Daily Archives: December 7, 2021

With the emergence of genetic sequencing, advances in diagnostics and wearable devices, there has been a swell of excitement around precision medicine or customised healthcare. The story in itself has fuelled a billion dollar market for public consumption. However, the industry is outpacing the science, and as yet, it is not so straight forward.

I have compiled a list of some of the key areas and advances in personalised medicine, which we will see come in to focus over the next few years:

1. Hormones: Such as oestrogen, progesterone, testosterone and thyroid, to name but a few. As physicians, we have been fortunate enough to tailor the needs to the individual, depending on the patients blood results and their symptoms. Although this is not new, treatments can vary, based on conventional wisdom, body-identical, bio-identical and natural supplements. It can be difficult for patients to navigate, as some practitioners have become more like alchemists, trialing different treatments (by their very nature it is not always evidence-based). For more detail please read my articles on correcting hormonal imbalance.

2. Cancer risk and diagnosis: Home DNA genetic test-kits have made checking for inheritable diseases widely available, but with some controversy (I have elaborated on this in my other article). They have also discovered new techniques for identifying cancer cell DNA markers in the blood, also known as liquid biopsies. This could potentially pick up of over 50 early stage cancers. Current trials are underway in the US and UK, which could lead to a paradigm shift in early-cancer detection for individuals, the likes of which we have not seen for over 30 years. Using polygenic risk scores (different combinations of genetic variance for a particular disease), multiple data points can be stacked for each individual (i.e. demographics/family history etc) and offer greater diagnostic precision.

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Is 'personalised medicine' the future of healthcare? - Tatler

National Health Institute Director Francis S. Collins served for 12 years under three presidents and presided over an expansion of the agency's budget and efforts to develop new cures to diseases. Graeme Jennings/POOL/AFP via Getty Images hide caption

National Health Institute Director Francis S. Collins served for 12 years under three presidents and presided over an expansion of the agency's budget and efforts to develop new cures to diseases.

It's Dr. Francis Collins' last few weeks as director of National Institutes of Health after 12 years, serving three presidents. Collins made his name doing the kind of biomedical research NIH is famous for, especially running The Human Genome Project, which fully sequenced the human genetic code. The focus on biomedicine and cures has helped him grow the agency's budget to over $40 billion a year and win allies in both political parties.

Still, in a broad sense, Americans' health hasn't improved much in those 12 years, especially compared to people in peer countries, and some have argued the agency hasn't done enough to try to turn these trends around. One recently retired NIH division director has quipped that one way to increase funding for this line of research would be if "out of every $100 dollars, $1 would be put into the 'Hey, how come nobody's healthy?' fund."

In a wide-ranging conversation, Collins answers NPR's questions as to why for all the taxpayer dollars going to NIH research there haven't been more gains when it comes to Americans' overall health. He also talks about how tribalism in American culture has fueled vaccine hesitancy, and he advises his successor on how to persevere on research of politically charged topics like guns and obesity and maternal health even if powerful lobbies might want that research not to get done.

This interview has been edited for length and clarity.

Selena Simmons-Duffin: After you announced you'd be stepping down from the director role, you told the New York Times that one of your "chief regrets" was the persistence of vaccine hesitancy during the pandemic. How are you thinking about the role NIH could play in understanding this problem?

Francis Collins: I do think we need to understand better how in the current climate people make decisions. I don't think I anticipated the degree to which the tribalism of our current society would actually interfere with abilities to size up medical information and make the kinds of decisions that were going to help people.

To have now 60 million people still holding off of taking advantage of life saving vaccines is pretty unexpected. It does make me, at least, realize, boy, there are things about human behavior that I don't think we had invested enough into understanding. We basically have seen accurate medical information overtaken, all too often, by the inaccurate conspiracies and false information on social media. It's a whole other world out there. We used to think that if knowledge was made available from credible sources, it would win the day. That's not happening now.

So you mentioned the idea of investing more in the behavioral research side of things. Do you think that should happen?

We're having serious conversations right now about whether this ought to be a special initiative at NIH to put more research into health communications and how best to frame those [messages] so that they reach people who may otherwise be influenced by information that's simply not based on evidence. Because I don't think you could look at the current circumstance now and say it's gone very well.

Looking at how America has fared in the pandemic more broadly, it really is astoundingly bad. The cases and deaths are just so high. CDC Director Robert Redfield, when he was leaving, told NPR he thought the baseline poor health of Americans had something to do with how powerfully the pandemic has hit America. What do you think about the toll of the pandemic, even as it's clearly not over?

It's a terrible toll. We've lost almost 800,000 lives. In 2020, before we had vaccines, there was not a really good strategy to protect people other than social distancing and mask-wearing, which were important, but certainly not guarantees of safety. And yes, it is the case that the people who got hit hardest, oftentimes, were people with underlying medical conditions.

But in 2021, we should have been better off. We had vaccines that were safe, that were available for free to all Americans. The ability to get immunized really went up very steeply in March and April, and yet it all kind of petered out by about May or June. The [vaccine] resistant group of 60 million people remains, for the most part, still resistant. Unfortunately, now, with delta having come along as a very contagious variant and with omicron now appearing, which may also be a real threat, we have missed the chance to put ourselves in a much better place.

Let's step back from the pandemic. In your 12 years as director, the NIH has worked on developing cures and getting them from the lab to patients faster, and the agency's budget has grown.

But, in that time, Americans haven't, on a broader scale, gotten healthier. They're sicker than people in other countries across the board, all races and incomes. When you were sworn in in 2009, life expectancy was 78.4 years, and it's been essentially stuck there.

Does it bother you that there haven't been more gains? And what role should NIH play in understanding these trends and trying to turn them around?

Well, sure, it does bother me. In many ways, the 28 years I have been at NIH have just been an amazing ride of discoveries upon discoveries. But you're right, we haven't seen that translate necessarily into advances.

Let's be clear, there are some things that have happened that are pretty exciting. Cancer deaths are dropping every year by one or two percent. When you add that up over 20 years, cancer deaths are down by almost 25% from where they were at the turn of the century. And that's a consequence of all the hard work that's gone into developing therapeutics based on genomics, as well as immunotherapy that's made a big dent in an otherwise terrible disease.

But we've lost ground in other areas, and a lot of them are a function of the fact that we don't have a very healthy lifestyle in our nation. Particularly with obesity and diabetes, those risk factors have been getting worse instead of better. We haven't, apparently, come up with strategies to turn that around.

On top of that, the other main reason for seeing a drop in life expectancy other than obesity and COVID is the opioid crisis. We at NIH are working as fast and as hard as we can to address that by trying to both identify better ways to prevent and treat drug addiction, but also to come up with treatments for chronic pain that are not addictive. Because those 25 million people who suffer from chronic pain every day deserve something better than a drug that is going to be harmful.

In all of these instances, as a research enterprise because that's our mandate it feels like we're making great progress. But the implementation of those findings runs up against a whole lot of obstacles, in terms of the way in which our society operates, in terms of the fact that our health care system is clearly full of disparities, full of racial inequities. We're not at NIH able to reach out and fix that, but we can sure shine a bright light on it and we can try to come up with pilot interventions to see what would help.

A 300-page report called "Shorter Lives, Poorer Health" came out in 2013 it was requested and financed by NIH and conducted by a National Academies of Science, Engineering and Medicine panel. It documented some of the things you just talked about, in terms of how Americans' health falls short compared to other countries. And it is filled with recommendations for further research, many specifically for NIH, including looking to how other countries are achieving better health outcomes than the U.S.

I'm curious, since this report came out when you were director, if it made an impact at the agency and whether there's been any progress on those recommendations or was a decision not to pursue those ideas?

