therapies much earlier in life.

Whats unique about AmbryShares approach is that we collect genetic information from clinics and families from all over the world to answer questions that cant be answered with just a handful of patients, said Brigette Tippin Davis, PhD, Ambrys Director of Emerging Genetic Medicine. The great thing about Ambry partnerships is that we are building connections between research institutions and empowering them to develop new approaches to treating patients with autism based on genetic profiles.

So far, dozens of behavioral clinics and other medical offices have contributed to AmbryShare studies by encouraging participation from their patients. Ambry strives to enroll more than 10,000 patients from clinics nationally and internationally.

Genetic testing would allow us to personalize treatment from a genetic profile and optimize it together with our rich behavioral data, said Dennis Dixon, PhD, Chief Strategy Officer at Center for Autism and Related Disorders (CARD). I really value working with Ambry, knowing this data will have an impact on treatment for our patients and then will still be available for other researchers to access to answer additional research questions. As we each put more samples in, it increases the overall likelihood that were going to find something that really makes a difference.

One in 64 children in the United States is diagnosed with an autism spectrum disorder (ASD), which can impact social interaction, communication and behavior. Genetic testing can help identify an underlying cause in up to 40% of autism spectrum disorders. Some genetic causes include chromosome microdeletions/microduplications, fragile X syndrome, Angelman syndrome, and tuberous sclerosis. New gene discovery can allow clinicians to determine their patients course of treatment and the gene-disease relationship associated with their individual case of autism. Through the recruitment of a massive cohort, more data will be collected to discover more genes, develop medical management plans and enact preventive strategies.

The scientists need the data to be out there, said Charles Dunlop, Ambrys President and Chairman. We need to know what these diseases are actually doing, what causes them, what gene mutations are associated with them so we can move forward as an industry and move onto the next phase where there is no disease of any kind. A phase where pharmaceutical researchers know exactly what to do, or exactly what problems theyre trying to solve at a minutiae levelthats when the cures come.

In 2016, Mayo Clinic and University of Utah collaborated with Ambry on a new research study of more than 60,000 patients to help refine breast cancer risk estimates from predisposition genes that are either previously lacking data or have limited data. The study, Breast cancer risks associated with mutations in cancer predisposition genes identified by clinical genetic testing of 60,000 breast cancer patients represented the largest genetic study of women with hereditary breast cancer. The large amount of data was able to provide researchers with new information about genes that contributed to breast cancer risk. Ambry wants to provide researchers with the same capabilities for autism.

Since 2001, Ambry has been dedicated to scientific research to help empower the scientific community and refine clinician management guidelines so patients may receive tailored medical management. AmbryShares initial launch in 2016 provided scientific researchers and clinicians with the largest open, de-identified database of hereditary breast and ovarian cancer cohorts with the goal of achieving a greater understanding of human disease.

For more information and to enroll in the AmbryShare autism study, visit the AmbryShare portal here.

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ABOUT AMBRY GENETICS

Ambry Genetics is both College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified. Ambry leads in clinical genetic diagnostics and genetics software solutions, combining both to offer the most comprehensive testing menu in the industry. Ambry has established a reputation for sharing data while safeguarding patient privacy, unparalleled service, and responsibly applying new technologies to the clinical molecular diagnostics market. For more information about Ambry Genetics, visit http://www.ambrygen.com.

About the Center for Autism and Related Disorders (CARD)

CARD treats individuals of all ages who are diagnosed with autism spectrum disorder (ASD) at treatment centers around the globe. CARD was founded in 1990 by leading autism expert and clinical psychologist Doreen Granpeesheh, PhD, BCBA-D. CARD treats individuals with ASD using the principles of applied behavior analysis (ABA), which is empirically proven to be the most effective method for treating individuals with ASD and recommended by the American Academy of Pediatrics and the US Surgeon General. CARD employs a dedicated team of over 3,000 individuals across the nation and internationally.

