Stanford Center Hopes to Take Stem Cell and Gene Therapies to a New Level – Sickle Cell Anemia News

The new Stanford Center for Definitive and Curative Medicine will fosterthe development ofstem cell and gene therapies for genetic diseases, including sickle cell anemia.

More than280 million people around the world have diseases with genetic causes, experts estimate. While research has identified the underlying causes of several, scientists have developed few therapies that can address the causes or cure the diseases.

Treatments have been developed thatsignificantly improve patients health, however. They include public health initiatives, targeted therapies and surgery.

Scientists believe stem cell and gene therapy can cure some genetic diseases. They would likely do this either by rewiring cells to fight a disease more efficiently or by correcting a genetic errorin a patients DNA.

Stanford not only does excellent research in disease mechanisms, cell and stem cell biology, but also promotes collaboration between its medical schools and hospitals.

The initiative is a joint venture of theStanford University School of Medicine,Stanford Health CareandStanford Childrens Health.

Dean Predicts Center Will Be Major Force in the Precision-health Revolution

The Center for Definitive and Curative Medicine is going to be a major force in theprecision-health revolution, Dr. Lloyd Minor, dean of the School of Medicine, said in a press release. Our hope is that stem cell and gene-based therapeutics will enable Stanford Medicine to not just manage illness but cure it decisively and keep people healthy over a lifetime.

We are entering a new era in medicine, one in which we will put healthy genes into stem cells and transplant them into patients,said Christopher Dawes, the president and CEO of Stanford Childrens Health. And with the Stanford Center for Definitive and Curative Medicine, we will be able to bring these therapies to patients more quickly than ever before.

The work of the center is not being done anywhere else in the country only at Stanford, said David Entwistle, president and CEO of Stanford Health Care. We have a pipeline of clinical translational therapies that the center is now driving forward, enabling us to translate basic science discoveries into state-of-the-art therapies for diseases which up until now have been considered incurable.

Dr. Maria Grazia Roncarolo will direct the center,which will be in the Department of Pediatrics.The renowned medical doctor and scientist is the George D. Smith Professor of Stem Cell and Regenerative Medicine.

It is a privilege to lead the center and to leverage my previous experience to build Stanfords preeminence in stem cell and gene therapies, said Roncarolo, who is also chief of pediatric stem cell transplantation and regenerative medicine, co-director of theBass Center for Childhood Cancer and Blood Diseases,and co-director of theStanford Institute for Stem Cell Biology and Regenerative Medicine.

Main Mission Will Be to Turn Scientific Discoveries Into Treatments

Stanford Medicines unique environment brings together scientific discovery, translational medicine and clinical treatment, Roncarolo added. We will accelerate Stanfords fundamental discoveries toward novel stem cell and gene therapies to transform the field and to bring cures to hundreds of diseases affecting millions of children worldwide.

The centers main mission will be to turn scientific discoveries into treatments. A world-classinterdisciplinary team of scientists should help it deliver on that promise.

Leaders of the team will include Dr. Matthew Porteus, an associate professor of pediatrics, and Dr. Anthony Oro, the Eugene and Gloria Bauer Professor of dermatology. Dr. Sandeep Soni will direct the centers stem cell clinical trial office.

The center will provide novel therapies that can prevent irreversible damage in children, and allow them to live normal, healthy lives, said Dr. Mary Leonard, chair of pediatrics at Stanford Childrens Health. The stem cell and gene therapy efforts within the center are aligned with the strategic vision of the Department of Pediatrics and Stanfordsprecision-healthvision, where we go beyond simply providing treatment for children to instead cure them definitively for their entire lives.

A unique feature of the center will be a close association with the Stanford Laboratory for Cell and Gene Medicine, which is working on new cell and gene therapies.

The lab has already developed genetically corrected bone marrow cells as a treatment for sickle cell anemia. Other genetically modified cells it has created include skin grafts for children with the genetic disease epidermolysis bullosa and lymphocytes for children with leukemia.

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Stanford Center Hopes to Take Stem Cell and Gene Therapies to a New Level - Sickle Cell Anemia News

Nicotine ameliorates schizophrenia cognitive deficits in mice [PreClinical] – 2 Minute Medicine

1. A gene alteration in the nicotinic acetylcholine receptor(nAChR) 5 subunit, previously found to be associated with schizophrenia, was recapitulated in mice and led to increased neuron firing in the prefrontal cortex and reduced pyramidal cell activity.

2. Following the administration of nicotine, neuronal firing was normalized in mice deficient in the 5 subunit.

Evidence Rating Level: 2 (Good)

Study Rundown: Schizophrenia is a complicated mental illness that is not fully understood mechanistically. A recent genome-wide association study found a single nucleotide polymorphism (SNP) associated with schizophrenia in the nAChR 5 subunit gene. The researchers in this study developed mouse models with alterations in this gene to mechanistically characterize this mutation and to determine its role in schizophrenia.

First, mice expressing the 5 SNP were behaviorally and cognitively tested. These mice showed impaired social ability as well a decrease in prepulse inhibition (PPI), two characteristics seen in patients with schizophrenia. A knockout mouse model was then produced that lacked the 5 subunit. These mice showed decreased activity of neurons in layer II/III of the prefrontal cortex (PFC) and reduced pyramidal cell activity, recapitulating the hypofrontality that is a defining feature of schizophrenia. Neuronal activity was restored when this subunit was re-expressed in these mice. Finally, 5SNP mice were treated with nicotine due to prior evidence that it can improve schizophrenia symptoms. Mice treated with nicotine showed a restoration of neuronal firing, demonstrating the potential clinical efficacy of this drug. Overall, this study clarified specific neuronal changes that occur in schizophrenia and provided evidence for using nicotine administration as a therapeutic strategy for schizophrenic patients.

Click to read the study in Nature Medicine

Relevant Reading: Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia

In-Depth [animal study]: First, a mouse line was generated to express the human 5 SNP associated with schizophrenia. A three-chamber social test demonstrated impaired social ability in these mice, specifically a lack of preference to interact with another mouse compared to an inanimate object as well as a decrease in exploration (p<0.001). The PPI of these mice was then tested. The 5SNP mice had a decreased PPI over a range of decibel levels.

Next, the 5 subunit was knocked out in a mouse model to elucidate the role of this gene in neuronal firing. The neurons in these mice showed decreased firing of neurons in layer II/III of the PFC (p<0.001), paralleling the hypofrontality commonly seen in schizophrenia patients. When this subunit was re-expressed in these PFC layers, pyramidal neuron activity was completely restored (p<0.001). Conversely, when an 5-Cas9 lentiviral vector was used to knockdown 5, there was an increase in interneuron activity and reduced pyramidal cell activity. Researchers concluded that in layers II/III of the PFC, the 5 subunit serves to inhibit interneurons, leading to the activation of pyramidal cell activity.

Finally, due to the potential benefit of nicotine administration in schizophrenia, nicotine treatment was tested in 5SNP mice. A mini-pump was subcutaneously implanted that secreted 2.4 mg nicotine per kg body weight per day to mimic the nicotine concentration seen in smokers. These mice were treated for 1 to 2 weeks, and an increase in pyramidal neuron activity was observed (p<0.001).

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Nicotine ameliorates schizophrenia cognitive deficits in mice [PreClinical] - 2 Minute Medicine

Rare Gene Mutations Inspire New Heart Drugs – New York Times


New York Times
Rare Gene Mutations Inspire New Heart Drugs
New York Times
Added to the existing arsenal of cholesterol-reducers and blood pressure medications, the new medications will drive the final nail in the coffin of heart disease, predicted Dr. John Kastelein, a professor of vascular medicine at the University of ...