I do remember that report and there have been a lot of other reports along the lines since then that have tried to point to things that other countries may be doing better than we are. One of the things I've tried to do is to provide additional strength and resources to our Office of Disease Prevention, because that's a lot of what we're talking about here. One of the knocks against the National Institutes of Health is that we often seem to be the National Institutes of Disease that a lot of the focus has been on people who are already diagnosed with some kind of health condition. And yet what we really want to do is to extend health span, not just lifespan, and that means really putting more research efforts into prevention.

One of the things that I'm excited about in that regard is the All of Us study, which is in the process of enrolling a million Americans, following them prospectively, many of them currently healthy. They share their electronic health records, they have blood samples taken that measure all kinds of things, including their complete genome sequences; they answer all kinds of questionnaires, they walk around with various kinds of wearable sensors. That's going to be a database that gives us information about exactly what's happened to the health of our nation and what could we do about it.

You've served under both Democratic and Republican administrations. One thing you've talked about in interviews is the culture wars. What role do you think NIH has to play in terms of developing trust and trying to get past some of that tribalism that you talked about before?

I think medical research should never be partisan. It should never get caught up in culture wars or tribal disagreements. But in our current society, it's hard to think of anything that hasn't at least been touched by those attitudes.

My goal as NIH director over these 12 years, serving three presidents, was to always try to keep medical research in a place that everybody could look at objectively and not consider it to be tainted in some way by political spin. I've made friends in Congress in both parties and both houses, in a way that I think has really helped the view of medical research to remain above the fray. And many of the strongest supporters for medical research over these 12 years have been in the Republican Party.

This is not something that people can really disagree about. You want to find answers to medical problems that are threatening yourself or your family or your community or your constituents. So I don't have a hard job in terms of explaining the mission or why we work so hard at what we do.

But I do have to sometimes worry that for whatever reason, politics will creep into this. And certainly with COVID, politics has crept into the space of misinformation in a fashion that has not helped with vaccine hesitancy. Frankly, I think it's pretty shameful if political figures trying to score points or draw attention to themselves put forward information about COVID that's demonstrably false.

Some of the reasons why Americans tend to be less healthy than people in other countries can get political pretty quickly like healthy environments and gun injuries and drug overdoses and maternal health. But the research is important.

Do you have any guidance or thoughts for your successor on how to support the kind of research that's not as universally embraced on both sides of the aisle?

I think the guidance is you have to look at all the reasons why people are not having a full life experience of health and figure out what we, as the largest supporter of medical research in the world, should be doing to try to understand and change those circumstances. A lot of this falls into the category of health disparities. It is shameful that your likelihood of having a certain lifespan depends heavily on the zip code where you were born, and that is a reflection of all of the inequities that exist in our society in terms of environmental exposures, socioeconomics, social determinants of health, et cetera.

We are ramping up that effort right now, especially not just to observe the situation or, as some cynics have said, admire the situation. We actually want to try pilot interventions to see if some of those things can be changed. But that's about as far as we can go. Again, if there's a major societal illness right now of tribalism and over-polarization and hyper-partisanship about every issue, probably the NIH is not well positioned all by ourselves to fix that. We have an urgent need, I think, across society, to recognize that we may have lost something here our anchor to a shared sense of vision and a shared sense of agreement about what is truth.

You are leaving this post. Where do you imagine the agency might go next? I know you're still going to be doing your work on Type 2 diabetes you'll still be a part of it. So what do you see in NIH's future?

I think it is in a remarkably positive place right now as far as what we are called to do, which is to make discoveries, to learn about how life works and then apply that in a way that will lead to answers for diseases that currently don't have them. I think of NIH as not just the National Institutes of Health, but the National Institutes of Hope, and we are able now to provide hope for lots of situations that previously couldn't have really been confident in that. Look what's happened in terms of gene therapies we're curing sickle cell disease now, something I thought would never happen in my lifetime, with gene therapies. Look at what we're able to do with cancer immunotherapy, saving people who have stage IV disease, in certain circumstances, by activating the immune system. And of course, in infectious diseases not only have we now got mRNA vaccines for the terrible COVID-19 situation, we can apply those to lots of other infections as well.

So, anybody listening to this who's thinking maybe of moving into a career in biomedical research, this is the golden era and we need all the talent and the vision that we can possibly recruit into our midst because it's going to be a grand adventure in the coming decades.

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Francis Collins on medical advances, vaccine hesitancy and Americans' ill health : Shots - Health News - NPR

Global Gene Expression Analysis Market: Overview

Gene expression makes an analysis of the study of the activity or occurrence of the making of a gene product from its coding gene. This process is considered a delicate indicator of biological activity in which a change in the gene expression pattern leads to a change of biological process.

Growth in the global gene expression analysis market is basically driven by various factors such as increased availability of gene expression databases, emerging areas of genomics, and rise in the incidences of cancer worldwide. Comparison of expression levels of one or more genes from various samples is one of the most common uses of gene expression analysis. Some of the common and interesting comparisons comprise before and after treatment, Mutant versus Wild type, normal versus diseases, spatial variations inside tissues, organs, or any other sample type.

The report on the global gene expression analysis market captures a closer view of the leading changes that have taken place lately in the techniques of chemical analysis. It also provides a view of how those changes are shaping the contours of the global gene expression analysis market. These insights are forecasted to help the industry players and investors to assess the entire ecosystem and accordingly formulate strategies.

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Global Gene Expression Analysis Market: Trends and Opportunities

Declining Cost of Sequencing to Accelerate Growth of the Market

The rise in the need for personalized medicine is likely to influence the global gene expression analysis market over the timeframe of projection. Besides, increase in the funding of associated programs is estimated to fuel growth of the market over the projection period.

In addition to that, a decline in the cost of sequencing is likely to emerge as another growth promoting factor for the global gene expression analysis market. Emergence of new areas of genomics application and augmented availability of database of gene expression is estimated to support expansion of the growth of the global gene expression analysis market in the years to come.

Another significant factor that is likely to influence the growth of the global gene expression analysis market is strong emphasis on laboratory research. The drug discovery and development is another factor that is likely to offer lucrative growth opportunities for the growth of the market.

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Clinical diagnostics is see an increasing application of gene expression analysis over the tenure. The microbiological and biotechnological use of gene expression analysis is estimated to see a rise over the projection period. These factors are expected to drive the market toward growth over the assessment tenure, from 2018 to 2026.

Biotechnology and pharmaceutical companies make use of gene expression analysis products and services to meet clinical research goals like biotech research, and drug development and discovery. Biopharmaceutical companies emphasize on the invention of targeted therapies, particularly for the treatment of diseases like rare and complicated genetic disorders, cancer, and others. These factors are likely to offer lucrative opportunities of growth for the market.

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Global Gene Expression Analysis Market: Regional Outlook

In the global gene expression analysis market, North America is likely to wield its influence over the market over the tenure of assessment. Augmented focus on life science research on cancer by governments, increased focus on research and development activities, and setting up of bioresearch centers across the regions are likely to fuel regional growth. In addition to that, increased support from the government to raise the standard of healthcare facilities is expected to boost the expansion of the market in North America.

Emerging countries such as Brazil, China, and India are also forecasted to play an important role in offering promising growth opportunities for the global gene expression analysis market. Many established market players are seen to enter into collaborations with local players of the region to widen scope of the regional market in near future.

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Global Gene Expression Analysis Market: Companies Mentioned in Report

Key players mentioned in the report are Luminex Corporation, Oxford Gene Technologies, Ltd., Thermo Fisher Scientific, Inc, Agilent Technologies Inc., F. Hoffmann-La Roche Ltd., and Eurofins Scientific.

