Category Archives: Genetic medicine

News Release

Wednesday, November 20, 2019

Studies in cell and animal models reveal insights into cancer cells vulnerability that could lead to new strategies against brain cancers.

Researchers have devised a new plan of attack against a group of deadly childhood brain cancers collectively called diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma. Scientists at the National Institutes of Health, Stanford University, California, and Dana-Farber Cancer Institute, Boston, identified a drug pair that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases.

The researchers showed that combining the two drugs panobinostat and marizomib was more effective than either drug by itself in killing DMG patient cells grown in the laboratory and in animal models. Their studies also uncovered a previously unrecognized vulnerability in the cancer cells that scientists may be able to exploit to develop new strategies against the cancer and related diseases. The results were published Nov. 20 in Science Translational Medicine.

DMGs are aggressive, hard-to-treat tumors that represent the leading cause of brain cancer-related death among U.S. children. DMGs typically affect a few hundred children a year between ages 4 to 12; most children die within a year of diagnosis. Most cases of DMG are caused by a specific mutation in histone genes. Histones are protein complexes in the cell nucleus. DNA wraps around histones to form chromatin, which packages DNA in the nucleus. How DNA winds and unwinds around histones is influenced by enzymes, including histone deacetylases. These enzymes add or remove chemical tags, which indirectly controls if genes are turned on or off.

In an earlier study, Stanford neuro-oncologist Michelle Monje. M.D., Ph.D., and her colleagues showed that panobinostat, which blocks key histone deacetylase enzymes, could restore the DIPG histone function to a more normal state. While panobinostat is already in early clinical testing in DIPG patients, its usefulness may be limited because cancer cells can learn to evade its effects. So Monjes team wanted to identify other possible drugs and combinations of them that could affect the cancer.

Very few cancers can be treated by a single drug, said Monje, a senior author of the study who treats children with DIPG and other diffuse midline gliomas. Weve known for a long time that we would need more than one treatment option for DIPG. The challenge is prioritizing the right ones when there are thousands of potential options. Were hopeful that this combination will help these children.

Monje and the National Cancer Institutes Katherine Warren, M.D., now at Dana-Farber Cancer Institute and Boston Childrens Hospital, collaborated with Craig Thomas, Ph.D., and his colleagues at the NIHs National Center for Advancing Translational Sciences (NCATS). Thomas and his team used NCATS drug screening expertise and matrix screening technology to examine drugs and drug combinations to see which ones were toxic to DIPG patient cells.

NCATS robotics-enabled, high-throughput screening technologies enable scientists to rapidly test thousands of different drugs and drug combinations in a variety of ways. Scientists can examine the most promising single drugs and combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.

The NCATS researchers first studied the effects of single approved drugs and investigative compounds on DIPG cell models grown in the laboratory from patient cells. They focused on agents that could both kill DIPG cells and cross the brains protective blood-brain barrier, a necessity for a drug to be effective against DIPG in patients. The team then tested the most effective single agents in various combinations.

Such large, complex drug screens take a tremendous collaborative effort, said Thomas, also a senior study author. NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.

While there were multiple, promising outcomes from these screens, the team focused on the combination of histone deacetylase inhibitors (like panobinostat) with drugs called proteasome inhibitors (such as marizomib). Proteasome inhibitors block cells normal protein recycling processes. The panobinostat-marizomib combination was highly toxic to DIPG cells in several models, including DIPG tumor cell cultures that represented the main genetic subtypes of the disease and mice with cells transplanted from patient tumors. The combination also reduced tumor size in mice and increased their survival. A similar response was found in spinal cord and thalamic DMG models developed from cells grown in culture from patient cells.

The screening studies also provided important clues to the ways the drugs were working. Building on these data, the collaborative team subsequently conducted a series of experiments that showed the DIPG cells responded to these drugs by turning off a biochemical process in the cells mitochondria that is partly responsible for creating ATP, which provides energy to cells. The drug combination essentially shuts down tumor cell ATP production.

The panobinostat-marizomib drug combination exposed an unknown metabolic vulnerability in DIPG cells, said first author Grant Lin, Ph.D., at Stanford University School of Medicine. We didnt expect to find this, and it represents an exciting new avenue to explore in the development of future treatment strategies for diffuse midline gliomas.

Plans are underway for clinical trials of the drug combination and of marizomib alone.