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Rare Gene Mutations Inspire New Heart Drugs - New York Times

Will this gene-editing tool cure the diseases of the future? – Sacramento Bee


Sacramento Bee
Will this gene-editing tool cure the diseases of the future?
Sacramento Bee
We delete the gene, and we investigate what changes in behavior or physiology are the result of the deletion of that gene, Wood said. The results are being compared against human medical records, and this will find potential new models and sources ...

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Will this gene-editing tool cure the diseases of the future? - Sacramento Bee

Early-life BPA exposure reprograms gene expression linked to fatty liver disease – Medical Xpress

April 2, 2017 3D chemical structure of bisphenol A. Credit: Edgar181 via Wikimedia Commons

Exposure during infancy to the common plasticizer bisphenol A (BPA) "hijacks" and reprograms genes in the liver of newborn rats, leading to nonalcoholic fatty liver disease (NAFLD) in adulthood. A new study has found how this process occurs, and researchers will present the results Saturday at ENDO 2017, the Endocrine Society's 99th annual meeting in Orlando, Fla.

NAFLD is a buildup of extra fat in liver cells that is not caused by alcohol and that can lead to cirrhosis, or scarring, of the liver. This common disease occurs more often in people with obesity, diabetes, high cholesterol or high triglycerides (blood fats).

BPA is an industrial chemical found in polycarbonate plastics, such as many food and beverage containers, and in epoxy resins that line food cans. Past studies show that BPA and many other chemicals in our environment are endocrine-disrupting chemicals that can interfere with the body's hormones and eventually lead to obesity and other diseases.

"We believe this disease risk occurs via developmental reprogramming of the epigenome, which can persist throughout a lifetime," said the study's lead investigator, Lindsey Trevio, Ph.D., an instructor and researcher at Baylor College of Medicine, Houston, Texas. "These persistent changes lead to alterations in gene expression in ways that correlate with increased disease susceptibility."

In both rats and humans, the epigenome programs our complete set of DNA (the genome), but unlike genetic defects, epigenomic reprogramming can be reversed, Trevio said.

"Understanding the mechanisms underlying this endocrine disruptor-mediated epigenomic reprogramming may lead to the identification of biomarkers for people at risk as well as possible interventions and therapeutics for NAFLD," she said.

In research funded by the National Institute of Environmental Health Sciences, Trevio and her colleagues sought to identify the molecular causes of the developmental reprogramming they had observed in past animal studies. They treated newborn rats with low, environmentally relevant doses of BPA during a critical period of liver development: the five days after birth. The liver, she explained, is "a central player in fat metabolism and obesity." Then they examined liver tissue from the BPA-exposed rats immediately after exposure or when the rats were adults. These tissue samples were compared with liver samples from control rats who did not receive BPA.

Trevio reported that BPA-exposed rats, but not control rats, that were fed a high-fat diet as adults had increased liver weight and raised levels of total cholesterol, "bad" (LDL) cholesterol and triglycerides. Furthermore, genes involved in the progression of NAFLD exhibited increased expression in the liver of the BPA-exposed rats, but not in control animals. Specifically, she said they found that BPA created two new activating epigenomic marks on genes driving progression of NAFLD. These marks appear at key regulatory regions of affected genes, thus likely becoming "super promoters" that code the gene to turn on. However, she noted that this change appears to require a later-in-life challenge, such as eating a high-fat diet.

The researchers have reportedly seen BPA and other endocrine disruptors promoting epigenomic reprogramming in additional tissues in rats. Trevio said, "Our findings could be useful in other diseases as well. Because these endocrine disruptors are ubiquitous in the environment, a large portion of the population may be affected by developmental reprogramming."

Explore further: Endocrine disruptors cause fatty liver

Exposure to low doses of hormone-disrupting chemicals early in life can alter gene expression in the liver as well as liver function, increasing the susceptibility to obesity and other metabolic diseases in adulthood, a new ...

A new study presented today demonstrates that a build-up of fat around the waist can cause more serious complications than obesity in the development of non-alcoholic fatty liver disease (NAFLD). The study was presented at ...

Adult offspring of mothers who used fluoxetine, a common antidepressant, during pregnancy were more likely to develop a fatty liver, a new animal study has found. The results will be reported Saturday at the joint meeting ...

EPFL scientists have discovered a new biological mechanism behind nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. NAFLD is a frequent finding in patients with type 2 diabetes, but the exact prevalence of NAFLD, as well as whether patients ...

The type of sugar you eatand not just calorie countmay determine your risk for chronic disease. A new study is the first of its kind to compare the effects of two types of sugar on metabolic and vascular function. The ...

Mothers who binge drink before they become pregnant may be more likely to have children with high blood sugar and other changes in glucose function that increase their risk of developing diabetes as adults, according to a ...

Exposure during infancy to the common plasticizer bisphenol A (BPA) "hijacks" and reprograms genes in the liver of newborn rats, leading to nonalcoholic fatty liver disease (NAFLD) in adulthood. A new study has found how ...

Animals can pass the damaging effects of nighttime light exposure to their offspring, a new study has found, adding to a growing body of evidence that there's a health cost to our increasingly illuminated nights.

Northwestern Medicine scientists have identified a novel pathway that regulates cellular iron, which could lead to new therapies for patients with either an overload or deficiency of iron.

Lungs take in oxygen and release carbon dioxide. Yet despite their existential importance, the development of the lungs and the rules governing the process that enables respiration is still not well understood at the molecular ...

Researchers from the European Bioinformatics Institute (EMBL-EBI), University of Cambridge, the Wellcome Trust Sanger Institute and the Cancer Research UK-Cambridge Institute (CRUK-CI) have shed light on a long-standing debate ...

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Early-life BPA exposure reprograms gene expression linked to fatty liver disease - Medical Xpress

Zallen: Genetic testing bill is modern eugenics – Roanoke Times

By Doris T. Zallen | Zallen is professor emerita of science studies and humanities at Virginia Tech. She is the author of To Test or Not to Test: A Guide to Genetic Screening and Risk.

The Preserving Employee Wellness Programs Act (HR 1313), now being pushed by Republicans in the House of Representatives, is a threat to employees, will not improve wellness programs, and has the potential to unleash a corrosive force that could undermine the future of genomic medicine.

Genetic testing is becoming a central tool in the 21st century medical arsenal. Advances in genetics first made it possible to identify specific genes that bring on specific, relatively rare, health conditions such as cystic fibrosis, sickle-cell disease and muscular dystrophy.

Recent advances have yielded genetic tests that can identify people who, though healthy now, are at a higher-than-average risk for developing an illness in the future. Examples here include breast cancer, Parkinsons disease and Alzheimers disease all quite common.

However, these risk-raising genes are imperfect predictors. Environmental factors, including diet and exercise, also play key roles. The reality is that being found to have a risk-raising gene does not mean you will get the disease and, because of the involvement of environmental factors, you can get the disease without having the gene.

HR 1313 would allow employers to require genetic testing of employees in their wellness programs and assess harsh financial penalties on those who refuse. This is bad news. There are perfectly good reasons for people to decide to not have genetic testing for particular genes. Many people, learning of a higher risk for developing a future illness, suffer severe emotional distress, especially when there are no effective treatments or known cures to ward them off.

James Watson, Nobel laureate for the discovery of the structure of DNA, had his entire genome sequenced and made available online to aid in genetic research. But, he insisted that information about one of his own genes, the APOE gene, not be revealed. One form of the APOE gene is a known risk factor for late-onset Alzheimers. He did not want the burden of knowing.