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Wearable Injectors Market:

In the presence of various new technologies that have come to the fore of healthcare sector, it is easy to popularise wearable injectors that can work in tandem with other devices and technologies. Delivery systems are an important component of treatment processes as they help in timely administration of medical doses. In light of these factors, it is safe to expect that the global wearable injectors market would tread along a lucrative pathway in the times to follow

Polymerase Chain Reaction Consumables Market:

The global polymerase chain reaction (PCR) market is primarily segmented based on type of product and end user. Based on the type of product, the global market is mainly segmented into consumables, reagents, and instruments. Among these, the segment of reagents has been the most dominant one in terms of value. This dominance of the segment is due to its high levels of consumption. This segment is expected to witness a promising CAGR in the coming years of the forecast period because of the rising innovation in the field of specificity of reagents. In addition to this, large scale availability of different types of tests which need different types of reagents, increasing geriatric population, growing prevalence of infectious diseases, and increasing demand for innovation in specificity of reagents are some of the other factors helping to drive overall growth of the reagent segment.

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Gene Expression Analysis Market: Rise in the need for personalized medicine is likely to influence the global market - BioSpace

First approval of Clinical Trial Application was received from United Kingdom Medicines & Healthcare products Regulatory Agency (MHRA)

EVRY, France, December 06, 2021--(BUSINESS WIRE)--Atamyo Therapeutics, a biotechnology company focused on the development of new-generation gene therapies targeting neuromuscular diseases, today announced the first authorization of a Clinical Trial Application (CTA) in Europe for ATA-100, its gene therapy for the treatment of the fukutin-related protein (FKRP) limb-girdle muscular dystrophy Type 2I/R9 (LGMD2I/R9). This authorization was granted by the United Kingdom Medicines & Healthcare products Regulatory Agency (MHRA). Additional CTAs were filed in France and Denmark.

"We are thrilled to obtain our first CTA approval in the U.K. for the devastating LGMD2I/R9 disease," said Dr Sophie Olivier, Chief Medical Officer of Atamyo. "Atamyo plans to initiate dosing in patients for ATA-100 in the first half of 2022".

"LGMDR9 is a severe muscular dystrophy with progressive symptoms for which there is currently no approved treatment," said Pr John Vissing, Director of the Copenhagen Neuromuscular Center at the National Hospital, Rigshospitalet (Denmark), and principal investigator of this trial. "It is a great motivation to know that the work we are doing has the potential to make a life-changing difference for the patients affected by this disease."

"We are eager to start treating the first European patient and mark this as a milestone for the field in advancing a potential one-time treatment for patients with LGMD-R9," said Pr Volker Straub, Professor of Medicine and Director of the John Walton Muscular Dystrophy Research Centre, Newcastle University (UK).

"This is an important step in our mission to bring to patients suffering from limb-girdle muscular dystrophies (LGMD) a new generation of safe and effective gene therapies, after only one year of activity," said Stphane Degove, CEO of Atamyo Therapeutics.

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LGMD2I/R9 is a rare genetic disease caused by mutations in the gene that produces fukutin-related protein (FKRP). It affects an estimated 5,000 people in the US and Europe. Symptoms appear around late childhood or early adulthood. Patients suffer from progressive muscular weakness leading to loss of ambulation. They also are prone to respiratory impairment and myocardial dysfunction. There are currently no curative treatments for LGMDR9.

ATA-100, a gene therapy candidate for LGMD21/R9, delivers a normal copy of the gene for production of FKRP proteins. The therapy is based on the research of Atamyo Chief Scientific Officer Isabelle Richard, Ph.D., Research Director at CNRS who heads the Progressive Muscular Dystrophies Laboratory at Genethon.

In preclinical mice models, ATA-100 demonstrated its tolerability and capability to correct symptoms and biomarkers of the pathology at unprecedented low doses for systemic AAV-mediated gene transfer addressing muscle diseases.

About Atamyo Therapeutics

Atamyo Therapeutics is focused on the development of a new generation of effective and safe gene therapies for neuromuscular diseases. A spin-off of gene therapy pioneer Genethon, Atamyo leverages unique expertise in AAV-based gene therapy and muscular dystrophies from the Progressive Muscular Dystrophies Laboratory at Genethon. Atamyos most advanced programs address different forms of limb-girdle muscular dystrophies (LGMD). The name of the company is derived from two words: Celtic Atao which means "Always" or "Forever" and Myo which is the Greek root for muscle. Atamyo conveys the spirit of its commitment to improve the life of patients affected by neuromuscular diseases with life-long efficient treatments. For more information visit http://www.atamyo.com

View source version on businesswire.com: https://www.businesswire.com/news/home/20211206005081/en/

Contacts

U.S. Contact: Charles Craig, Opus Biotech CommunicationsCharles.s.craig@gmail.com, 404-245-0591

European contact: contact@atmayo.com

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Atamyo Therapeutics Obtains First Regulatory Authorization in Europe to Initiate a Clinical Trial for ATA-100, its Gene Therapy to Treat Limb-Girdle...

DURHAM, N.C. and SEATTLE, Dec. 2, 2021 /PRNewswire/ -- Tune Therapeutics, a biotechnology company pioneering the creation of epi-therapeutic medicines, launched today with its powerful and precise genetic tuning platform, TEMPO. This cutting-edge technology dials gene expression up or down to desired levels with the potential to reverse pathways of cancer, genetic disease, and aging by changing cell fate and function at will.

"Genetic medicine is at a tipping point," said Matt Kane, CEO of Tune Therapeutics. "We now understand that the driving force of human health and disease is not our genes, but the epigenomic elements that shape and control them. Until now, scientists and bioengineers lacked the combined understanding, clinical expertise, and technology needed to make epigenomic therapies a practical reality. Now, we have all three."

TEMPO Platform

Tune's proprietary TEMPO platform can rapidly target and adjust the epigenomic machinery of the cell, which shapes DNA and controls gene expression. By varying specific control modules in an iterative process, TEMPO can fine-tune expression toward healthy levels even in diseases involving multiplex or polygenic interactions.

Unlike genome editing, the tuning process does not generate double- or single-strand breaks in DNA and makes no permanent changes to the DNA sequence. This de-risks the precise targeting of entire gene networks, allowing Tune to simultaneously turn silenced genes on and dial over-expressed genes down, in a practical, therapeutic context.

Tune has already shown that TEMPO can locate epigenomic elements involved in several intractable genetic conditions revealing targets and networks that would be invisible or inaccessible to gene editing approaches. Moreover, Tune can optimize TEMPO to command expression of individual genes or networks with remarkable specificity and precision. This opens the door to an entirely new class of epi-therapeutics.

"The exciting challenge in front of us is taking these transformative advances in technology and extending their potential for our greater society," said Charlie Gersbach, PhD, Acting Chief Scientific Officer, Tune Therapeutics. "From proof of concept in rare, single-gene disorders to common conditions that aren't linked to a single gene mutation but are treatable through epigenomic control and constitute the vast majority of human diseases."

Veteran Genomic Medicine Leadership Team

Tune is launching with a veteran leadership team, endowed with deep expertise in gene and cell therapy, genome editing, and epigenetics.

In addition, Tune's Board of Directors includes Mr. Kane, Dr. Gersbach, Ali Behbahani, M.D., (New Enterprise Associates), and co-founder Dan McHugh (Emerson Collective).

Drawing upon deep, local talent pools in Durham and Seattle, Tune has assembled two highly seasoned discovery and development teams, secured foundational intellectual property from Duke University, and raised $40 million from top-tier investors including co-leads New Enterprise Associates and Emerson Collective, with Hatteras Venture Partners, Mission BioCapital, and others joining the round. This financing will enable Tune to rapidly advance its preclinical research, attract top-tier talent, and further develop its therapeutic platform.

"Tune is effectively pioneering a brand-new therapeutic modality," said Dr. Behbahani. "With the unbound potential of this approach, and their collective successes in the field, Tune is primed to become a transformative presence in modern biomedicine."