Many drugs that we test have multiple effects on DIPG cells, said Warren, a senior study author. Panobinostat, for example, inhibits a specific enzyme, but it has other mechanisms working in tumor cells that may contribute to its effectiveness. Were still trying to understand the various Achilles heels in these cancer cells. This work is an important step in translating our preclinical data into patients.

Monje stressed the panobinostat-marizomib combination might be an important component of a multitherapy strategy, including approaches that harness the immune system and those that disrupt factors in the tumor microenvironment that the glioma cells depend on to grow. Like Warren, Monje emphasized the need to better understand how drugs target and impact the DIPG cells vulnerabilities.

Our work with NCATS showed the need to gather more preclinical data in a systematic, high-throughput way to understand and prioritize the strategies and agents to combine, Monje said. Otherwise were testing things one or two drugs at a time and designing clinical trials without preclinical data based on hypothesized mechanisms of action. We want to move past this guesswork and provide preclinical evidence to guide clinical decisions and research directions.

Lin added, The idea is to get as many effective tools as possible to work with that can have an impact on patients.

The research was funded by Alexs Lemonade Stand Foundation, Izzys Infantry Foundation, McKenna Claire Foundation, Unravel Pediatric Cancer, Defeat DIPG Foundation, ChadTough Foundation, N8 Foundation, Kortney Rose Foundation, Cure Starts Now Foundation and the DIPG Collaborative, Sam Jeffers Foundation, Lyla Nsouli Foundation, Abbies Army Foundation, Waxman Family Research Fund, Virginia and D.K. Ludwig Fund for Cancer Research, National Institute for Neurological Disorders and Stroke (R01NS092597) and NIH Directors Common Fund (DP1NS111132), Maternal and Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, The DIPG All-In Initiative and the NCATS and NCI intramural programs.

Reference:GL Lin et al. Therapeutic Strategies for Diffuse Midline Glioma from High-Throughput Combination Drug Screening. Science Translational Medicine. DOI: 10.1126/scitranslmed.aaw0064

About the National Center for Advancing Translational Sciences (NCATS):NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visithttps://ncats.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Scientists find promising drug combination against lethal childhood brain cancers - National Institutes of Health

By Clare Wilson

Tetra Images/Getty Images

Plans for the National Health Service to sequence the DNA of every baby born in the UK, starting with a pilot scheme of 20,000 children, were announced by health minister Matt Hancock this week. It sounds like the UK is leading the way in high-tech healthcare but doctors are saying the idea is ethically questionable.

Babies are already tested for certain health conditions soon after birth, so it may seem as though sequencing their genome, their entire set of genes, is a simple upgrade of this routine screening, but that isnt the case.

UK babies are tested for nine carefully selected conditions, all of which can be avoided or lessened with pre-emptive treatment. For instance, the metabolic disorder phenylketonuria can cause brain damage, but this can be avoided through a low-protein diet.

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Unfortunately, most illnesses arent as simple or treatable. We are only at the beginning of our journey to understand the complexity of the human genome, and some of the information we have learned so far can create difficult dilemmas.

Take the genetic condition Huntingtons disease, which starts with mild symptoms in middle age, eventually progressing to severe disability and early death. There is no cure.

When people learn that Huntingtons is in their family, they may spend years deciding whether to take the test. Many choose not to. Parents who ask doctors to test their child are turned down, as set out in international guidelines. Deciding to learn if you have the gene responsible is such a personal choice that it must be left to the individual concerned once they turn 18.

Huntingtons is rare, but there are similar dilemmas over more common conditions such as genes that predispose people to Alzheimers disease and some types of cancer. There is currently little you can do to avoid dementia, and for women who learn they have a certain gene that increases cancer risk, the safest step is to have their breasts and ovaries removed.

Some people would rather not know about these risks before it is necessary. We have endless discussions about [the ethics of] testing children for conditions that dont manifest until later life, says Frances Elmslie of the British Society for Genetic Medicine.

Nor would it make sense to sequence children at birth then wait until they are 18 to give the results. In the intervening years, DNA sequencing is bound to become cheaper and more powerful. It would make more sense to offer it to every 18-year-old, says Martin Brunet, a family doctor in Surrey, UK.

There is a small group of children for whom genome sequencing can be useful: those with rare undiagnosed medical conditions. In one study, sequencing led to a diagnosis in a fifth of children in intensive care, and that figure is likely to improve over time. In these cases, parents can consent for their children because there is a medical benefit but that is very different to sequencing everyone out of curiosity.