Nancy Wexler, whose pioneering research led to the development of the genetic test for Huntington Disease a disease that runs in her own family decided against having that very test. For her, living with the uncertainty about her own genetic status is better than knowing for sure. Because genes are shared within families, a genetic test of one person is also a test of a whole family. Some relatives want to know; others do not.

Research has shown that genetic information spreading through families, often without any proper explanation, can bring on discord and deep divisions fueled by anger and guilt. And then, there is also the sad history of the misuse of genetic information, particularly the debacle of eugenics policies practiced widely in the U.S. during the first half of the last century. An abundance of prejudice, coupled with baseless beliefs about inheritance, led to Americans being forcibly sterilized for supposedly having sub-par genes.

More than 60,000 people, typically poor and uneducated, were victims of these policies. Sadly, eugenic policies were vigorously pursued in this part of Virginia. There are real concerns that HR 1313 can usher in a new era of eugenics an era in which employers, under the guise of improving health, are able to use genetic information to weed out those who may develop health conditions that could interfere with their productivity at some point in the future.

Existing legislation, the Genetic Non-Discrimination Act of 2008 (or GINA), has restricted the use of genetic information in the workplace. These protections will evaporate if HR 1313 becomes law. Genetic testing needs to remain an individual decision a decision determined by ones own values, life experience, family realities and attitudes about privacy. People should decide on their own what, if any, genetic tests they want and follow up with their own doctors to determine a course of action once the results are received.

Wellness programs can continue to help their clients achieve better health through smoking cessation, better diets, more exercise, and the like without any need for requiring genetic testing. If such testing is inflicted on people, then genetic information may well become viewed as a mode of punishment something to be feared instead of the valuable adjunct to the personalized medical care that is the promise of genomic medicine.

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Zallen: Genetic testing bill is modern eugenics - Roanoke Times

Genetic errors associated with heart health may guide drug development – Washington University School of Medicine in St. Louis

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One family with rare gene mutation gives clues to preventing heart attacks

Patients with mutations that disable a gene called ANGPTL3 have extremely low levels of cholesterol in the bloodstream. They also show no evidence of plaque in the coronary arteries, suggesting the mutations protect against heart attacks. Studying such patients can help guide drug development with the goal of preventing heart attacks.

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimers disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting individuals with these helpful genetic mistakes from developing common diseases.

A new study of such beneficial genetic mutations, led by Washington University School of Medicine in St. Louis, may provide guidance on the design of new therapies intended to reduce the risk of heart attacks.

The study is published March 29 in the Journal of the American College of Cardiology.

The researchers studied members of a family with rare mutations in a gene called ANGPTL3. The gene is known to play important roles in processing lipoproteins, molecules that package and transport fat and cholesterol through the bloodstream. Partial or complete loss of this gene was known to cause low cholesterol and triglyceride levels in the bloodstream. But whether it affects risk of heart attack was unclear.

Three of these family members those with a complete loss of this gene showed extremely low blood cholesterol and no evidence of plaque in their coronary arteries. According to the study authors, it was noteworthy that one of these patients showed no evidence of atherosclerosis despite having high risk factors for it, including high blood pressure and a history of type 2 diabetes and tobacco use.

The family members with complete loss of ANGPTL3 have extraordinarily low cholesterol, said first author Nathan O. Stitziel, MD, PhD, an assistant professor of medicine and of genetics. The interesting thing about this family is the individuals with total loss of this gene had siblings with normal copies of the same gene. So we could compare people with differences in the function of this gene who are otherwise closely related genetically and share similar environments. Its an anecdotal study of one family, but we felt it might provide some insight into the effects of blocking ANGPTL3.

While the individuals with nonfunctional copies of the gene showed no coronary plaque, their siblings with working copies of the gene showed evidence of plaque in the coronary arteries, though it was not yet causing symptoms a situation that is common in the general population, according to Stitziel.

To study the gene beyond the experience of a single family, the scientists also analyzed data available from large population studies. In data from one study of about 20,000 patients, the researchers found those with a partial loss of this gene had, on average, 11 percent lower total cholesterol, 12 percent lower LDL cholesterol, and 17 percent lower triglycerides, measured in the blood, than individuals with full gene function.

Analysis of data from other large population studies showed a link between partial loss of the gene and a lower risk of coronary artery disease and an association between lower circulating levels of ANGPTL3 protein and a lower risk of heart attack.

Taken together, these findings provide support for efforts to develop drugs that inhibit ANGPTL3 in order to reduce the risk of coronary artery disease and heart attack. The same reasoning led to the development of a class of drugs known as PCSK9 inhibitors, which have recently been shown to be effective at reducing the risk of heart attack in a large clinical trial of more than 27,000 men and women.

Several years ago, researchers found natural beneficial mutations in the PCSK9 gene that lowered peoples cholesterol levels and protected them from coronary artery disease, much as mutations in ANGPTL3 seem to do. Both PCSK9 and ANGPTL3 are important in the bodys processing of cholesterol from the diet. Any drugs that inhibit them, then, work differently than commonly prescribed statins, which reduce cholesterol levels in the blood by blocking the bodys internal cholesterol manufacturing.

While reducing cholesterol levels in the blood typically is thought to be good for the heart, Stitziel pointed out that there may be dangers to inhibiting the normal function of a gene. Not all genetic mutations that result in low cholesterol in the bloodstream are healthy. For example, there is one genetic disorder in which cholesterol levels in the blood are low because cholesterol gets stuck in the liver, resulting in fatty liver disease.

We need a better understanding of how cholesterol is processed in individuals with complete loss of ANGPTL3 function before we can fully say what effect inhibiting ANGPTL3 is going to have, Stitziel said. Studies of people with mutations that completely knock out a genes function are important because they can provide insight into the potential effects both good and bad of drugs inhibiting that genes function.

Along with Washington University School of Medicine, other institutions that played key roles in the study included the Broad Institute of MIT and Harvard and the Perelman School of Medicine at the University of Pennsylvania.

This study was supported by the National Institutes of Health (NIH), grant numbers R01HL131961, K08HL114642, R01HL118744, R01HL127564, R21HL120781, U54HG003067, UM1HG008895, UM1HG008853, TR001100, T32HL007734, RC2HL101834 and RC1TW008485; the Barnes-Jewish Hospital Foundation; the Fannie Cox Prize for Excellence in Science Teaching, Harvard University; a MGH Research Scholar Award; an ACCF/Merck Cardiovascular Research Fellowship; a John S. Ladue Memorial Fellowship at Harvard Medical School; the BHF and NIHR Senior Investigator support; and Fogarty International, grant number RC1TW008485.

The authors report grant funding or consulting fees from AstraZeneca, Aegerion Pharmaceuticals, Merck, Amarin, Alnylam Pharmaceuticals, Eli Lilly and Company, Pfizer, Sanofi, Novartis, Regeneron, Genentech, Bayer Healthcare, Leerink Partners, Noble Insights, Quest Diagnostics and Genomics PLC. One author, Rader, reports being an inventor on a patent related to lomitapide that is owned by the University of Pennsylvania and licensed to Aegerion Pharmaceuticals. He also reports co-founding Vascular Strategies and Staten Biotechnology. Another author, Kathiresan, reports holding equity in San Therapeutics and Catabasis Pharmaceuticals.