For more information, visit http://www.centerforautism.com or call (855) 345-2273.

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Ambry Genetics Recruits Patient Cohorts to Discover New Links between Genes and Autism - Yahoo Finance

Dermatology – Stanford University School of Medicine …

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Researchers named Outstanding Investigators by the National Cancer Institute-Howard Chang, Professor of Dermatology isfeaturedthis article...Full Article

How to reduce wrinkles without lasers or chemicals - S. Tyler Hollmig, Clinical Assistant professor of Dermatology is featured in this article...Full Article

Stanford team is growing healthy skin for ill patients-Jean Tang, Associate Professor of Dermatology;Peter Marinkovich, Associate Professor of Dermatology; andAnthony Oro, Professor of Dermatology are quoted in this article...Full Article

KGO TV- Filmmakers Tap Quarterback Legend To Fight Skin Cancer - Susan Swetter, MD, Stanford Professor of Dermatology isfeatured in this article...Full Article

Automated dermatologist' detects skin cancer with expert accuracy- Roberto Novoa, Clinical Assistant Professor is featured in this article...Full Article

Deep learning algorithm does as well as dermatologists in identifying skin cancer- Susan Swetter, MD, Justin Ko, MD MBA, Roberto Novoa, MD are featured in this article...Full Article

Gene therapy for blistering skin disease appears to enhance healing in clinical trial- Peter Marinkovich, MD, andJean Tang, MD, PhD, Associate Professors of Dermatologyare featured in this articleFull Article

Factors to consider before genetic testing -Joyce Teng, Clinical Associate Professor of Dermatology is featured in this articleFull Article

USPSTF: Not enough proof for visual skin Ca screening- Susan Swetter, MD, Stanford Professor of Dermatology is quoted in this article...Full Article

Possible psoriasis drug target identified - Peter Marinkovich, MD, Stanford Associate Professor of Dermatology is featured in this articleFull Story

5 Questions: Susan Swetter on choosing a sunscreen-Susan Swetter, MD, Stanford Professorof Dermatology is featured in this article....Full Article

Acne treatments: A Q&A with Stanford dermatologist Justin Ko-Justin Ko, MD, MBA, Stanford clinical assistant professor of Dermatology is featured in this article....Full Article

Ultraviolet light-induced Mutation Drives Many Skin Cancers-Paul Khavari, MD, PhD, Carl J Herzog Professor of Dermatology and chair of the Department of Dermatology is quoted on this study...Full Story

Disproportionate Rates of Melanoma Found in Marin County-Stanford professor of Dermatology, Susan Swetter, MD,, is featured in this audio forum...Audio

Antifungal drug may treat common skin cancer, study finds-Stanford associate professor of Dermatology, Jean Tang, MD, PhD, is featured in this article...Full Story

Inflammatory skin damage in mice blocked by bleach solution, study finds...Thomas Leung, MD, PhD, Stanford instructor of Dermatology and lead author comments....Full Story

New study: Genes may affect skin youthfulness...Anne Lynn S Chang, MD, Stanford assistant professor of Dermatology comments....SCOPE Blog

Melanoma deaths more likely in young men than women...Susan Swetter, MD., professor of Dermatology at Stanford is quoted....Full Story

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How to weather summer's health challenges...Playing it safe in the sun...Susan Swetter, MD and Brooks Bahr, MD., Stanford Dermatologists are featured....See Newsletter

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Dermatology - Stanford University School of Medicine ...

AskBio Enters Research Collaboration and Licensing Agreement with University of North Carolina (UNC) for Angelman Syndrome – Associated Press

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RESEARCH TRIANGLE PARK, N.C. and CHAPEL HILL, N.C., March 18, 2020 (GLOBE NEWSWIRE) -- Asklepios BioPharmaceutical, Inc. (AskBio), a leading clinical-stage adeno-associated virus (AAV) gene therapy company, today announced that it has entered into a research collaboration and licensing agreement with the University of North Carolina at Chapel Hill (UNC) for the development and commercialization of gene therapy for Angelman syndrome.