A US group has begun a small trial of routine genome sequencing of healthy babies. The families are being monitored to see how they cope and to measure any harms and benefits.

No details are available about the UK plans and Hancock didnt respond to New Scientists requests for comment. But introducing sequencing for everyone is a massive step. It will require public consultation over the ethical questions not to mention on practical issues like how the data will be stored securely and the impact on doctors workloads, says Elmslie. We need to think really carefully about this.

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Sequencing the genome of every UK baby would be an ethical minefield - New Scientist News

Could one woman's rare genetic mutation one day have a global impact on dementia risk?

It's possible, say investigators who report on a potentially groundbreaking case of a woman whose genetic mutation staved off dementia for decades, even though her brain hadalreadybeen damaged by Alzheimer's disease.

While most Alzheimer's cases are not driven by genetic predisposition, one woman in Colombia is among about 1,200 in her country who do face a genetically higher risk for early-onset Alzheimer's.

Why? They all carry the E280A mutation of a gene called Presenilin 1 (PSEN1), which is known to increase the chances for Alzheimer's at a far younger age than usual.

"We identified an individual that was predisposed to develop Alzheimer's in her 40s," noted study author Dr. Joseph Arboleda-Velasquez. He's an assistant professor of ophthalmology with the Schepens Eye Research Institute of Mass Eye and Ear at Harvard Medical School, in Boston.

But, strangely, the woman "remained unimpaired until her 70s," Arboleda-Velasquez added.

The twist: the woman had, in fact, developed clear telltale signs of Alzheimer's in her brain. She just hadn't developed dementia.

For example, while she had fewer neural "tangles" in her brain than is typical for Alzheimer's patients, by the time she hit her 40s she did have the same unusually high level of brain amyloid-beta deposits as her E280A peers. Such deposits are a key signature of Alzheimer's.

So why didn't she develop middle-aged dementia like her peers?

To unravel the mystery, Arboleda-Velasquez and his colleagues ran an in-depth genetic analysis on the woman. And what they found is that she had not just one mutation, but two.

In addition to the E280A mutation, she also carried the so-called "Christchurch" mutation in the APOE3 gene.

But there's more. Not only did she carry the Christchurch mutation, but she hadtwoof them. Some of her E280A peers (about 6%) also carried a single copy of Christchurch. But she was the only one who carried two, the investigators found.

"It is ultra-rare, with an approximate prevalence of less than one in every 200,000 individuals," Arboleda-Velasquez said.

And having one such rare mutation did not appear to be enough. No protection against dementia was linked to only one Christchurch mutation. But as this woman's case suggests, having two such mutations did seem to throw up a shield against Alzheimer's, preserving her ability to remember things and think clearly for a few decades, long after her E280A peers had started experiencing cognitive decline.

"This is the first time a specific patient who carries the [double] mutation has been linked to such a protective benefit," Arboleda-Velasquez noted.

How does it work? It seems that "the mutation puts a block on the cascade of events linking amyloid accumulation to neural [brain cell] death," he explained.

The team did acknowledge that more research will be needed to definitively confirm the Christchurch mutation's impact, and to further explore how this mutation/dementia delay connection truly works.

But, in theory, the incredibly rare experience of this one woman in Colombia could ultimately have profound ramifications for Alzheimer's patients around the world, if "new drugs that mimic the effect of [the] mutation" could be developed, said Arboleda-Velasquez. Rather than stopping Alzheimer's from developing, such drugs would prevent Alzheimer's from causing dementia.

The study was published Nov. 4 in the journalNature Medicine, and was partly funded by the U.S. National Institutes of Health and the Alzheimer's Association.

Heather Snyder, vice president of medical and scientific relations at the Alzheimer's Association, characterized the findings as "an important discovery."

The insights gleaned from a look at this particular patient's experience are "full of possibilities for increasing our understanding of Alzheimer's disease and all dementia, and advancing potential avenues for treatment," Snyder suggested.

"Understanding what is happening in the brains of people when there appears to be a delay or stopping of the disease progression because of this gene form or otherwise gives rise to many possibilities for investigating new treatment and risk-reduction opportunities," she added.

At the same time, Snyder cautioned that "more research is needed to understand more thoroughly how genetics impacts Alzheimer's/dementia risk, and to expand and confirm these findings in a larger number of people."