Stitziel NO, Khera AV, Wang X, Bierhals JB, Vourakis C, Sperry AE, Natarajan P, Klarin D, Emdin CA, Zekavat SM, Nomura A, Erdman J, Schunkert H, Samani NJ, Kraus WE, Shah SH, Yu B, Boerwinkle E, Rader DJ, Gupta N, Frossard PM, Rasheed A, Danesh J, Lander ES, Gabriel S, Saleheen D, Musunuru K, Kathiresan S, PROMIS and Myocardial Infarction Genetics Consortium Investigators. ANGPTL3 deficiency and protection against coronary artery disease. Journal of the American College of Cardiology. March 29, 2017.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Genetic errors associated with heart health may guide drug development - Washington University School of Medicine in St. Louis

Genetic errors associated with heart health may guide drug development – Medical Xpress

March 30, 2017 by Julia Evangelou Strait Credit: Washington University School of Medicine

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimer's disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting individuals with these helpful genetic mistakes from developing common diseases.

A new study of such "beneficial" genetic mutations, led by Washington University School of Medicine in St. Louis, may provide guidance on the design of new therapies intended to reduce the risk of heart attacks.

The study is published March 29 in the Journal of the American College of Cardiology.

The researchers studied members of a family with rare mutations in a gene called ANGPTL3. The gene is known to play important roles in processing lipoproteins, molecules that package and transport fat and cholesterol through the bloodstream. Partial or complete loss of this gene was known to cause low cholesterol and triglyceride levels in the bloodstream. But whether it affects risk of heart attack was unclear.

Three of these family membersthose with a complete loss of this geneshowed extremely low blood cholesterol and no evidence of plaque in their coronary arteries. According to the study authors, it was noteworthy that one of these patients showed no evidence of atherosclerosis despite having high risk factors for it, including high blood pressure and a history of type 2 diabetes and tobacco use.

"The family members with complete loss of ANGPTL3 have extraordinarily low cholesterol," said first author Nathan O. Stitziel, MD, PhD, an assistant professor of medicine and of genetics. "The interesting thing about this family is the individuals with total loss of this gene had siblings with normal copies of the same gene. So we could compare people with differences in the function of this gene who are otherwise closely related genetically and share similar environments. It's an anecdotal study of one family, but we felt it might provide some insight into the effects of blocking ANGPTL3."

While the individuals with nonfunctional copies of the gene showed no coronary plaque, their siblings with working copies of the gene showed evidence of plaque in the coronary arteries, though it was not yet causing symptomsa situation that is common in the general population, according to Stitziel.

To study the gene beyond the experience of a single family, the scientists also analyzed data available from large population studies. In data from one study of about 20,000 patients, the researchers found those with a partial loss of this gene had, on average, 11 percent lower total cholesterol, 12 percent lower LDL cholesterol, and 17 percent lower triglycerides, measured in the blood, than individuals with full gene function.

Analysis of data from other large population studies showed a link between partial loss of the gene and a lower risk of coronary artery disease and an association between lower circulating levels of ANGPTL3 protein and a lower risk of heart attack.

Taken together, these findings provide support for efforts to develop drugs that inhibit ANGPTL3 in order to reduce the risk of coronary artery disease and heart attack. The same reasoning led to the development of a class of drugs known as PCSK9 inhibitors, which have recently been shown to be effective at reducing the risk of heart attack in a large clinical trial of more than 27,000 men and women.

Several years ago, researchers found natural beneficial mutations in the PCSK9 gene that lowered people's cholesterol levels and protected them from coronary artery disease, much as mutations in ANGPTL3 seem to do. Both PCSK9 and ANGPTL3 are important in the body's processing of cholesterol from the diet. Any drugs that inhibit them, then, work differently than commonly prescribed statins, which reduce cholesterol levels in the blood by blocking the body's internal cholesterol manufacturing.

While reducing cholesterol levels in the blood typically is thought to be good for the heart, Stitziel pointed out that there may be dangers to inhibiting the normal function of a gene. Not all genetic mutations that result in low cholesterol in the bloodstream are healthy. For example, there is one genetic disorder in which cholesterol levels in the blood are low because cholesterol gets stuck in the liver, resulting in fatty liver disease.

"We need a better understanding of how cholesterol is processed in individuals with complete loss of ANGPTL3 function before we can fully say what effect inhibiting ANGPTL3 is going to have," Stitziel said. "Studies of people with mutations that completely knock out a gene's function are important because they can provide insight into the potential effectsboth good and badof drugs inhibiting that gene's function."

Explore further: What you need to know about cholesterol

(HealthDay)Cholesterol plays a vital role in your health, so it's important to understand the different types of cholesterol and how to influence their levels, a heart specialist says.

To reduce risk of heart attack, the benefits of a healthy lifestyle are clear. But genetics can still stack the deck. Some people's genes bestow a natural advantageor disadvantagein protecting against heart disease, ...

Rare mutations that shut down a single gene are linked to lower cholesterol levels and a 50 percent reduction in the risk of heart attack, according to new research from Washington University School of Medicine in St. Louis, ...

Heart disease patients taking PCSK9 inhibitors to achieve very low levels of cholesterol do not experience an increase in adverse events, including memory impairment or nervous system disorders, but may have an increased ...

When an adult gets an annual physical, physicians commonly check the levels of fat cells, known as triglycerides, in their blood stream. Triglycerides are a type of fat, or lipid, which are consumed when you eat, and are ...

Reducing our cholesterol levels to those of a new-born baby significantly lowers the risk of cardiovascular disease, according to new research.

Fish do it, amphibians do it, so why can't we? Scientists are questioning why human hearts lose the ability to regenerate, while other animals don't.

An online metabolic calculator developed by a University of Virginia School of Medicine doctor and his research partner at the University of Florida predicts patients' risk of developing heart disease and diabetes more accurately ...

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimer's disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting ...

Determining the cause of an ischemic stroke - one caused by an interruption of blood supply - is critical to preventing a second stroke and is a primary focus in the evaluation of stroke patients. But despite that importance, ...

Further evidence has been found by Universities of Leicester and Bristol researchers to suggest statins could "significantly reduce" the occurrence of blood clotting in certain parts of the body.

Human heart muscle cells can be created in the lab, but researchers have been unable to grow the immature cells to the point where they could be useful.

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Genetic errors associated with heart health may guide drug development - Medical Xpress

NIH allergist awarded Drukier Prize by Weill Cornell Medicine – Cornell Chronicle

Studio Brooke/Provided

From left, Dr. Augustine M.K. Choi, Gale and Ira Drukier, Dr. Joshua Milner and Dr. Gerald Loughlin.

Dr. Joshua Milner, an allergist and immunologist who has made key discoveries into the origin of previously unidentified disorders that affect children and families, has been awarded the second annual Gale and Ira Drukier Prize in Childrens Health Research, Weill Cornell Medicine announced March 29.

The Drukier Prize honors an early-career pediatrician whose research has made important contributions toward improving the health of children and adolescents. Milner, chief of the Genetics and Pathogenesis of Allergy Section at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is being recognized for his innovative research focusing on the discovery and understanding of the genetic and physiologic basis for allergic diseases and his work to find advanced treatments and cures.

Dr. Milners important discoveries have greatly contributed to our understanding of genetic and allergic diseases that affect children, helping to illuminate the causes behind previously unknown disorders and providing hope for the future for many families, said Dr. Augustine M.K. Choi, the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine. As a young investigator dedicated to advancing the field of pediatric research using inventive scientific approaches, Dr. Milner exemplifies the spirit of the Gale and Ira Drukier Prize in Childrens Health Research. We are thrilled to honor him this year.