About Tune Therapeutics

Tune Therapeutics, Inc. is orchestrating the power of the epigenome to treat complex, pervasive diseases that have long eluded treatment. With its versatile and powerful TEMPO epigenomic control platform, Tune's experienced team is pioneering a new therapeutic modality that can fine-tune any gene network. In breaking free from the limitations of traditional gene and cell therapies, Tune is developing solutions for even the most challenging and intractable diseases and building the capacity to transform human health and medicine.

SOURCE Tune Therapeutics

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Tune Therapeutics Launches with Pioneering Epigenomic Control Platform to Master Gene Networks, Treat Broad Range of Diseases - PRNewswire

LONDON--(BUSINESS WIRE)--Gyroscope Therapeutics Holdings plc, a clinical-stage gene therapy company focused on diseases of the eye, today announced the appointment of biotech industry veteran Anthony (Tony) Adamis, M.D., to the Gyroscope Board of Directors, effective immediately. Dr. Adamis most recently served as Senior Vice President of Development Innovation at Genentech/Roche and brings more than 30 years of industry research and development experience to the role.

With his deep research and industry expertise, Dr. Adamis is best known for co-discovering the central role of vascular endothelial growth factor (VEGF) in ocular vascular disease, including age-related macular degeneration (AMD) and diabetic retinopathy. He has guided the development of 20 medicines in global clinical trials involving more than 25,000 patients. These development programmes led to 24 approvals by the U.S. Food and Drug Administration (FDA) across various indications.

As an ophthalmologist, Tony has seen first-hand the devastating impact of vision loss on peoples lives, and through his research, he helped pioneer a new field of medicines for people with wet AMD, said Khurem Farooq, Chief Executive Officer. Tonys expertise as a physician, industry executive and clinical researcher will be invaluable to us as we work to advance gene therapies for people with dry AMD who currently have no approved medicines. We are very excited to welcome him to the Gyroscope team.

Dr. Adamis received his medical degree with honours from the University of Chicago Pritzker School of Medicine. He completed his ophthalmology residency at the University of Michigan and his fellowship at Harvard. In 2000, Dr. Adamis co-founded Eyetech Pharmaceuticals, which developed and obtained FDA approval for the first anti-VEGF medicine in ophthalmology. With the introduction of anti-VEGF drugs, the rates of legal blindness from neovascular AMD and diabetic eye disease have decreased by half globally. Dr. Adamis also recently joined the board of directors of RD Funds, the venture arm of the Foundation Fighting Blindness.

About Gyroscope: Vision for Life

Gyroscope Therapeutics is a clinical-stage gene therapy company developing gene therapy beyond rare disease to treat diseases of the eye that cause vision loss and blindness. Our lead investigational gene therapy, GT005, is currently being evaluated in Phase II clinical trials for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), a leading cause of blindness. GT005 has received Fast Track designation from the U.S. Food and Drug Administration for the treatment of people with GA.

Supported by leading life sciences investors and biopharmaceutical companies, Gyroscope has built a global organisation combining discovery, research, drug development, a manufacturing platform and surgical delivery capabilities. Headquartered in London with locations in Philadelphia and San Francisco, our mission is to preserve sight and fight the devastating impact of blindness.

For more information visit: https://www.gyroscopetx.com/ and follow us on Twitter (@GyroscopeTx) and on LinkedIn.

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Gyroscope Therapeutics Announces Appointment of Tony Adamis to Board of Directors - Business Wire

-- RareStone to seek marketing authorization for IMCIVREE to treat obesity due to biallelic POMC, PCSK1 and LEPR deficiencies and Bardet-Biedl and Alstrm syndromes in mainland China, Hong Kong and Macau ---- Rhythm to receive $12 million upfront in cash and equity, up to $63.5 million in future milestone payments and sales royalties --

BOSTON, Dec. 06, 2021 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a biopharmaceutical company aimed at developing and commercializing therapies for the treatment of rare genetic diseases of obesity, and RareStone LTD, formerly Citrine Medicine, a China-based rare disease company, today announced an exclusive licensing agreement for the development and commercialization of IMCIVREE (setmelanotide) in China, including mainland China, Hong Kong and Macau. This licensing agreement marks the first expansion of Rhythms pipeline into Asia and is designed to accelerate patient access to IMCIVREE where there remains significant unmet need to address the severe, early-onset obesity and hyperphagia that characterize both acquired and genetic diseases of the melanocortin-4 receptor (MC4R) pathway.

According to the terms of the agreement, RareStone will seek local approvals to commercialize IMCIVREE for the treatment of obesity and hyperphagia due to biallelic proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency, as well as Bardet-Biedl and Alstrm syndromes. Additionally, RareStone will fund efforts to identify and enroll patients from China in Rhythms global EMANATE trial, a Phase 3, randomized, double-blind, placebo-controlled trial to evaluate setmelanotide in five independent sub-studies in patients with obesity due to a heterozygous variant of POMC/PCSK1 or LEPR; certain variants of the SRC1 gene, certain variants of the SH2B1 gene, or PCSK1 N221D deletions within the MC4R pathway.

RareStone, a company committed to treating rare diseases, is well-positioned to leverage its network of hospitals and key opinion leaders, deep regulatory experience and community-building infrastructure to advance IMCIVREE through clinical development and regulatory approvals in China, said David Meeker, M.D., Chair, Chief Executive Officer and President of Rhythm. We are thrilled to enter into this agreement, which substantially accelerates our ability to address the needs of patients living in China and potentially make IMCIVREE available to many more patients with rare genetic diseases of obesity.

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RareStone was founded in 2019 with funding from leading health care investors, including Eight Roads, F-Prime Capital, Vivo Capital, Quan Capital, 3H Health Investment and WU Capital. The Shanghai-based company is focused on building an ecosystem to support patients and families living with rare diseases in Greater China and has dedicated itself to improving the lives of patients with rare and intractable diseases by making diagnosis and essential treatments available and accessible to those who need them.

There is a significant need in China for a therapeutic option to treat patients with early-onset, severe obesity and hyperphagia caused by variants in genes of the MC4R pathway, said Shawn Xiang, Ph.D., CEO of RareStone. Rhythms precision medicine, IMCIVREE (setmelanotide), approved by FDA and authorized by the European Commission and Great Britains Medicines & Healthcare Products Regulatory Agency, has transformed the treatment paradigm for rare genetic diseases of obesity. We are eager to deliver the proven clinical benefit of IMCIVREE to patients in China and plan to pursue local approvals rapidly in five initial indications, while supporting Rhythms ongoing clinical development efforts more broadly.

According to the terms of the licensing agreement, RareStone will make an upfront payment to Rhythm of $7 million and issue $5 million in equity to Rhythm. Rhythm will be eligible to receive development and commercialization milestones of up to $63.5 million, as well as tiered royalty payments on annual net sales of IMCIVREE.

About Rhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the treatment paradigm for people living with rare genetic diseases of obesity. Rhythms precision medicine, IMCIVREE (setmelanotide), was approved in November 2020 by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing and in July and September 2021, respectively, by the European Commission (EC) and Great Britains Medicines & Healthcare Products Regulatory Agency (MHRA) for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. IMCIVREE is the first-ever FDA-approved and EC- and MHRA-authorized therapy for patients with these rare genetic diseases of obesity. The Company submitted a supplemental New Drug Application (sNDA) to the FDA, which was accepted for filing in November 2021 and assigned a Prescription Drug User Fee Act (PDUFA) goal date of March 16, 2022. Rhythm also submitted a Type II variation application to the European Medicines Agency in October 2021 seeking regulatory approval and authorization for setmelanotide to treat obesity and control of hunger in adult and pediatric patients 6 years of age and older with BBS or Alstrm syndrome in both the United States and European Union. Additionally, Rhythm, along with its partners, is advancing a broad clinical development program for setmelanotide in other rare genetic diseases of obesity and is leveraging the Rhythm Engine, the largest known obesity DNA database -- now with approximately 45,000 sequencing samples -- to improve the understanding, diagnosis and care of people living with severe obesity due to certain genetic deficiencies. Rhythms headquarters is in Boston, MA.