This collaboration allows us to leverage groundbreaking research from UNC and apply our AAV development capabilities to find a gene therapy treatment for Angelman syndrome, said Sheila Mikhail, JD, MBA, AskBio Chief Executive Officer and co-founder. We look forward to advancing this program together.

Angelman syndrome is a rare neurogenetic disorder caused by the loss of function of the UBE3A gene. The disorder occurs in approximately one in 15,000 people, or about 500,000 individuals worldwide, and there is currently no cure. In addition to life-altering symptoms such as speech and motor deficits, more than 80 percent of Angelman syndrome patients experience epilepsy, which typically does not respond well to standard anti-seizure medications.

A UNC School of Medicine team, led by Mark Zylka, PhD, and Ben Philpot, PhD, has generated preclinical evidence that gene therapy may help individuals with Angelman syndrome by improving seizure and motor outcomes.

Individuals with Angelman syndrome face lifelong challenges, and our gene therapy approaches hold the potential to correct this disorder at its genetic roots. We are incredibly excited to partner with AskBio, as they have been vanguards of clinical gene therapies for rare diseases, said Mark Zylka, PhD, Director of the UNC Neuroscience Center. Ben Philpot, PhD, Associate Director of the UNC Neuroscience Center added, We look forward to advancing this transformative treatment to the clinic and potentially improving the lives of individuals with Angelman syndrome.

The partnership between AskBio and UNC could transform the lives of people living with Angelman syndrome by providing them with a potential therapy for this rare disease, said Amanda Moore, Angelman Syndrome Foundation CEO. The Angelman Syndrome Foundation has long been proud to support the work of UNC researchers, Drs. Ben Philpot and Mark Zylka, and invest in science that positively affects the Angelman syndrome community. The collaboration between UNC and AskBio brings us a step closer to delivering a viable gene therapy to the people and families we serve.

The financial terms of the agreement were not disclosed.

More about Angelman SyndromeDeletion of the maternally inherited copy of the UBE3A gene causes Angelman syndrome. Symptoms include microcephaly (small head circumference), severe intellectual disability, seizures, balance and movement problems (ataxia), lack of speech, and sleep problems. Behavioral symptoms include frequent laughing, smiling and excitability. Angelman syndrome was first described in 1965, yet no treatment options have been approved in the 55 years since. While individuals with the disorder have a normal lifespan, they require life-long care and are not able to live independently.

About Angelman Syndrome FoundationThe mission of the Angelman Syndrome Foundation is to advance the awareness and treatment of Angelman syndrome through education and information, research and support for individuals with Angelman syndrome, their families and other concerned parties. We exist to give them a reason to smile, with the ultimate goal of finding a cure. To learn more, visit https://www.angelman.org.

About AskBioFounded in 2001, Asklepios BioPharmaceutical, Inc. (AskBio) is a privately held, clinical-stage gene therapy company dedicated to improving the lives of children and adults with genetic disorders. AskBios gene therapy platform includes an industry-leading proprietary cell line manufacturing process called Pro10 and an extensive adeno-associated virus (AAV) capsid and promoter library. Based in Research Triangle Park, North Carolina, the company has generated hundreds of proprietary third-generation AAV capsids and promoters, several of which have entered clinical testing. An early innovator in the space, the company holds more than 500 patents in areas such as AAV production and chimeric and self-complementary capsids. AskBio maintains a portfolio of clinical programs across a range of neurodegenerative and neuromuscular indications with a current clinical pipeline that includes therapeutics for Pompe disease, limb-girdle muscular dystrophy 2i/R9 and congestive heart failure, as well as out-licensed clinical indications for hemophilia (Chatham Therapeutics acquired by Takeda) and Duchenne muscular dystrophy (Bamboo Therapeutics acquired by Pfizer). Learn more at https://www.askbio.com or follow us on LinkedIn.