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Alzheimer's disease: Rare genetic mutation might hold clues to preventing or treating dementia - CBS News

BRISBANE, Calif.--(BUSINESS WIRE)--Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine company, announced today that is has established a new Scientific Advisory Board (SAB). The SAB comprises an eclectic group of industry and academic experts who will advise Sangamo on its current and future clinical programs and research and development strategy.

I am excited to be working with such a distinguished, diverse, and imaginative group of experts who have joined our Scientific Advisory Board to provide input into Sangamos research and clinical development strategy, with a view to helping us identify new opportunities for differentiation and innovation in the genomic medicine space, and to define and address future trends, said Adrian Woolfson, B.M., B.Ch., Ph.D., Head of Research and Development. As Sangamo continues to advance programs from our technology platforms into clinical programs, it is critical that we obtain input from individuals with diverse expertise across a broad range of relevant research and development areas."

The Sangamo SAB members are as follows:

For more information, please visit https://www.sangamo.com/about-us/leadership.

About Sangamo Therapeutics

Sangamo Therapeutics, Inc. is focused on translating ground-breaking science into genomic medicines with the potential to transform patients' lives using gene therapy, ex vivo gene-edited cell therapy, in vivo genome editing, and gene regulation. For more information about Sangamo, visit http://www.sangamo.com.

Forward-Looking Statements

This press release contains forward-looking statements regarding Sangamo's current expectations. These forward-looking statements include, without limitation, statements regarding the Company's ability to develop and commercialize product candidates to address genetic diseases with the Company's proprietary technologies and the timing of commencement or next stages of such programs and the anticipated benefits therefrom. These statements are not guarantees of future performance and are subject to certain risks, uncertainties and assumptions that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, the outcomes of clinical trials, the uncertain that members of the SAB will remain engaged with Sangamo and the uncertainties of the regulatory approval process. Actual results may differ from those projected in forward-looking statements due to risks and uncertainties that exist in Sangamo's operations and business environments. These risks and uncertainties are described more fully in Sangamo's Annual Report on Form 10-K for the year ended December 31, 2018 as filed with the Securities and Exchange Commission on March 1, 2019 and Sangamo's Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 that it filed on November 6, 2019. Forward-looking statements contained in this announcement are made as of this date, and Sangamo undertakes no duty to update such information except as required under applicable law.

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Sangamo Therapeutics Announces New Scientific Advisory Board - Business Wire

New testing at the University of Vermont Medical Center will help determine the role DNA plays in your health.

We want to improve peoples lives, said Dr. Debra Leonard, chair of Pathology and Laboratory Medicine at the University of Vermont Medical Center.

For the past year and a half, shes been working along with a team of physicians and specialists to develop Genomic DNA Testing.

It really is to integrate genetic information into routine medical care, she said.

Dr. Leonard said that information can be very helpful in improving outcomes for patients if they know their disease risk in advance. The testing will allow patients to learn about differences in their DNA that can make certain diseases more likely.

What we will be focusing on is diseases related to the heart and diseases related to cancer risk, Dr. Leonard said.

UVM Health Network is partnering with Invitae and LunaPBC on the project which will provide information on nearly 150 genes that are indicators for illnesses. The goal is to recognize if a patient is at risk for one of those diseases before they actually experience their first symptom, allowing doctors to intervene early and make informed decisions.

So we can use preventive strategies or close monitoring to catch the diseases earlier or even implement strategies to prevent the diseases, she said.

Right now, the testing is in its beginning phases. Last Friday, it was offered to the first patient, who agreed to have their blood drawn and sent out for testing, fully funded by the department. Over the next year, UVMMC is aiming to test 1,000 patients ages 18 and older.

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Genetic testing at UVMMC aims to improve patient care - Local 22/44 News

Somewhere along the road from sickness to health, the American medical system took a wrong turna big one.

The cost of care in our country is sky-high, yet our population health outcomes tend to be worse than those of other developed countries (many of which have universal health care). Major surgeries, treatments for long-term illnesses like cancer, and medical attention for catastrophic injuries are so expensive that people can lose their homes or be forced to declare bankruptcy. Even a routine visit to a general practitioner can cost hundreds of dollars. Yet Americans have some of the highest rates of heart disease, diabetes, and obesity in the world.

How did we get here?