About RareStone LTD.RareStone, formerly Citrine Medicine, is dedicated to improving the lives of patients with rare and intractable diseases by making diagnosis and essential treatments available and accessible to those who need them in Greater China. Our mission is to build the first rare disease ecosystem in China, and in doing so, enable people with rare diseases to live more normal lives. In addition to developing and marketing rare disease drugs, RareStone aims to establish a patient-centric platform which educates people on rare diseases, trains doctors on diagnosis and treatment, and helps doctors develop a full disease management protocol. RareStones lead product candidate, Wakix (pitolisant), is an investigational oral drug in development for the treatment of narcolepsy and obstructive sleep apnea in China. RareStone also recently announced two strategic partnerships that will gives the company exclusive Greater China rights to develop, register, and commercialize Alkindi for pediatric congenital adrenal hyperplasia (CAH) patients and Efmody for adolescent and adult CAH and adrenal insufficiency patients. RareStone is headquartered in Shanghai, China and has other offices in Beijing, China and Cambridge, Mass. For more information, visit http://www.rarestonegroup.com

IMCIVREE (setmelanotide) IndicationIn the United States, IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by an FDA-approved genetic test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

In the EU and Great Britain, IMCIVREE is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. IMCIVREE should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology.

Limitations of UseIMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign;

Other types of obesity not related to POMC, PCSK1 or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity.

Important Safety Information

WARNINGS AND PRECAUTIONS

Disturbance in Sexual Arousal: Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections in males and sexual adverse reactions in females occurred in clinical studies with IMCIVREE. Instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

Depression and Suicidal Ideation: Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation. Monitor patients for new onset or worsening of depression. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors.

Skin Pigmentation and Darkening of Pre-Existing Nevi: IMCIVREE may cause generalized increased skin pigmentation and darkening of pre-existing nevi due to its pharmacologic effect. This effect is reversible upon discontinuation of the drug. Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmentary lesions.

Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: IMCIVREE is not approved for use in neonates or infants.

ADVERSE REACTIONS

The most common adverse reactions (incidence 23%) were injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection.

USE IN SPECIFIC POPULATIONSDiscontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Treatment with IMCIVREE is not recommended for use while breastfeeding.

To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

See U.S. Full Prescribing Information, EU SmPC and MHRA SmPC for IMCIVREE.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding activities in connection with the exclusive licensing agreement with RareStone and potential payments thereunder, the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide, including the anticipated timing for initiation of clinical trials and release of clinical trial data and our expectations surrounding potential regulatory submissions, approvals and timing thereof, and our business strategy and plans, including regarding commercialization of setmelanotide. Statements using word such as expect, anticipate, believe, may, will and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our liquidity and expenses, the impact of the COVID-19 pandemic on our business and operations, including our preclinical studies, clinical trials and commercialization prospects, and general economic conditions, and the other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and our other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise.

Corporate Contact:David ConnollyHead of Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com

Investor Contact:Hannah DeresiewiczStern Investor Relations, Inc.212-362-1200hannah.deresiewicz@sternir.com

Media Contact:Adam DaleyBerry & Company Public Relations212-253-8881adaley@berrypr.com

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Rhythm Pharmaceuticals and RareStone Ltd. Announce Exclusive Licensing Agreement for the Development and Commercialization of IMCIVREE (setmelanotide)...

Never in recent history has the world been so engrossed by the most mundane stages of the scientific process. But for the last two years, each incremental step in sciencefrom lab research to understand the evolution of COVID-19 and develop a vaccine to fight it, to clinical trials, to pharmaceutical approvalmeant one thing: Hope. And thats what this list of the years best health innovations highlights. In addition to two novel vaccines released to combat the most deadly pandemic of our time, the world also saw the first-ever drug approved to treat rare progeria, a new insulin formulation that might finally make the life-saving therapy affordable for all, and a malaria vaccine decades in the making.

Looking for the complete list of 100 winners? Check it out here.

A pair of COVID-19 vaccines, which are highly effective at preventing COVID-19, were authorized for emergency use in 2021. Pfizer/Moderna

To pull humankind out of the COVID-19 pandemic, doctors and public health experts knew we would need a safe and effective vaccine. Pharmaceutical companies around the world have raced to characterize the SARS-CoV-2 virus, understand how it invades our immune systems, and develop a targeted injection to prevent it. As of November 2021, at least 28 promising vaccines have been trialed in humans, and 15 have been authorized for emergency use around the world. But two stood out enough to win our top award: Pfizers Comirnaty, developed in partnership with Germany-based biotechnology company BioNTech, and Modernas SpikeVax, which the Cambridge, Mass., company developed with the help of the National Institutes of Allergy and Infectious Disease.

The jabs are unlike any other inoculation on the market today. They are the first so-called mRNA vaccinesa technology that has been in development for decades. They work by harnessing messenger RNA, the genetic bits of code that tell our cells how to make proteins. The vaccines carry mRNA with instructions for making a protein found on the outside of SARS-CoV-2, the novel virus that causes COVID-19. Our bodies quickly destroy the errant mRNA instructions, but not before our cells build the corresponding proteins. Those proteins then attach to specialized immune cells, triggering the system to recognize them as invaders and develop antibodies against their ilk. If a vaccinated person comes into contact with SARS-CoV-2, those antibodies can spring into action, reproduce, and destroy the virus before it replicates out of control, thwarting the disease.

This duo of shots also work remarkably well. In clinical trials, both of the two-dose regimens were at least 94 percent effective at preventing symptomatic cases of COVID-19. The vaccines also fended off hospitalization nearly 100 percent of the time. While a multitude of inoculation options were crucial to curbing the spread of the virus, these two mRNA therapies are especially poised to change the course of the pandemicand the future of preventative medicine.

Zokinvy is the first FDA-approved treatment for Hutchinson-Gilford progeria syndrome, a rare disease that causes premature aging. Eiger Pharmaceuticals

People diagnosed with Hutchinson-Gilford progeria syndrome rarely live beyond 15 years of age, and until now treatments could only target its symptoms and complications. The disease occurs when a genetic mutation changes the shape of a protein in the nuclei of a carriers cells. The faulty protein, called progerin, causes cells to prematurely die. Zokinvy prevents the buildup of defective progerin, thereby minimizing the damage it can do. In addition to prolonging lifespan by several years, the new drug also reduces symptoms of heart and bone problems associated with the rare condition, which affects roughly 400 children worldwide.

In a first, researchers successfully treated a genetic liver disease by injecting the CRISPR gene editing tool directly into a persons body. Intellia Therapeutics

Since 2012, researchers have been tweaking CRISPR, the gene-editing tool that easily edits the human genome, to treat diseases caused by DNA mutations. But until this year, the method, which involves injecting a patient with tweaked stem cells, had only been used to treat conditions whose mutations are in the bloodstream, such as sickle-cell anemia.In August of 2021, researchers published the results of a six-person clinical trial in which doctors attempted to fix a genetic defect that causes a rare liver condition called transthyretin amyloidosis. Packaged inside a tiny blob called a lipid nanoparticle, the gene-editing tech made its way to the liver, where it went to work correcting defective cells. Theres still a long way to go before this treatment, which is still in the first phase of clinical trials, finds its way to the market. But, if successful, it could pave the way for healing a wide variety of genetic conditions.

The FDA approved a number of monoclonal antibody treatments this year, including Regenerons Inmazeb. Regeneron Pharmaceuticals, Inc.