Media Contacts: AskBio Robin Fastenau Vice President, Communications +1 984.275.2705 rfastenau@askbio.com Angelman Syndrome Foundation Amanda Moore Chief Executive Officer +1 317.514.6918 amoore@angelman.org UNC Health | UNC School of Medicine Mark Derewicz Director, Research & News +1 984.974.1915 Mark.Derewicz@unchealth.unc.edu

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AskBio Enters Research Collaboration and Licensing Agreement with University of North Carolina (UNC) for Angelman Syndrome - Associated Press

Redpin Launches with $15.5 Million Series A to Focus on Pain and Epilepsy – BioSpace

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Redpin Therapeutics closed on a $15.5 million Series A financing round. The round was led by 4BIO Capital and Arkin Bio Ventures. They were joined by new investor Takeda Venture Investments, as well as existing seed-round investors, New York Ventures and Alexandria Venture Investments.

Based in New York City, Redpin has a proprietary chemogenetics platform for targeted cell therapies. Its a mix of synthetic biology, gene therapy and traditional pharmacotherapy. The focus is built on an ultrapotent ion channel-based chemogenetics platform that allows targeted cell activation or inhibition controlled by low doses of the Pfizers anti-smoking drug varenicline (Chantix). The company has a worldwide exclusive license from the Howard Hughes Medical Institute for therapeutic use of the technology.

The funds will let Redpin continue to progress its platform to disorders with neural circuit dysfunction, including epilepsy, neuropathic pain and Parkinsons disease. Treatment for these usually uses systemic drugs that target local neuron dysfunction. This has the downside of adverse, off-target side effects. The lead programs are for epilepsy and chronic pain.

Redpins approach, the company believes, will be more targeted on the dysfunctional neurons while not affecting normal functioning cells. The company indicates its approach will only be activated in the presence of Chantix.

These new funds combined with the support and expertise of our new and existing investors will allow Redpin to swiftly progress to the next phase of its development in bringing highly targeted treatments to patients with neurological and psychiatric disorders, said Elma Hawkins, co-founder, president and chief executive officer of Redpin.

Chantix attaches to proteins called ion channels, which control neuron signaling. By controlling which neurons receive these proteins, researchers can modulate specific cells. In March 2019, Scott Sternson, group leader at the Howard Hughes Medical Institutes Janelia Research Campus, noted that chemogenetics often use molecules that would not be appropriate for human therapy. Its still many steps to the clinic, but were trying to shorten that route.

Sternson is one of the companys founders, along with Hawkins, Jeffrey M. Friedman at Howard Hughes, Michael Kaplitt, with Weill Cornell Medicine, Sarah Stanley at Icahn School of Medicine Mount Sinai, and Jonathan S. Dordick, Rensselaer Polytechnic Institute.

At that time, Sternson and his team modified the structure of two different ion channel proteins so the drug would be more likely to bind. One protein stimulates neurons to send messages when Chantix attaches. Another protein blocks neurons from sending those messages when Chantix is present. At that time, doses of Chantix much lower than required to quit smoking were found to have a large effect on neural activity.

Redpins technology uses adeno-associated virus (AAV) vectors to transport engineered ion channels to targeted cells. Once activated, they can control the function of the particular cell. Chantix was chosen because it is approved in 80 countries, has the necessary pharmacokinetic properties, and can penetrate the blood-brain barrier. The company has other small molecule-receptor pairs in its pipeline.

Chantix basically acts as a switch to turn the ion channel on and off.

Dmitry Kuzmin, managing partner at 4BIO, said, Our goal is to support and grow advanced therapy companies with the potential to cure chronic disease. Redpin has a highly compelling, validated chemogenetics approach that could have significant potential in the targeted treatment of neuropathic disorders. The strength of Redpins science alongside the world-class knowledge and expertise of the Companys founders and management team make us fully confident in the future success of the Company towards this goal.