Milners investigations through basic, translational and clinical research have yielded many significant breakthroughs, including the discovery of a genetic change that causes elevated blood levels of the protein tryptase, which is frequently linked toallergic reactions like hives and itching, but also to other conditions such as irritable bowel syndrome, headaches and chronic pain. His discovery of alpha tryptase genetic duplications offered a medical explanation for patients suffering from difficult-to-treat symptoms, many of whom had spent much of their lives without a diagnosis. Multiple copies of the gene are present in approximately 4 percent of the population, Milner found, suggesting that what investigators had previously believed to be a rare and unexplained disease was, in fact, an extreme form of more common conditions. Those findings were published Oct. 17, 2016, in Nature Genetics, and Milner is now seeking ways to block alpha tryptase, with the goal of curing or reducing patients symptoms.

Milner also identified a rare genetic disorder as well as the mutation that drives it that is characterized by an allergic reaction to cold temperatures. Patients who have been diagnosed with the condition, called PLAID, experience hives or occasionally more severe physical reactions. While further study of the mutation is needed, recognizing the disorder may provide relief for patients through improved disease management. Additionally, Milner also discovered PGM3 deficiency, another rare genetic disorder, in which a mutation in the PGM3 enzyme leads to multiple types of severe allergies and infections that start in childhood. His research team is investigating new approaches to diagnose and treat this disease.

Milner formally accepted the award and delivered a public lecture on March 29 about the increasing prevalence of allergies in the United States and their connection to environmental and lifestyle changes, as well as to genetic disease.

The genetic cause of allergy, particularly in relation to childrens health, is an area of science that we are only now truly beginning to uncover, said Dr. Gerald M. Loughlin, the Nancy C. Paduano Professor and chairman of the Department of Pediatrics at Weill Cornell Medicine, and pediatrician-in-chief at the Phyllis and David Komansky Center for Childrens Health at NewYork-Presbyterian/Weill Cornell Medical Center. Dr. Milners commitment to making new discoveries and finding innovative treatments for allergic disease in children has greatly advanced this area of pediatric research. He is an ideal recipient of this award, and we hope it will help bolster his work as he continues to investigate these disorders and provide care for this vulnerable population.

Dr. Milner exemplifies the kind of passion and innovation we need in pediatric research, said Dr. Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Childrens Health. His medical discoveries are helping to shed light on the science behind hard-to-diagnose genetic and allergic diseases in children. This research will open the path for understanding more common allergic disorders, finding new therapies and bringing relief for countless families. The Drukier Institute is delighted to honor Dr. Milner with this award.

The Gale and Ira Drukier Prize in Childrens Health Research was established in December 2014 as part of a $25 million gift to Weill Cornell Medicine. The gift also created the Gale and Ira Drukier Institute for Childrens Health a premier, cross-disciplinary institute dedicated to understanding the underlying causes of diseases that are devastating to children. As part of its mission, the institute awards the prize annually to recognize the work of young investigators in the pediatric research community.

Milner received a bachelors degree in biology from the Massachusetts Institute of Technology and a medical degree from the Albert Einstein College of Medicine. Following a residency in pediatrics at the Childrens National Medical Center in Washington, he was the recipient of the Pediatric Scientist Development Program Fellowship and completed a clinical fellowship in allergy and immunology at NIAID. He was then appointed to the NIAID Transition Program in Clinical Research, and was hired in 2009 in the Laboratory of Allergic Diseases (LAD) in the NIAID. He received tenure and became a senior investigator in 2013, as chief of the Genetics and Pathogenesis of Allergy Section within the LAD.

Milner is board-certified in allergy and immunology, and in pediatrics. He is an elected member of the American Society for Clinical Investigation and the Henry Kunkel Society, and is a recent recipient of the Phadia Allergy Research Forum Award and multiple NIH awards. He has published multiple studies on immunology and allergies and serves on the editorial board of numerous scientific journals.

Kathryn Inman is a writer for Weill Cornell Medicine.

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NIH allergist awarded Drukier Prize by Weill Cornell Medicine - Cornell Chronicle

Genetic Errors Linked With Heart Health May Guide Drug Development – Bioscience Technology

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimers disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting individuals with these helpful genetic mistakes from developing common diseases.

A new study of such beneficial genetic mutations, led by Washington University School of Medicine in St. Louis, may provide guidance on the design of new therapies intended to reduce the risk of heart attacks.

The study is published March 29 in the Journal of the American College of Cardiology.

The researchers studied members of a family with rare mutations in a gene called ANGPTL3. The gene is known to play important roles in processing lipoproteins, molecules that package and transport fat and cholesterol through the bloodstream. Partial or complete loss of this gene was known to cause low cholesterol and triglyceride levels in the bloodstream. But whether it affects risk of heart attack was unclear.

Three of these family members those with a complete loss of this gene showed extremely low blood cholesterol and no evidence of plaque in their coronary arteries. According to the study authors, it was noteworthy that one of these patients showed no evidence of atherosclerosis despite having high risk factors for it, including high blood pressure and a history of type 2 diabetes and tobacco use.

The family members with complete loss of ANGPTL3 have extraordinarily low cholesterol, said first author Nathan O. Stitziel, M.D., Ph.D., an assistant professor of medicine and of genetics. The interesting thing about this family is the individuals with total loss of this gene had siblings with normal copies of the same gene. So we could compare people with differences in the function of this gene who are otherwise closely related genetically and share similar environments. Its an anecdotal study of one family, but we felt it might provide some insight into the effects of blocking ANGPTL3.

While the individuals with nonfunctional copies of the gene showed no coronary plaque, their siblings with working copies of the gene showed evidence of plaque in the coronary arteries, though it was not yet causing symptoms a situation that is common in the general population, according to Stitziel.

To study the gene beyond the experience of a single family, the scientists also analyzed data available from large population studies. In data from one study of about 20,000 patients, the researchers found those with a partial loss of this gene had, on average, 11 percent lower total cholesterol, 12 percent lower LDL cholesterol, and 17 percent lower triglycerides, measured in the blood, than individuals with full gene function.

Analysis of data from other large population studies showed a link between partial loss of the gene and a lower risk of coronary artery disease and an association between lower circulating levels of ANGPTL3 protein and a lower risk of heart attack.

Taken together, these findings provide support for efforts to develop drugs that inhibit ANGPTL3 in order to reduce the risk of coronary artery disease and heart attack. The same reasoning led to the development of a class of drugs known as PCSK9 inhibitors, which have recently been shown to be effective at reducing the risk of heart attack in a large clinical trial of more than 27,000 men and women.

Several years ago, researchers found natural beneficial mutations in the PCSK9 gene that lowered peoples cholesterol levels and protected them from coronary artery disease, much as mutations in ANGPTL3 seem to do. Both PCSK9 and ANGPTL3 are important in the bodys processing of cholesterol from the diet. Any drugs that inhibit them, then, work differently than commonly prescribed statins, which reduce cholesterol levels in the blood by blocking the bodys internal cholesterol manufacturing.

While reducing cholesterol levels in the blood typically is thought to be good for the heart, Stitziel pointed out that there may be dangers to inhibiting the normal function of a gene. Not all genetic mutations that result in low cholesterol in the bloodstream are healthy. For example, there is one genetic disorder in which cholesterol levels in the blood are low because cholesterol gets stuck in the liver, resulting in fatty liver disease.

We need a better understanding of how cholesterol is processed in individuals with complete loss of ANGPTL3 function before we can fully say what effect inhibiting ANGPTL3 is going to have, Stitziel said. Studies of people with mutations that completely knock out a genes function are important because they can provide insight into the potential effects both good and bad of drugs inhibiting that genes function.

Along with Washington University School of Medicine, other institutions that played key roles in the study included the Broad Institute of MIT and Harvard and the Perelman School of Medicine at the University of Pennsylvania.