In a talk at Singularity Universitys Exponential Medicine summit this week in San Diego, Dr. Jordan Shlain shared his thoughts on that question, as well as a framework for moving American healthcare forward. The first step, he believes, is a new Hippocratic oath, one thats been updated for our high-tech age.

It was the fifth century BC when Hippocrates put forth the idea that physicians should try to help people and do no harm (a pretty intuitive concept, one would think), among other ethical standards. The Hippocratic oath was born, and over time its been modified to reflect shifts in medicine and society. But the field of medicine has changed even more than the oath has, and Shlain believes its time for another overhaul.

He pointed to the beginning of early modern medicine as pivotal to the field. As new technologies came along that had potential to treat people more effectively, everyone wanted access to those technologies, so someone had to start manufacturing themand the incentive to do so was a profit.

When X-rays and penicillin were invented, we could see things wed never seen before and treat things wed never been able to treat before, Shlain said. Someone had to make X-ray machines and someone had to form a pharmaceutical company. But the convergence of medicine and business fed mounting costs, conflicts of interest, bureaucracy, and a focus on profits over patients.

Medical technology companies and pharmaceutical companies are now massive and complex, as are the medical and regulatory systems. Theres a lot standing between physicians and patients, Shlain said. It leads us to reactive medicine, and theres physician burnout.

The root of this problem, he believes, is that a corporate oath has superseded the Hippocratic oath in healthcare. The corporate oath says to increase shareholder value, generate profits, and constantly grow margins. But they dont know the outcomes on the other side, Shlain said. Exhibit A? The opioid crisis.

Since 1970, the costs of medications and medical devices have only gone upand so have corporate revenues. went up, cost of devices went up. But despite spending all this money and having all this expensive technology and medications, were not doing too well, Shlain said, pointing to a graph that shows life expectancy in the US falling since 2014. We need to differentiate between consumers and patients.

Shlains new oath consists of nine different statements.

1. I shall endeavor to understand what matters to the patient and actively engage them in shared decision making. I do not own the patient, nor their data. I am a trusted custodian.

Shlain pointed out that rather than asking patients What matters to you? physicians ask, Whats the matter with you? But to get the right answer, it should be a combination, and not just between doctors and patients, but in every interaction in the healthcare system.

2. I shall focus on good patient care and experience to make my profits. If I cant do well by doing good and prove it, I dont belong in the field of the healing arts.

We need to have some version of transparency for our outcomes, Shlain said.

3. I shall be transparent and interoperable. I shall allow my outcomes to be peer-reviewed.

Silicon Valley has gotten better at embracing a culture of learning from failure and even encouraging failure as a path to eventual advancement, but the medical field hasnt done the sameand perhaps rightfully so, since failure can mean a life lost. However, Shlain added, a byproduct of failure is almost always some sort of lesson.

4. I shall enable my patients the opportunity to opt in and opt out of all data sharing with non-essential medical providers at every instance.

Data privacy should be respected both as a path to trust and as a basic patient right.

5. I shall endeavor to change the language I use to make healthcare more understandable; less Latin, less paternal language; I shall cease using acronyms.

I would rename type two diabetes the over-consumption of processed food disease, because thats what it is, Shlain said. You dont get it, you participate in its process. But you didnt know it, because the language obfuscates that. So we really need to dig into language here, because language does tie to the metaphors we live by.

6. I shall make all decisions as though the patient was in the room with me and I had to justify my decision to them.

7. I shall make technology, including artificial intelligence algorithms that assist clinicians in medical decision making, peer-reviewable.

Everyone has proprietary technology and were supposed to use it despite not knowing how it works, Shlain said. Its in the interest of both practitioners and patients for this to change.

8. I believe that health is affected by social determinants. I shall incorporate them into my strategy.

Someones zip code can tell you more about their health than their genetic code, Shlain said. We need to focus on community.

9. I shall deputize everyone in my organization to surface any violations of this oath without penalty. I shall use open-source artificial intelligence as the transparency tool to monitor this oath.

Shlain pointed out that feedback loops in big corporations often arent productive, because people worry about losing their jobs. We need to create some mechanism of a feedback loop to ensure that this happens, he said.

This new oath isnt just for clinicians, Shlain emphasized. Its for everyone who touches the healthcare system in any way. That includes pharmaceutical companies, device manufacturers, medical suppliers, hospitals, and so on.