When infected with Zaire ebolavirus, people can experience high fevers, severe bleeding, and organ failure, which is fatal in half of cases. Researchers at biotech company Regeneron have now created monoclonal antibodieslab-crafted molecules that mimic the work of the immune systems natural defenses to help take down invadersto target the illness. Inmazeb is a combination of three antibodies that target a protein on the surface of the Ebola virus. In a clinical trial, 66.2 percent of the 154 people who received Inmazeb survived, compared to only 49 percent of the 153 people who didnt. While not a surefire cure, monoclonal antibodies have been crucial in treating many viral diseases. The FDA gave an emergency-use authorization to two monoclonal antibody therapies for COVID-19 in 2021, and approved another one to treat Ebola as well.

Ellume delivers a result in as little as 20 minutes. Ellume

Vaccines greatly reduce the risk of acquiring and spreading COVID-19, but theyre not perfect. Breakthrough cases will continue to emerge even among highly vaccinated communities. Thats where testing comes in. The Ellume at-home COVID-19 test was the first of its kind to get FDA authorization, allowing consumers to check their COVID-19 status without going to the doctor. The test consists of a nasal swab, a dropper, processing fluid, and an analyzer. An app takes you through step-by-step instructions: Connect the analyzer via Bluetooth, empty the processing fluid into the dropper, swab both nostrils, attach the swab to the dropper, squeeze five drops onto the analyzer, and wait 15 minutes for your results. Ellume reports that the test identifies positive cases 95 percent of the time and negative ones 97 percent of the time.

The Bridge-Enhanced ACL Restoration Implant by Miach Orthopaedics offers a less invasive way to repair a persons ACL. Boston Childrens Hospital

The ACL, or anterior cruciate ligament, stretches diagonally across the middle of the knee and is vital in keeping our bodies upright and stable. Its also prone to failure; according to a 2016 report in the Journal of Clinical Orthopedics and Trauma, its the most common source of significant knee injury. Repairing a torn ACL requires surgery, and sometimes reconstructionan invasive procedure where a piece of tendon and bone is taken from another part of the body, or from a donor, to rebuild the torn ligament. The newly FDA-approved BEAR Implant takes the place of that material. Made of bovine collagen, its secured in place between the two torn ends of the ACL to bind them together. The patients body absorbs the device within a few months, by which time, new, healthy tissue has grown in its place.

The sharpest, clearest CT scanner, yetSiemens

CT scans provide detailed images of the inside of the human body that help diagnose and track disease and injury. Conventional scanners create images by combining the total energy from several x-rays. During this process, some energy from the x-ray is lost, leading to lower resolution. Siemens new scanner, called the Naeotom Alpha, uses detectors that count photons to measure every particle of light that comes through, leading to sharper, higher contrast images of the inner workings of your body.

An insulin product that everyone can afford. Viatris, Inc

Some 34 million people live with diabetes in the United States alone. For many of them, insulina hormone usually produced in the pancreas that helps process glucoseis necessary for survival. Despite this, insulin remains an extremely expensive product, even for those who are fully insured. Semglee could change that. Its an interchangeable, biosimilar insulin productthe first of its kind to gain recognition from the FDA. A biosimilar is a biological therapy (hormones and vaccines are examples) that has no meaningful difference from one thats already FDA-approved and on the marketthink of it as a generic medication that pharmacists can swap for a name-brand drug, but that doesnt require prior approval from a doctor to make the switch. Semglee, which comes in 10 mL vials and 3 mL prefilled pens and is administered subcutaneously once daily, is medically identical to Lantus, the name brand for insulin.

Mosquirix, developed to prevent malaria, is also the first vaccine to prevent a parasitic disease. GlaxoSmithKline

By some estimates malaria kills about half a million people worldwide every year. GlaxoSmithKlines Mosquirixa vaccine decades in the makinggenerates an immune response against Plasmoduim falciparum, which is among the most deadly of the fiveparasites that cause malaria, and the most prevalent strain throughout Africa. The vaccine received an endorsement from the World Health Organization; a distinction that gives it the go-ahead for wider distribution and use. While the inoculation is only about 50 percent effective against severe malaria, with a significant drop in efficacy after a year, its still one of the best ways to prevent the deadly disease.

The first new antifungal in decades treats vaginal yeast infections. SCYNEXIS, Inc.

According to the CDC, about 1.4 million people in the US go to the doctor for vaginal yeast infections each year. While over-the-counter treatments often work just fine, more stubborn cases can resist. Brexafemme is the first novel antifungal in more than two decades, representing an entirely new class called triterpenoids. It works by blocking an enzyme that helps create a protective coating around Candida fungi, which cause vaginal yeast infections. Without this covering, the microbe quickly dies off. The two-tablet formulation starts working within a few days, and remains in a persons system for as long as two weeks to prevent a resurgence.

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The top 10 health and medicine breakthroughs of 2021 - Popular Science

Introduction

Intracranial aneurysm (IA) is a complex disease characterised by pathological dilatation of the cerebral arteries. IA may rupture, leading to subarachnoid haemorrhage (SAH) and significant morbidity and mortality, one of the most devastating neurological events.1 Although the pathogenesis of IA has been explored for many years, the mechanisms of its formation, growth, and rupture remain largely unknown. Various theories have been proposed to develop IA, which is generally believed to be a multifactorial disorder that occurs due to the interaction of environmental and genetic factors.2,3 Environmental factors, such as alcohol consumption, smoking, sex, and hormonal background of the patient, and hypertension seem to be common risk factors.4,5 In addition, there have been many studies on genetic markers for the risk of IA,6,7 which vary according to ethnicity and may not be generalisable to different populations.

Extracellular matrix (ECM) remodelling plays an important role in maintaining the structure and integrity of intracranial arteries. Disruption of the ECM of the arterial wall is a likely factor in the pathogenesis of IA.8 The VCAN gene, located at 5q12-q14, has 15 exons encoding a large 372.82 kDa chondroitin sulphate proteoglycan in the ECM, which plays a key role in maintaining ECM function.9 It has also been implicated in cell proliferation, cell adhesion, cell migration, and invasion. The VCAN gene produces four subtypes, V0, V1, V2, and V3, by alternate splicing of exons 7 and 8. The two largest exons, 7 and 8, encode glycosaminoglycan (GAG) attachment sites, GAG alpha and GAG beta, respectively.9,10 The latter contains a proteoglycan class with heparin sulphate. The loss of function of similar protein-binding domains may lead to the rupture of these components in certain proteins in the ECM, softening the artery wall, forming an aneurysm.

VCAN is a candidate gene for IA because it plays a vital role in ECM assembly and is localised in a previously implicated locus for IA on chromosome 5q.11 However, polymorphisms can have various effects in these gene regions that can be race-specific (since polymorphisms are known to be race-specific). Previous linkage studies have indicated that the three VCAN SNPs, rs251124, rs173686, and rs2287926, are associated with aneurysms.10,12,13 Nevertheless, replication studies in different ethnicities have provided conflicting results regarding IAs.10,12,14,15 Considering the genetic differences among different races and regions and the uncertainty of the correlation between VCAN gene polymorphism and IA incidence in the Chinese population, we aimed to explore the association of the VCAN gene variants rs251124, rs173686, and rs2287926 with IA prevalence in the Eastern Chinese population.

This study complied with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board and Ethics Committee of the First Affiliated Hospital of Anhui University of Science and Technology. All participants provided written informed consent (Approval No. 2019B20,2019-1-1).

This case-controlled prospective study included 162 patients with sporadic IAs and 182 age-matched controls admitted to the First Affiliated Hospital of Anhui University of Science and Technology between January 2017 and December 2020. All cases with confirmed IAs based on digital subtraction angiography (DSA) were retrospectively confirmed by a neuroradiologist and two highly qualified cerebrovascular neurosurgeons. Patients were excluded if they had a family history of IA, fusiform and dissection aneurysms, or traumatic and infectious aneurysms. A total of 182 controls were symptomatically normal and did not have a medical or family history of IA or SAH. Controls subjects were sex- and age-matched individuals, diagnosed negative for IA by DSA or CTA from the same hospital, and matched to IA patients for the area of residence to eliminate the effect of population stratification by heterogeneity.