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Genetic Errors Linked With Heart Health May Guide Drug Development - Bioscience Technology

Possible genetic marker for ALS found might prove useful for measuring effectiveness of treatments – Medical Xpress

March 30, 2017 by Bob Yirka report Motor neurons from mice that received an experimental ALS treatment (top) displayed lower levels of a newly identified biomarker (brown areas) than observed in untreated animals (bottom). Credit: T.F. Gendron et al., Science Translational Medicine (2017)

(Medical Xpress)A very large team of researchers with members from the U.S., Italy and the Netherlands has found what might be a marker for ALS, which the team suggests could be used as a yardstick for measuring the effectiveness of treatments in clinical trials. In their paper published in the journal Science Translational Medicine, the team describes how they connected a genetic abnormality common in ALS patients with a protein they found in blood cells and cerebrospinal fluid.

Amyotrophic lateral sclerosis (ALS), aka Lou Gehrig's disease, is a disorder that causes nerve degeneration leading to muscle atrophy and eventually death. To date, there is no known cure, though one drug has been found to delay the progression of the disease for a few months. One of the things standing in the way of a cure is a lack of tests that can tell researchers if a treatment under study is having any discernable positive impact. This is because there is no test for the disorder itself. In this new effort, the researchers believe they may have found a marker that could be used to test for the disorder, and more importantly, serve as a means for measuring whether a drug developed to reduce symptoms, or better yet a cure for the disease, actually does what is hoped.

The researchers started by looking at patients with a gene mutation called C9ORF72 which is believed to be behind the onset of most types of genetically caused ALS (and also some types of dementia.) During their research, they discovered that many such patients had more than normal amounts of a protein called polyGP in their cerebrospinal fluid and also in their blood cells. Inspired, they conducted a study comparing patients with polyGP in their cerebrospinal fluid with those that had the mutation and with control groups.

The team reports that they found the protein buildup in 134 people who had the mutation, which included 83 people who had ALS, 27 people who had no symptoms, and 24 people who had other types of diseases. Furthermore, they found that the protein buildup was not found in 120 people who did not have the mutation, including those with different types of ALS.

These findings, the group suggests, mean that testing for polyGP might someday soon be used as a viable way to measure treatment success, which could perhaps one day lead to better therapies or perhaps a cure.

Explore further: Children of patients with C9orf72 mutations are at a greater risk of frontotemporal dementia or ALS at a younger age

More information: Tania F. Gendron et al. Poly(GP) proteins are a useful pharmacodynamic marker for-associated amyotrophic lateral sclerosis, Science Translational Medicine (2017). DOI: 10.1126/scitranslmed.aai7866

Abstract There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNAmediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNAbased therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

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Possible genetic marker for ALS found might prove useful for measuring effectiveness of treatments - Medical Xpress

Stem cells help explain varied genetics behind rare neurologic disease – Medical Xpress

March 30, 2017

Researchers at Case Western Reserve University School of Medicine have successfully grown stem cells from children with a devastating neurological disease to help explain how different genetic backgrounds can cause common symptoms. The work sheds light on how certain brain disorders develop, and provides a framework for developing and testing new therapeutics. Medications that appear promising when exposed to the new cells could be precisely tailored to individual patients based on their genetic background.

In the new study, published in The American Journal of Human Genetics, researchers used stem cells in their laboratory to simultaneously model different genetic scenarios that underlie neurologic disease. They identified individual and shared defects in the cells that could inform treatment efforts.

The researchers developed programmable stem cells, called induced pluripotent stem cells, from 12 children with various forms of Pelizaeus-Merzbacher Disease, or PMD. The rare but often fatal genetic disease can be caused by one of hundreds of mutations in a gene critical to the proper production of nerve cell insulation, or myelin. Some children with PMD have missing, partial, duplicate, or even triplicate copies of this gene, while others have only a small mutation. With so many potential causes, researchers have been in desperate need of a way to accurately and efficiently model genetic diseases like PMD in human cells.

By recapitulating multiple stages of the disease in their laboratory, the researchers established a broad platform for testing new therapeutics at the molecular and cellular level. They were also able to link defects in brain cell function to patient genetics.

"Stem cell technology allowed us to grow cells that make myelin in the laboratory directly from individual PMD patients. By studying a wide spectrum of patients, we found that there are distinct patient subgroups.

This suggests that individual PMD patients may require different clinical treatment approaches," said Paul Tesar, PhD, study lead, Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics, and Associate Professor of Genetics and Genome Sciences at Case Western Reserve University School of Medicine.

The researchers watched in real-time as the patients' stem cells matured in the laboratory. "We leveraged the ability to access patient-specific brain cells to understand why these cells are dysfunctional. We found that a subset of patients exhibited an overt dysfunction in certain cellular stress pathways," said Zachary Nevin, first author of the study and MD/PhD student at Case Western Reserve University School of Medicine. "We used the cells to create a screening platform that can test medications for the ability to restore cell function and myelin. Encouragingly, we identified molecules that could reverse some of the deficits." The promising finding provides proof-of-concept that medications that mend a patient's cells in the laboratory could be advanced to clinical testing in the future.

The stem cell platform could also help other researchers study and classify genetic diseases with varied causes, particularly other neurologic disorders. Said Tesar, "Neurological conditions present a unique challenge, since the disease-causing cells are locked away in patients' brains and inaccessible to study. With these new patient-derived stem cells, we can now model disease symptoms in the laboratory and begin to understand ways to reverse them."

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Stem cells help explain varied genetics behind rare neurologic disease - Medical Xpress

Fighting canine ALS – Medical Xpress

March 30, 2017 by Genevieve Rajewski Giving these pets another one-and-a-half to two years of life would be a major success, Dominik Faissler said. Better yet, wed be doing something for dogs that at the same time contributes to human medicine. Credit: iStock

A gene-silencing therapy under development for people with amyotrophic lateral sclerosis (ALS) is being tested at Tufts in dogs with degenerative myelopathy, a fatal paralytic disease that is similar to ALS.

"If you look at the clinical progression [of degenerative myelopathy], a dog will go from dragging a toe, to stumbling, to falling over when it turns quickly," said Dominik Faissler, the veterinary neurologist at Cummings School who is leading the study. As the disease progresses, a dog can no longer stand.

"What's so extraordinary is that the dog is a naturally occurring model of one form of the human disease," said Robert H. Brown Jr., a University of Massachusetts Medical School neurologist who is one of the world's foremost experts on ALS and other neurodegenerative diseases. He approached Cummings School about testing the therapy developed in his lab, with the goal of speeding up clinical trials in humans.

"In dogs, it turns out there's a mutation in the SOD1 gene, which normally makes an antioxidant protein that helps protect nerve cells from a variety of cellular stresses and injuries. When this gene gets mutated, it becomes toxic to nerves, killing off the motor neurons in dogs the same way that this genetic mutation does in some people with ALS," said Brown, the Leo P. and Theresa M. LaChance Chair in Medical Research and chair of neurology at UMass Medical School.

Canine degenerative myelopathy causes progressive paralysis in older dogs in a number of breeds, including German shepherds, boxers, corgis, Chesapeake retrievers, Rhodesian ridgebacks and Bernese mountain dogs, Faissler said. "There is likely a genetic defect that interferes with the survival of the spinal cord tissue and brain tissue," he said. As in humans with ALS, dogs with degenerative myelopathy eventually die when the respiratory system stops working, but often pets are euthanized before, because their quality of life is poor.