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Redpin Launches with $15.5 Million Series A to Focus on Pain and Epilepsy - BioSpace

Gene ID’d as potential therapeutic target for dementia in Parkinson’s – Washington University School of Medicine in St. Louis

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Targeting gene linked to Alzheimers may reduce dementia risk in Parkinsons

Clumps of the Parkinsons protein alpha-synuclein (red) are visible inside neurons (green) in the brain of a mouse. Researchers at Washington University School of Medicine in St. Louis have discovered that the genetic variant APOE4 long linked to dementia spurs the spread of harmful clumps of Parkinsons proteins through the brain. The findings suggest that therapies that target APOE might reduce the risk of dementia for people with Parkinsons disease.

Dementia is one of the most debilitating consequences of Parkinsons disease, a progressive neurological condition characterized by tremors, stiffness, slow movement and impaired balance. Eighty percent of people with Parkinsons develop dementia within 20 years of the diagnosis, and patients who carry a particular variant of the gene APOEare at especially high risk.

In new research, scientists at Washington University School of Medicine in St. Louis have found a clue to the link between Parkinsons, APOEand dementia. They discovered that harmful Parkinsons proteins spread more rapidly through the brains of mice that have the high-risk variant of APOE, and that memory and thinking skills deteriorate faster in people with Parkinsons who carry the variant. The findings, published Feb. 5 in Science Translational Medicine, could lead to therapies targeting APOEto slow or prevent cognitive decline in people with Parkinsons.

Dementia takes a huge toll on people with Parkinsons and their caregivers, said Albert (Gus) Davis, MD, PhD, an assistant professor of neurology and the studys lead author. The development of dementia is often what determines whether someone with Parkinsons is able to remain in their home or has to go into a nursing home.

An estimated 930,000 people in the U.S. live with Parkinsons. The disease is thought to be caused by toxic clumps of a protein called alpha-synuclein that build up in a part of the brain devoted to movement. The clumps damage and can kill brain cells.

Cognitive problems tend to arise many years after the motor symptoms. The protein clusters implicated in movement problems also are linked with dementia, but how this happens is not clear. Davis and his colleagues including senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of theDepartment of Neurology saw a clue in the risky nature of APOE.

A variant of APOE known as APOE4 raises the risk of Alzheimers disease threefold to fivefold. Like Parkinsons, Alzheimers is a neurodegenerative condition caused by the spread of toxic protein clusters throughout the brain, although some of the proteins involved are different. APOE4 increases the chance of Alzheimers dementia partly because it spurs Alzheimers proteins to collect into clumps that injure the brain. The researchers suspected that APOE4 similarly triggers the growth of toxic clusters of Parkinsons proteins.

Studying mice with a form of alpha-synuclein prone to clumping, Davis, Holtzman and colleagues genetically modified the mice to carry human variants of APOE APOE2, APOE3 or APOE4 or no APOE at all.

The researchers found that APOE4 mice had more alpha-synuclein clusters than APOE3 orAPOE2mice. Further experiments showed that the clumps spread more widely in APOE4 mice as well. Together, the findings showed that APOE4 was directly involved in exacerbating signs of disease in the mices brains.

What really stood out is how much less affected the APOE2 mice were than the others, Davis said. It actually may have a protective effect, and we are investigating this now. If we do find that APOE2 is protective, we might be able to use that information to design therapies to reduce the risk of dementia.

To study the effect of APOEvariants on dementia in people with Parkinsons, the researchers analyzed publicly available data from three separate sets of people with Parkinsons. Two of the cohorts one from the Parkinsons Progression Markers Initiative, with 251 patients, and the other from the Washington University Movement Disorders Center, with 170 patients had been followed for several years. In both cohorts, cognitive skills declined faster in people with APOE4 than in those with APOE3. People with two copies of APOE2 are very rare, but none of the three patients in the group with two copies of APOE2showed any cognitive decline over the period of the study.