Candidate SNPs were selected by searching for SNPs in previous studies and genome-wide association studies (GWAS) that showed significant associations with IA. DNA was extracted from peripheral blood leukocytes using the TIANamp Blood DNA Extraction Kit (TIANGEN Biotech Co., Ltd., Beijing, China). The DNA samples were stored at 80 C until use. SNP genotyping for rs251124, rs2287926, and rs173686 was performed using Kompetitive Allele Specific PCR (KASP). The SNP data were analysed with CFX Manager Software version 3.1 (Bio-Rad).

General clinical features of the case and control groups were described as mean standard deviation (SD) and compared using Students t-test for continuous variables. Genotype and allele frequencies were computed and checked for deviation from the HardyWeinberg equilibrium (ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl). Categorical variables were presented as proportions and were compared using the chi-square test or Fishers exact test (two-tailed). Further stratification of the patients based on sex and aneurysm rupture status was performed to understand the role of the VCAN variant within the sexes and between the ruptured aneurysm and non-ruptured aneurysm groups. The association of SNPs with the risk of sporadic IA was investigated using logistic regression analysis. Statistical significance was set at P<0.05. All statistical analyses were performed using GraphPad Prism 8.02 (San Diego, CA, USA) and SPSS software (version 21.0; IBM Corp., Armonk, NY, USA).

A total of 162 IA patients and 182 control subjects were included in this study. The demographic characteristics of patients and controls are shown in Table 1. In the case group, 72.8% of the patients had a single aneurysm. The aneurysms were primarily located in the internal carotid artery (38.3%), followed by the middle cerebral artery (19.1%), anterior communicating artery (13.6%), and other locations. Additional details are provided in Table 2.

Table 1 Characteristics of Cases vs Controls

Table 2 Clinical Characteristics of Intracranial Aneurysm

The distribution of the SNP genotypes was consistent with the HardyWeinberg equilibrium. As shown in Table 3, there were significant differences in the genotype and allele frequency distributions of rs251124 and rs173686 between the IA cases and controls (P<0.05). A significant association was observed with rs251124 at the allelic (OR=1.489, CI: 1.0892.044; P=0.0137) and genotypic (P=0.0415) levels. The frequency of rs251124-TT in IA patients was higher than in controls (2= 6.364, P=0.0415). The risk allele frequencies of rs173686 were significantly different between patients with IA and controls (OR=1.558, CI: 1.1152.171; P=0.0096). For SNP rs2287926, there was no statistically significant difference in genotype or allele frequencies between the patient and control groups (Table 3).

Table 3 Genotype and Allele Frequencies of SNPs of VCAN

Table 4 shows the genotypes of the SNPs and their associations with IA. Logistic regression analysis showed that the T/T genotype and T allele of rs251124 were independent risk factors for IA (OR=1.726, 95% CI: 1.1362.263; P=0.011). Similarly, for the SNP rs173686, G allele carriers were also at a significantly higher risk of IA (OR=2.52, 95% CI: 1.2615.037; P=0.009).

Table 4 Logistic Regression Model of Genotype Analysis

Table 5 shows no significant difference in genotype frequencies between the ruptured and unruptured aneurysm groups at either of the two SNPs rs251124 and rs173686 (P>0.05).

Table 5 Genotypic Results of Ruptured and Unruptured Aneurysms

Table 6 shows no significant difference in genotype frequencies among aneurysm groups at either of the two SNPs rs251124 and rs173686 (P> 0.05).

Table 6 Genotype Frequencies of SNPs rs251124 and rs173686 at Different Locations

Table 7 suggests that the rs251124 T allele and rs173686 G allele contribute to a significantly higher risk for males and females at both allelic and genotypic levels when stratified based on sex (P<0.05).

Table 7 Comparison of the Genotype and Allele Frequencies of rs251124 and rs173686 Within Males and Females in Cases and Control

There are various theories about the development of aneurysms, most of which reflect an imbalance in the ECM remodelling. ECM remodelling plays an important role in maintaining the structure and integrity of intracranial arteries and its reduction is a prominent feature of cerebral aneurysms. The VCAN gene localised on 5q12q14 has 15 exon codes9 for a large 372.82 kDa chondroitin sulphate proteoglycan found abundantly in the ECM and plays various roles in maintaining ECM functions. Some studies have shown that a decreased density of smooth muscle cells results in decreased production of CSPG2 (also known as versican), which in turn weakens the vascular wall. VCAN (CSPG2) also plays an important role in the assembly of ECM, and diminished maintenance of the ECM has been increasingly regarded as an important factor in the development of IA.16

This study investigated the associations between three SNPs in the VCAN gene and IA susceptibility in the Eastern Chinese population. The results showed that rs251124T/T genotype and T allele and rs173686 G/G genotype and G allele increased the risk of IA formation. No significant differences in genotype or allele frequencies between the case and control groups were detected at the rs2287926 SNP. Our findings further support the VCAN gene as an IA susceptibility gene.

The VCAN gene (also known as chondroitin sulphate proteoglycan [CSPG2]) predicts the risk of aneurysm development and subsequent rupture.12,15,16 Nevertheless, the association between the SNPs of VCAN and the risk of IA remains controversial due to contrary reports. For example, Sathyan et al10 found that the minor allele T of rs251124 showed an increased risk of IA. The CT genotype has been defined as a risk factor for the occurrence and rupture of aneurysms in a South Indian population. In addition, rs2287926 further substantiates the potential role of VCAN in the pathogenesis of IA.

Moreover, no confirmed association between rs173686 at genotypic and allelic levels and IA in the South Indian population has been reported. However, in a Dutch population, the VCAN (CSPG2) genes were identified as susceptibility genes for IA, and the rs173686 polymorphism has also been linked to IA.12 The association between the rs173686 polymorphism and IA risk has also been observed in a Kazakh population.14 Similarly, another study replicated the association of rs251124 with the risk of IAs in a Japanese IA population.15 In contrast, replication studies reported a lack of association between the CSPG2 variants (rs173686 and rs251124) with IA susceptibility.15 The above studies suggest that race and geography may influence these contradictory results. On the other hand, this may be explained by the heterogeneity of ethnic origin and/or small sample size.

Consistent with previous studies and meta-analyses,10,12,13 we found that rs251124 was associated with sporadic IAs, and rs251124T/T genotype and T allele were risk factors for IA in the Eastern Chinese population, but not in agreement with the results of Sun et al,15 who found no confirmed association in a study of Han Chinese. Additionally, our study found that the rs173686 G/G genotype and G allele significantly increased the risk of IA formation, which was similar to the results of studies conducted among European,12 Kazakh,13 and Japanese populations,14 but inconsistent with the results of Sun et al.15 The contrary results indicate that individuals from the same ethnic group also have different susceptibilities. Sun et al15 reported that the two SNPs rs173686 and rs251124 of the CSPG2 gene were not susceptible to IAs in Northern Chinese (Beijing) Han nationality. Alternatively, we observed that rs173686 and rs251124 highly increased the risk of IA formation in the Eastern Chinese population. To the best of our knowledge, the occurrence of IA is the result of the combined effects of genetic and environmental factors. One of the underlying causes of this discrepancy might be regional differences. Our research subjects included patients from eastern China; the possibility of different genetic backgrounds and surroundings caused by ethnic and regional differences might affect the experimental results. In addition, our study group was relatively small; therefore, our results require validation in a large-scale population. Overall, it has been hypothesised that genetic heterogeneity among diverse populations can lead to such paradoxical results.