The dogs in the Tufts trial receive a single spinal fluid injection of an engineered adenovirusfrom a family of viruses that can infect the nervous system, but is best known for causing the common cold. The engineered virus was designed to breach the blood-brain barrier to deliver DNA particles that turn offor silencethe mutated gene.

"This barrier is normally a very good thing, because it keeps bacteria out of our nervous system," Brown said. "But we must get the treatment to the cells where it can actually take effect, and a virus knows how to wend its way through that iron curtain." The therapy has shown promising results in mice genetically engineered to have a condition similar to ALS, he said, and it also was safe when tested in normal monkeys.

Dogs in the Cummings School trial, which began in December 2016, are checked every three months and undergo tests, which are videotaped, to assess their neurological and motor function. Four dogs are currently in the pilot study. So far, the therapy appears safe in pets, but Faissler and Brown said it's too early to determine whether it will halt or reverse the disease. "Does it work? That's the question I wake up and go to bed with every day," Brown said.

"Giving these pets another one-and-a-half to two years of life would be a major success," Faissler said. "Better yet, we'd be doing something for dogs that at the same time contributes to human medicine."

A successful trial in dogs could be a prelude to a clinical trial in people, Brown said. Ionis Pharmaceuticals, a California biotech company, is already testing a different gene therapy for SOD1-related ALS and for a similar type of mutation in patients with Huntington's disease, which attacks nerve cells in the brain. Such treatments one day could be used for a number of neurodegenerative and neuromuscular diseases, Brown said, including Parkinson's, Alzheimer's and a host of diseases known as ataxias, characterized by the loss of control over bodily movements.

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Have You Heard of the Neurologist Behind Louis-Bar… : Neurology Today – LWW Journals

By Dawn Fallik March 19, 2020

The woman who is associated with the eponymous Louis-Bar syndrome is the subject for discussionand an awardabout the challenges for a woman in neurology from an earlier era.

When Elizabeth A. Coon, MD, started researching Denise Louis-Bar, MD, the neurologist who helped define the eponymous pediatric neurologic syndrome, Dr. Coon wasn't sure if she'd chosen the right subject.

As an adult neurologist, Dr. Coon, an assistant professor of neurology at Mayo Clinic in Rochester, MN, had never met someone with the disease Dr. Louis-Bar helped discoverataxia telangiectasia. But that very afternoon in her clinic, she met a gentleman with familial ataxia and ocular telangiectasia, which has symptoms very similar to those in Louis-Bar syndrome.

It was meant to be, Dr. Coon said.

Her paper on Dr. Louis-Bar was published in Neurology in 2018. But this year, Dr. Coon is receiving the AAN McHenry Award in History for her research on the neurologist behind ataxia telangiectasia. The disease is caused by mutations in the ATM gene and appears as an early-onset multisystem neurodegenerative disorder, characterized by a progressive lack of coordination that appears in toddlers when they are starting to learn to walk. Patients also have a high rate of leukemia or lymphoma.

Dr. Louis-Bar first described the disorder in 1941 in the international journal Confinia Neurologica, published in Switzerland. She was 27 years old at the time. But as the Neurology article noted, she never really received credit for naming the disorder. Indeed, a citation in the Neurology article pulled from the literature underscores how being a woman in medicine at the time was perceived: Dr. M. Reznik recalled Louis-Bar during her time in Lige: I have really known Mrs. Louis-Bar when, myself a young student, she was a senior assistant at the Brull service. One recognized her by her lush red hair. As the article noted Dr. Louis-Bar had become a neuropsychiatrist within the department of internal medicine with renowned physiologist Professor Lucien Brull at the State University of Lige.

Dr. Coon discussed with Neurology Today what she learned about Dr. Louis-Bar and how it has influenced her own role as a neurologist today. Her excerpted remarks appear below.

I've been interested in medicine since I was a teenager. My uncle was in family medicine and I knew I wanted to care for people, but also be involved in a scientific and rigorous field. My interest in neurology arose from personal experiences. I remember as an undergrad, I was working in a research lab studying DNA sequences in zebrafish that had neurological disorders. I was also shadowing Hank Paulson [Henry Paulson, MD, PhD] who was caring for patients with Huntington's disease in a multidisciplinary clinic. So in the morning I was looking at genetic code and in the afternoon, I was seeing patients deal with significant symptoms stemming from mutations in their genetic code.

I knew about the disease, ataxia telangiectasia, but I wasn't sure who she was. I thought the disease was named after two different people at first and assumed they were men. But what became really interesting to me was how the disease became named after her. She was not really the first person to describe the diseaseit was two Czech physicians in 1926, but they described it as more of a dystonia-type of disorder and so it wasn't linked with Louis-Bar.

The group who really did the most work on ataxia telangiectasia was out of California in the mid-20th century, led by Dr. Elena Boder, an American pediatric neurologist. There was some controversy about calling the disease Louis-Bar syndrome versus ataxia telangiectasia, because it had been written about by other people, and there was some issue with Dr. Louis-Bar's pathophysiological description of AT. But when you look at the literature, her name still is frequently used.

It doesn't really bother me, as Elena Boder did advance the field significantly and I think that ataxia telangiectasia is a good descriptive name.

Reading between the lines of the historical writing, you get a sense that she wasn't fully part of the medical community of that time. There was a follow-up to the journal article she had written in 1941 from her coworkers and mentor, and they didn't even use her name; there was no description of her work. I feel like maybe she didn't have all the support she could have used.

She was clearly a very accomplished physician and researcher, but in the articles about her, they describe her appearance, particularly that she had lush, red hair. Those physical descriptors bothered me as we know that women are more frequently judged by appearance. She didn't stay in academia; her husband went to Belgium, and she left the academic world when she moved. She continued to practice and developed subspecialty clinics caring for disabled children and adults, which is noble.

When she was in academia, it was a very productive time for her. She later devoted her time to multidisciplinary care, particularly with mentally disabled children and she did amazing work in that regard. She was a very observant clinician and she really did a lot of work in internal medicine and in neurologic disorders, really emphasizing patient care, which demonstrated her diverse abilities and interests.

This is a wonderful time to be a woman in medicine. Women are increasingly in leadership positions and I'm grateful to be in a department led by a woman, Claudia Lucchinetti, MD. Finding mentors who support and help you navigate your career is vital, and I'm also grateful for my many mentors. As a woman, there will be microaggressions and roadblocks along the way, but finding mentors who help you manage and continue moving forward is quintessential.

I would say patients come with a variety of different symptoms and backgrounds. All patients need help in different ways. You have to learn to tailor your approach to the patient. It's not just knowing that a patient has a specific type of disease; it's about having to think about how that disease is affecting that particular patient, how the symptoms are impacting every aspect of their life. I was taught this is in residency with the Sir Williams Osler quote: It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.

Dr. Coon had no disclosures.

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DNA Discovery Could Lead to New Drugs for Aggressive Forms of Cancer – Technology Networks

Cells can both survive and multiply under more stress than previously thought, shows research from the Faculty of Health and Medical Sciences.

This was found by inhibiting the essential gene DNA polymerase alpha, or POLA1, which initiates DNA replication during cell division.

The discovery gives researchers new insights into DNA replication and may potentially be used for a new type of cancer treatment. Research Leader and Associate Professor Luis Toledo of the Center for Chromosome Stability at the Department of Cellular and Molecular Medicine states as follows:

'If we are visionaries, I would say that we might be at the birth of a whole new set of molecules that could be used in fighting cancer', adding:

'Basically, if we turn the finding on its head, this novel strategy aims at exploiting an in-built weakness in cancer cells and make them crash while they divide.'

Loose zippers

When a cell divides, the double DNA strand is opened lengthwise like a zipper that is unzipped. The new double strands are built at each of the separated strands, so that you gradually end up with two new "zippers".