Given how fast new technologies are changing the healthcare landscape, we may need a totally new oath in ten years; what happens when robots are performing surgery, AI systems have taken over diagnosis, and gene editing can cure almost any congenital disease? Well need to continuously stay aware of how doctors roles are evolving, and update the ethical codes they practice by accordingly.

What we need is a culture of care, at every level, Shlain said. In order to change our paradigm, we need to have a set of principles that get us there.

Image Credit: Wikimedia Commons

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Why Medicine Needs a New Hippocratic Oathand What It Should Be - Singularity Hub

Conceptualised by Optimal Media Solutions, a division of the Times Group, Times Health Excellence 2019, is a platform to celebrate and honour outstanding achievements in Indian medicine. Optimal Media Solutions has over the years emerged as an integrated media solutions partner; going beyond conventional advertising, to provide customized and innovative options to clients.

The 2nd edition of this milestone event culminated in a glittering ceremony at Sheraton Grand Bangalore Hotel at Brigade Gateway, Yeshwantpur on 17th October 2019. The august gathering included the presence of distinguished guests and illustrious awardees from the field of medicine. Conceived as an innovative approach to document, disseminate and project new approaches that involve medical and health professionals, the event was envisioned to provide a boost to the way success stories are preserved and shared. As a part of this initiative, the pioneering contributions of some eminent medical practitioners were presented and applauded. Several thought provoking and enlightening presentations were made by renowned doctors, who are eminent practicing professionals.

The proceedings began with a brilliant presentation by Dr. Meenakshi Bhat, Professor & Mazumdar-Shaw Research Chair in Clinical Genetics, Centre for Human Genetics Bangalore. Her presentation titled Rare Genetic Disorders: Every Life Matters was an eye-opener on medical conditions that are largely ignored, but can be identified through medical advancements.

Dr. N K Venkataramana, Founder Chairman & Chief Neurosurgeon BRAINS, followed with an engaging presentation on Frontiers in Neurosciences. He spoke about the various developments in the field with regard to cutting edge services in prevention, awareness, advocacy, acute and chronic care, regeneration, rehabilitation, research and training.

Dr. Ann Agnes Mathew, Paediatric Neuromuscular Specialist, Sagar Hospitals Bangalore, then made a presentation on Inherited Muscle and Nerve diseases: Can India lead the world? that outlined the challenges faced in the industry.

Dr. Sandeep Nayak, Director of Surgical Oncology, MACS Clinic & Fortis Hospitals, Bangalore, made a presentation on the topic Revolutionising Cancer Care: Which Way Are We Heading? He spoke at length about several surgical innovations in oncology, which have changed the way the disease is tackled.

Dr. Mahendra S K, Senior Consultant Orthopaedic surgeon and Chairman, Matru Multispecialty Hospital, made a presentation on Orthopaedic surgeries, reviving quality of life...empathy above techniques. His inspiring speech highlighted several case studies, where those who suffering chronic conditions that had been given up on, were treated successfully with appropriate interventions.

Celebrity guest, Ms. Swara Bhasker, a popular Bollywood actress was also in attendance at the event. She added a touch of glamour with her gracious presence.

Those who were applauded at Times Health Excellence 2019, were trailblazers who have pushed all possible boundaries, and nurtured a passion for innovation, continuously seeking out ways to make things better for the holistic development of our nation. Their skill, talent, discipline has paved the way for many game changing initiatives and helped fuel their growth and strengthen Indias position in healthcare.

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TIMES HEALTH EXCELLENCE 2019 - HONOURING OUTSTANDING CONTRIBUTIONS IN MEDICINE - Times of India

Summary

A study reports on a new way to determine who is most likely to benefit from immunotherapy. It may help explain why immunotherapy works differently in people around the world.

Since 2011, the immunotherapy drugs called checkpoint inhibitors have become an increasingly important treatment for certain cancers. This is especially true for people with melanoma and lung cancer.

Early on, investigators observed that these drugs are extremely effective for some people, even eliminating their cancer entirely. Unfortunately, they dont work at all for many others. Considerable research has tried to understand why this is the case and exactly how these drugs work.

Checkpoint inhibitors work by releasing a natural brake on your immune system so that immune cells called T cells recognize and attack tumors.

Memorial Sloan Kettering physician-scientist Timothy Chan has focused on these efforts. He is one of the corresponding authors of a study published November 7, in Nature Medicine that reports a new way to determine who is most likely to benefit from immunotherapy. The findings may help explain why immunotherapy works differently in people around the world.