In addition, our study included patients with ruptured and unruptured IAs. For either of the two SNPs rs173686 and rs251124, there was no statistically significant difference in genotype or allele frequencies between the two groups studied, suggesting that no associations were found in the SNPs rs173686 and rs251124 with IA rupture susceptibility in the Eastern Chinese population. To the best of our knowledge, this is the first study to investigate the association between the VCAN gene and IA rupture in a Chinese population.

Moreover, our study found no significant difference in genotype frequencies among aneurysm groups at either SNP rs251124 or rs173686 (P> 0.05). This suggests that the locations of aneurysm distribution may have nothing to do with SNP variation. Furthermore, subgroup analysis by sex showed that rs251124 T allele and rs173686 G allele contributed to high risk for both males and females at both allelic and genotypic levels, implying that sex has no significant effect on SNP variation. Another possible reason for this result is that the sample size was small.

This study had some limitations. It included only Eastern Chinese patients; therefore, the sample size was relatively small and may not be adequate for assessing the effect of these SNPs on the formation of IAs. Thus, additional studies using different populations are warranted to further validate ethnic and regional differences in the impact of the VCAN polymorphism on IA risk. Moreover, molecular biology experiments and reliable animal models are required to explore the specific mechanisms further.

This study revealed that rs251124 and rs173686 are genetic risk factors for IA formation in the Eastern Chinese population. No association was found between SNP rs2287926 and IA. Our findings suggest that the VCAN gene is an IA susceptible gene, which warrants further study as a screening marker for intracranial aneurysms.

The authors thank Key project of Education Department of Anhui Province (KJ2019A0096) and Huainan science and technology planning project (2016A26(3)) for supporting this work.

The authors report no conflicts of interest in this work.

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2. Boehme AK, Esenwa C, Elkind MS. Stroke risk factors, genetics, and prevention. Circ Res. 2017;120(3):472495. doi:10.1161/CIRCRESAHA.116.308398

3. Ruigrok YM, Rinkel GJ. From GWAS to the clinic: risk factors for intracranial aneurysms. Genome Med. 2010;2(9):61. doi:10.1186/gm182

4. Cho SM, Marquardt RJ, Rice CJ, et al. Cerebral microbleeds predict infectious intracranial aneurysm in infective endocarditis. Eur J Neurol. 2018;25(7):970975. doi:10.1111/ene.13641

5. Chen Y, Zhang Y, Chao YJ, et al. Stent-assisted coiling embolization of middle cerebral artery trifurcation wide-necked aneurysms. Eur Rev Med Pharmacol Sci. 2017;21(19):43464349.

6. Tromp G, Weinsheimer S, Ronkainen A, Kuivaniemi H. Molecular basis and genetic predisposition to intracranial aneurysm. Ann Med. 2014;46(8):597606. doi:10.3109/07853890.2014.949299

7. Bourcier R, Redon R, Desal H. Genetic investigations on intracranial aneurysm: update and perspectives. J Neuroradiol. 2015;42(2):6771. doi:10.1016/j.neurad.2015.01.002

8. Ruigrok YM, Rinkel GJ, Wijmenga C. Genetics of intracranial aneurysms. Lancet Neurol. 2005;4:179189. doi:10.1016/S1474-4422(05)70021-1

9. Iozzo RV, Naso MF, Cannizzaro LA, et al. Mapping of the versican proteoglycan gene (CSPG2) to the long arm of human chromosome 5 (5q125q14). Genomics. 1992;14(4):845851. doi:10.1016/S0888-7543(05)80103-X

10. Sathyan S, Koshy LV, Balan S, et al. Association of Versican (VCAN) gene polymorphisms rs251124 and rs2287926 (G428D), with intracranial aneurysm. Meta Gene. 2014;2:651660. doi:10.1016/j.mgene

11. Onda H, Kasuya H, Yoneyama T, et al. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet. 2001;69(4):804819. doi:10.1086/323614

12. Ruigrok YM, Rinkel GJ, Wijmenga C. The versican gene and the risk of intracranial aneurysms. Stroke. 2006;37(9):23722374. doi:10.1161/01.STR.0000236499.55301.09

13. Zholdybayeva EV, Medetov YZ, Aitkulova AM, et al. Genetic risk factors for intracranial aneurysm in the Kazakh population. J Mol Neurosci. 2018;66(1):135145. doi:10.1007/s12031-018-1134-y

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16. Ruigrok YM, Rinkel GJ, Vant Slot R, et al. Evidence in favor of the contribution of genes involved in the maintenance of the extracellular matrix of the arterial wall to the development of intracranial aneurysms. Hum Mol Genet. 2006;15:33613368. doi:10.1093/hmg/ddl412

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SNPs rs251124, rs2287926, and rs173686 with IA | NDT - Dove Medical Press

A study from the Yale Cancer Center potentially introduces a drug design platform to fight drug resistance for patients with HER2-positive breast cancer and ovarian cancer.

A therapeutic strategy that targets cancer-associated gene amplifications via triplex-forming oligonucleotides (TFOs) demonstrated in vivo efficacy, which compared favorably to current precision medicines in patients with HER2-positive breast and ovarian cancer, potentially introducing an alternative option to combat drug resistance in these patient populations, according to research published in Nature Biotechnology.1

In addition to its in-vivo efficacy, investigators reported that TFOs targeting HER2 yielded copy numberdependent DNA double strand breaks (DSBs) and were successful in activating p53-independent apoptosis in HER2 cancer cell and human xenograft models. Overall, treatment of HER2-positive breast cancer xenografts with a TFO, HER2-205, resulted in a 52% reduction in tumor volume when compared with untreated control groups. The finding is comparable with a 58% reduction garnered from treatment with trastuzumab (Herceptin).

Our findings are exciting as they offer a new option to fight breast and ovarian cancers as effectively as clinically utilized drugs now targeting the HER2 protein, senior author Faye Rogers, PhD, associate professor of Therapeutic Radiology at Yale Cancer, said in a press release.2 A number of anticancer therapies have been developed to inhibit the protein products of amplified cancer driver genes, but have met drug resistance.

The research teams goal was to develop a potential drug platform that could directly convert amplified oncogenic driver genes into DNA damage to ultimately induce cell death. The strategy utilizes TFOs that are capable of recognizing unique polypurine sites within the amplified chromosomal region to provoke apoptosis.

After assessing the correlation between level of triplex-induced DNA damage and increased gene copy numbers via a neutral comet assay, the team observed that HER2-205 better induced DNA damage than HER2-1. Moreover, HER2-205 induced significantly more DSBs than HER2-1 in cell lines that contained multiple copies of the HER2 gene.

When looking at HER2-targeting TFOs, the results suggest triplex-induced apoptosis may provide the foundation for potential therapeutic options capable of targeting cancers that develop from gene amplification and sparing tissues that are not gene amplified.

We plan to extend this platform, particularly focusing on cancers with limited precision medicine options, Rogers explained. We will also focus our efforts on drug delivery, since inadequate bioavailability to the tumor can significantly impact therapeutic effect.

Additional findings from the study indicated that tumor growth reduction was observed with intraperitoneal administration of HER2-205. Additionally, investigators reported a tumor tripling time of 29 5.7 days following initial dosing with HER2-205 compared with a of 24 2.1 days in tumors treated with trastuzumab. Moreover, control oligonucleotide MIX24 (ANOVA) did not appear to impact BT474's tumor growth vs the control buffer alone, investigators reported a tumor tripling time of 15.7 4.9 days for control tumors vs 16.3 6.6 days in tumors treated with MIX24 (P = .99).

We envision the use of this drug design platform as a treatment option for several cancers with gene amplification and resistance to current therapies, the investigators concluded.

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Potential New Therapeutic Option May Combat Drug Resistance in HER2+ Breast Cancer and Ovarian Cancer - Cancer Network