The third cohort, fromthe NeuroGenetics Research Consortium, was made up of 1,030 people with Parkinsons whose cognitive skills had been evaluated just once. The researchers found that people with APOE4 in the cohorthad developed cognitive problems at a younger age and had more severe cognitive deficits at the time they were evaluated than people with APOE3 or APOE2.

Parkinsons is the most common, but there are other, rarer diseases that also are caused by alpha-synuclein aggregation and also have very limited treatment options, Davis said. Targeting APOE with therapeutics might be a way to change the course of such diseases.

APOE doesnt affect the overall risk of developing Parkinsons or how quickly movement symptoms worsen, so an APOE-targeted therapy might stave off dementia without doing anything for the other symptoms. Even so, it could be beneficial, Davis said.

Once people with Parkinsons develop dementia, the financial and emotional costs to them and their families are just enormous, Davis said. If we can reduce their risk of dementia, we could dramatically improve their quality of life.

Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, Haines JN, Dhavale DD, Miller R, Choudhury FA, Sullivan PM, Cruchaga C, Perlmutter JS, Ulrich JD, Benitez BA, Kotzbauer PT, Holtzman DM. APOE Genotype Regulates Pathology and Disease Progression in Synucleinopathy. Science Translational Medicine. Feb. 5, 2020. DOI: 10.1126/scitranslmed.aay3069

This work was supported by an American Academy of Neurology/American Brain Foundation (Clinical Research Training Fellowship); the BrightFocus Foundation; the Mary E. Groff Charitable Trust; the Dobbins Family Fund; the Foundation for Barnes-Jewish Hospital (Elliot Stein Family Fund); the Riney Foundation; the American Parkinson Disease Association; the Greater St. Louis Chapter of the American Parkinson Disease Association; The JPB Foundation; and the National Institutes of Health (NIH), grant numbers K08NS101118, R01AG044546, RF1AG053303, RF1AG058501, U01AG052411, U01AG058922, NS075321, NS097799, R01NS090934 and R01AG047644.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Emerson College student with progeria heartened that first drug treatment could be approved soon – The Boston Globe

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Waldron has already lived considerably longer she turns 19 on March 1. She credits lonafarnib, an experimental medication shes taken since 2007 in clinical trials at Boston Childrens Hospital. A California drug firm plans to complete its application for approval by March 31, with the hope of a favorable ruling from the Food and Drug Administration by years end. It would be the first approved drug for the ultra-rare disease.

Its been proven that it helps in extending life, Waldron, a Deerfield native, said recently over hot chocolate at Caffe Nero near Emerson. Im almost 19. The life span is technically 14. A winsome smile brightened her face. Looks like its doing a good job.

Since 2007, Childrens Hospital has run four clinical trial of lonafarnib. Waldron has participated in all four, and researchers say the results are encouraging.

In perhaps the most compelling finding, a study published by the Journal of the American Medical Association in 2018 reported that children with progeria who took lonafarnib capsules twice a day had a dramatically lower mortality rate than those who didnt.

After slightly more than two years, one in 27 children who took lonafarnib, or 3.7 percent, had died compared with nine in 27 who didnt get it, or 33 percent, according to the article by a team of researchers from the Progeria Research Foundation, Brown University, and Childrens Hospital. Lonafarnib appeared to slow the progression of cardiovascular disease, although it had little or no effect on other symptoms, including stiff joints, stunted growth, wrinkled skin, and loss of body fat and hair.

The data looks fantastic, said Dr. Leslie Gordon, lead author of the JAMA study and medical director and cofounder of the Progeria Research Foundation, the Peabody-based nonprofit that funded the trials. Youve got a fatal childhood disease with no treatment, and youve shown a survival benefit.

For Gordon, a professor of pediatric medicine at Browns medical school who practices at Boston Childrens Hospital and Hasbro Childrens Hospital in Providence, the quest to treat progeria is profoundly personal.