Our results help solve part of the mystery of why there is such a large variation in the effectiveness of immune checkpoint drugs, says Dr. Chan, who leads the Immunogenomics and Precision Oncology Platform at MSK. Its important that future clinical trials of immune checkpoint drugs take our discovery into account. This is especially important for international phase III trials.

For decades, the human leukocyte antigen (HLA) genes have been known to govern how the immune system responds to foreign substances in the body. Over thousands of generations, as early humans migrated out of Africa and around the planet, they evolved variations in their HLA genes. These changes protected them from infectious organisms that were found in different parts of the world.

The classic battle between pathogens and the human immune system plays out in the HLA genes, Dr. Chan says. A 2017 study from Dr. Chan was the first to show that HLA genes are important for the bodys ability to see cancer after immunotherapy as well. That study reported that people who had a greater number of different copies, or alleles, in their HLA-1 genes responded better to immunotherapy compared with those whose HLA-1 genes had fewer alleles. The new study builds on this previous work.

To quantify how efficient the immune system is at detecting cancer, the researchers looked at the HLA genes from more than 1,500 people who had received immune checkpoint drugs as part of clinical trials at MSK and other hospitals. Most of those included in the study had melanoma or non-small cell lung cancer, but other kinds of cancer were also represented.

Study Uncovers Genetic Reasons Why Some People Respond to Immunotherapy Better than Others

Immunotherapy drugs called checkpoint inhibitors have been a game changer for some people with cancer. But for most patients, these drugs have been disappointing. Researchers are trying to figure out why.

People inherit one copy of HLA-1 from each parent. For each person analyzed, the team found that the more molecularly diverse, or different from each other, the two copies of each of their HLA-1 genes were, the more likely someone was to respond to treatment and survive their cancer. The investigators developed a novel way to measure this difference, which they call HLA evolutionary diversity (HED).

Dr. Chans co-corresponding author on the Nature Medicine paper, Tobias Lenz of the Max Planck Institute for Evolutionary Biology in Germany, is an expert in the evolution of the human immune system and the HLA genes. Research fellow Diego Chowell and graduate student Chirag Krishna from Dr. Chans lab and graduate student Federica Pierini from Dr. Lenzs lab were the co-first authors.

Dr. Chan has also looked at other factors that make immune checkpoint drugs more effective. In 2014, he led the first studies finding that patients who responded to these drugs tended to have a large number of gene mutations in their tumors. This is known as having a high tumor mutational burden (TMB). When tumors have a greater number of mutations, it is more likely that they will produce proteins that the immune system hasnt seen before.

For checkpoint inhibitor drugs to be effective, the immune system needs to be able to recognize cancer cells as foreign, Dr. Chan says. High TMB and diverse HLA genes are two sides of the same coin. Both make it more likely that the immune system will see the cancer.

The researchers note in their study that high TMB and high HED are independent of each other, but the combined outcome of the two led to benefits from immunotherapy drugs that were greater than either of these effects on their own. These are the yin and yang of T cellbased immune checkpoint treatment, Dr. Chan says. High TMB is less useful if a person is unable to present the mutations to the immune system. Having a high HED allows that to happen.

Our results help solve part of the mystery of why there is such a large variation in the effectiveness of immune checkpoint drugs.

Recent immunotherapy clinical trials have begun to include TMB in their evaluation of how effective checkpoint inhibitors are, Dr. Chan notes. But among different trials, there is great variation in the role that TMB plays. No one has been able to figure out whats going on, he says. It turns out, we should also be looking at HLA diversity. This finding may account for the unexplained variation thats seen in the role of TMB in immunotherapy trials.

He adds that it may also account for the different response rates that have been observed in different parts of the world. HED can vary dramatically depending on where someone lives.

The investigators are now working to develop a standardized way to report HED, so that it can be incorporated into future clinical studies. Dr. Chans team is in the process of evaluating HED with industry partners using global phase III trial data. They hope that this measure can eventually become a regular part of cancer diagnosis and be used to match people with cancer with the most personalized treatments.

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Genetic Variations Help Explain Why Immunotherapy Works Differently in Different People - On Cancer - Memorial Sloan Kettering

Researchers have identified complement genes that appear to play a role in vision loss associated with multiple sclerosis (MS), and this finding could help researchers monitor and predict the progression and severity of MS, according to a study published in Brain.

Even though previous studies have identified gene variants associated with the risk of developing MS, until now, there have been no identified gene variants associated with MS severity.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms, the authors explained.

In 374 patients with all types of MS, the researchers used an imaging technique that allows them to assess damage to the nerve cells in the retina. Patients underwent an average of 4.6 scans between 2010 and 2017, and the authors reported that the rate of deterioration was a loss of 0.32 micrometers of tissue per year per patient, on average.

After they identified the patients who had the fastest deterioration rates, the researchers collected DNA through blood samples to identify genetic mutations. They identified 23 DNA variations that mapped to the complement gene C3.

Once they identified the variants, they analyzed DNA from blood samples of 835 patients with MS in an existing clinical trial who underwent periodic vision testing. The researchers noted genetic changes in the complement genes C1QA and CR1 in patients whose ability declined the fastest in the vision tests. Patients with mutations in C1QA were 71% more likely to develop difficulty with the vision test and patients with changes in CR1 were 40% more likely.

The authors plan to repeat the studies in larger populations and conduct animal studies investigating the function of complement proteins to better understand the mechanism behind their ability to kill nerve cells in patients with MS.

"Although we have treatments for the type of MS where symptoms come on in burstscalled relapsing-remitting MSwe don't have any way to stop the kind of MS in which the nerve cells start to die, known as progressive MS," Peter Calabresi, MD, professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and codirector of the Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, said in a statement. "We believe that our study opens up a new line of investigation targeting complement genes as a potential way to treat disease progression and nerve cell death."

Reference

Fitzgerald KC, Kim K, Matthew D Smith, Aston SA, et al. Early complement genes are associated with visual system degeneration in multiple sclerosis. Brain, 2019; 142(9):2722. doi: 10.1093/brain/awz188.

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Researchers Identify Genes With Potential to Predict Progression and Severity of MS - AJMC.com Managed Markets Network

PTC Therapeutics announced a strategic partnership with Aldevronto ensure the production of high-quality plasmid DNA to be used with PTCs investigational gene therapies, including AGIL-AS for the treatment of Angelman syndrome (AS).

PTCs growing gene therapy pipeline for genetic disorders of the central nervous system (CNS) also includes an investigational gene therapy for AADC deficiencythats nearing submission to the U.S. Food and Drug Administration (FDA), as well as candidates for Friedreichs ataxiaand Angelman syndrome that are at earlier development stages. Other candidates for cognitive disorders and inherited retinal disorders are in preclinical research.

Our strategic collaboration with Aldevron represents our continued commitment to produce and provide the highest quality product to patients, Neil Almstead, PhD, PTCs chief technical operations officer, said in a press release.

Our gene therapy pipeline is addressing the unmet needs of multiple patient populations, and we feel an urgent need to develop safe products with the utmost speed. The development of relationships with top-tier companies like Aldevron aligns with our goal of partnering with the best collaborators as we drive meaningful improvements in the lives of patients, Almstead said.

PTCs gene therapy candidate for Angelmans syndrome is called AGIL-AS. It uses a modified virus that does not cause infection called an adeno-associated virus (AAV) to deliver a working copy of the UBE3Agene, the faulty gene in Angelman syndrome, to the brain and spinal cord of patients. The process is designed to restore production of the E6-AP protein produced by the UBE3A gene, this way improving cell function and rescuing neurological defects in Angelman syndrome.

Preclinical studieshave shown that AGIL-AS targets nerve cells in the brain, increases levels of E6-AP, and eases AS-like cognitive deficits in animal models of the disease.

AGIL-AS was granted orphan drug designationfrom the U.S. Food and Drug Administration in 2015, followed by a similar designation from theEuropean Commission in 2016.

Under the agreement, Aldevron will manufacture the plasmid DNA (circular molecules of DNA) where the functional version of UBE3A gene will be enclosed for delivery. The company ensures the materials are produced under Good Manufacturing Practice (GMP), a set of guidelines allowing products to be consistently made and controlled according to quality standards.

It is truly an honor to work with PTCs motivated team of experts. They are making enormous contributions to the future of genetic medicine, saidMichael Chambers, founder and CEO of Aldevron.

This is Aldevrons mission to serve scientists and researchers who are relentlessly pursuing cures for people who need them, he added.

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

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

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PTC, Aldevron Partner to Advance Angelman and Other Gene Therapy Candidates - Angelman Syndrome News