Her son, Sam Berns, a Foxborough High School junior, died of progeria in 2014 at age 17. Like Waldron, he began taking lonafarnib in 2007 in the clinical trials. An avid sports fan who played the snare drum in the Foxborough High School marching band, he was the subject of the 2013 HBO documentary Life According to Sam.

Gordon had never heard of progeria when Sam, her only child, was diagnosed with it at 22 months. She has since become an authority. In 2003, she was on the research team led by Dr. Francis S. Collins, director of the National Institutes of Health, that discovered the defective gene that causes the disease. She cofounded the progeria foundation with her husband and sister.

The genetic mutation that causes progeria results in an overabundance of the protein progerin. A buildup of progerin occurs within a cell in normal aging, but the rate of accumulation is dramatically accelerated in children with the disease. Progeria has no effect on a childs intellect, as anyone who meets Waldron who took an Advanced Placement class in European history in high school and rhapsodizes about Michelangelo can tell in an instant.

Lonafarnib was originally developed by the pharmaceutical giant Merck as a potential treatment for cancer. But researchers found that it can reverse an abnormality in cells of laboratory mice with progeria. Merck has licensed it to Eiger BioPharmaceuticals, a small drug maker in Palo Alto, Calif. David Cory, chief executive of Eiger, says the company has hired a chief commercial officer and a vice president of medical affair in anticipation of FDA approval.

Researchers are working on other potential treatments, including one that targets the genetic root of the disease. David Liu, a chemistry professor affiliated with the Broad Institute, Harvard University, and the Howard Hughes Medical Institute, recently announced that he and a team of scientists had used a new form of genome editing to correct the DNA mutation that caused the disorder in mice, extending their lives.

Waldron, who serves as an ambassador for the progeria foundation, said she was diagnosed with the disease when she was about 2. Her mother, a housekeeper at an assisted living facility, and her father, a solar energy contractor, were worried because she wasnt growing or gaining weight, and her hair was falling out.

Waldron realized she had progeria as an adolescent when she went on the foundations website and saw pictures of kids who looked like her, she said.

Obviously, I knew that I was different before that, she said. But it wasnt an awareness I-have-progeria thing until at a certain point.

The disease has hardly stopped her. She ran for the cross-country and track teams at the public Frontier Regional High School in Deerfield. She played violin in the middle school orchestra and cello in the high school orchestra.

She has met about a dozen other children with progeria from around the country at family weekends at the nonprofit Hole in the Wall Gang Camp in Connecticut for seriously ill children and their families.

When she started considering colleges, Waldron said, she had no interest in going to school in Boston. But she fell in love with the city on a visit to Emerson.

You can walk down the street or hop on a train and go anywhere, she said, citing the North End as one of her favorites places.

I have great friends," she added. "I always have.

Emerson has made several accommodations for her. For example, the college provides a stool for her to rest her feet on when she sits at a desk in her four classes. The handle on her wardrobe in her dorm room was lowered so she could reach it more easily.

Waldron says she generally feels fine despite problems with her joints. She has dislocated her right shoulder four times doing ordinary tasks, such as reaching for a light switch.

None of this has dimmed her spirit for adventure.

Meghan has a very strong personality. Shes driven, her father, Bill Waldron, said in a video posted last year on the progeria foundations Facebook page. I dont think she pays attention to the fact that she has progeria.

Indeed, after graduating from high school in June, she traveled in Europe alone for a month. The initial attraction was seeing Anne-Marie, a singer and occasional Ed Sheeran collaborator, perform in London. But Waldron decided she also wanted to experience Renaissance art. She visited Milan, Florence, Rome, Paris, and Dublin, staying in youth hostels along the way.

Waldrons parents were nervous, she said. She was, too, but only briefly.

There was a point of about five minutes when my parents said goodbye and I was getting on the plane where I started freaking out, she said, laughing. But then I was like, Oh, well. And then I was fine.

Jonathan Saltzman can be reached at jonathan.saltzman@globe.com

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Emerson College student with progeria heartened that first drug treatment could be approved soon - The Boston Globe