Before the new halfs of the zipper are made, a bit of DNA is temporally exposed in single stranded form. This process is required for the new zippers to form. Nevertheless, large amounts of single-stranded DNA have traditionally been considered by researchers to be a sign of pathological stress during cell proliferation.

However, the researchers behind the new study discovered that DNA unzippers act more loosely than expected. This can generate large amounts of single-stranded DNA, which the researchers now show is no more than a form of natural stress that cells can actually tolerate in high quantities.

Still, for this tolerance to exist, cells require a sufficient amount of the protective protein RPA to cover the single-stranded DNA parts.

'We have seen that cells can duplicate their genome, even with large amounts of single stranded DNA. They can divide and go on living healthily because they have a large excess of RPA molecules that acts as a protective umbrella.' says the study's first author and former postdoc at the University of Copenhagen Amaia Ercilla, adding:

'But there is a flip side of the coin. When we make the cells generate single strand DNA faster than what they can protect, chromosomes literally shatter in hundreds of pieces, a phenomenon we call replication catastrophe. We always thought that we could use this for instance to kill cancer cells,' she adds.

Weapon against cancer

Both Amaia Ercilla and Luis Toledo explain that under normal circumstances it is extremely difficult to deplete a cell's reserve of RPA.

The same was true in the new study, when researchers used different types of chemotherapy to increase the amount of single-stranded DNA. Even when using the best compounds available so far it took around one hour to deplete the RPA reserve in a cell, provoking a replication catastrophe and the associated cell death.

However, the researchers behind the new study believe to have found what Luis Toledo calls 'the ultimate single-stranded DNA generator': When the researchers used a so-called POLA1 inhibitor, the cells met their final destiny after just five minutes.

'Although no new DNA can be made when we inhibit POLA1, the DNA unzippers keep advancing and generate single-stranded DNA at very high speed,' says the Associate Professor, adding:

'All cells can be sensitive to POLA1 inhibitors, including cancer cells, and we might speculate that the strategy could be especially useful against very aggressive forms of cancer that proliferate at a high pace'.

The next step of the research group is to find more molecules that biologically inhibits the POLA1 gene and which, in combination with other substances, may be used in the treatment of cancer patients.

Reference: Ercilla, et al. (2020) Physiological Tolerance to ssDNA Enables Strand Uncoupling during DNA Replication. Cell Reports. DOI:https://doi.org/10.1016/j.celrep.2020.01.067

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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DNA Discovery Could Lead to New Drugs for Aggressive Forms of Cancer - Technology Networks

Carl June on CRISPR, CART and how the Vietnam War dropped him into medicine – Endpoints News

In August of 2011, Carl June and his team published a landmark paper showing their CART treatment had cleared a patient of cancer. A year-to-the-month later, Jennifer Doudna made an even bigger splash when she published the first major CRISPR paper, setting off a decade of intense research and sometimes even more intense public debate over the ethics of what the gene-editing tool could do.

Last week, June, whose CART work was eventually developed by Novartis into Kymriah, published in Sciencethe first US paper showing how the two could be brought together. It was not only one of the first time scientists have combined the groundbreaking tools, but the first peer-reviewed American paper showing how CRISPR could be used in patients.

June used CRISPR to edit the cells of three patients with advanced blood cancer, deleting the traditional T cell receptor and then erasing the PD1 gene, a move designed to unleash the immune cells. The therapy didnt cure the patients, but the cells remained in the body for a median of 9 months, a major hurdle for the therapy.

Endpoints caught up with June about the long road both he and the field took to get here, if the treatment will ever scale up, and where CRISPR and other advancements can lead it.

The interview has been condensed and edited.

Youve spoken in the past about howyou started working in this field in the mid-90s after your wife passed away from cancer. What were some of those early efforts? How did you start?

Well, I graduated from high school and had a low draft number [for the Vietnam War] and was going to go to study engineering at Stanford, but I was drafted and went into the Naval Academy in 1971, and I did that so I wouldnt have to go to the rice fields.

The war ended in 73, 74, so when I graduated in 1975, I was allowed to go to medical school, and then I had a long term commitment to the Navy because they paid for the Acadamy and Medical school. And I was interested in research and at the time, what the Navy cared about was a small scale nuclear disaster like in a submarine, and like what happened at Chernobyl and Fukushima. So they sent me to the Fred Hutchinson Cancer Center where I got trained in cancer, as a medical oncologist. I was going to open a bone marrow transplant center in Bethesda because the Navy wanted one in the event of a nuclear catastrophe.

And then in 1989, the Berlin Wall came down and there was no more Cold War. I had gone back to the Navy in 86 for the transplant center, which never happened, so then I had to work in the lab full time. But in the Navy, all the research has to be about combat and casualty. They care about HIV, so my first papers were on malaria and infectious disease. And the first CAR-T trials were on HIV in the mid-90s.

In 96, my wife got diagnosed with ovarian cancer and she was in remission for 3-4 years. I moved to the University of Pennsylvania in 1999 and started working on cancer because I wasnt allowed to do that with the Navy. My wife was obviously a lot of motivation to do that. She passed away in 2001. Then I started working with David Porter on adoptive transfer T cells.

I got my first grant to do CAR-T cells on HIV in 2004, and I learned a whole lot. I was lucky to have worked on HIV because we did the first trials using lentiviruses, which is an engineered HIV virus.

I was trained in oncology, and then because of the Navy forced to work on HIV. It was actually a blessing in disguise.

So if you hadnt been drafted, you wouldve become an engineer?

Yes. Thats what I was fully intending. My dad was a chemical engineer, my brother is an engineer. Thats what I thought I was going to do. No one in my family was ever a physician. Its one of those many quirks of fate.

Back then, we didnt have these aptitude tests. It was just haphazard. I applied to three schools Berkeley, Stanford and Caltech and I got into all three. It was just luck, fate.

And it turned out when I went to the Naval Academy, they had added a pre-med thing onto the curriculum the year before, so thats what I did when I started, I did chemistry.

I wouldve [otherwise] been in nuclear submarines. The most interesting thing in the Navy then was the nuclear sub technology.

You talked about doing the first CAR-T trials on HIV patients because thats where the funding was. Was it always in your head that this was eventually going to be something for cancer?

So I got out of the Navy in 99 and moved to Penn. I started in 98 working on treating leukemia, and then once I got to Penn, I continued working one day a week on HIV.

Its kind of a Back-to-the-Future thing because now cancer has paved out a path to show that CART cells can work and put down the manufacturing and its going to be a lot cheaper making it for HIV. I still think thats going to happen.

Jim Riley, who used to be a postdoc in my lab, has some spectacular results in monkeys with HIV models. They have a large NIH and NIAID research program.

So were going to see more and more of that. The CAR technology is going to move outside of cancer, and into autoimmune and chronic infections.

I want to jump over to cytotoxic release syndrome (CRS)because a big part of the CRISPR study was that it didnt provoke this potentially deadly adverse effect. When did you first become aware that CRS was going to be a problem?

I mean we saw it in the very first patient we treated but in all honesty, we missed it. Im an MD, but I dont see the patient and David Porter tookcare of the first three patients and our first pediatric patient,Emily Whitehead.

In our first patients, 2 out of 3, had complete remission and there were fevers and it was CRS but we thought it was just an infection, and we treated with antibiotics for 3 weeks and[eventually] it went away. And sort of miraculously he was in remission and is still in remission, 9 years later.

And then when we treated Emily. She was at a 106-degree fever over three days, and there was no infection.

Ive told this story before. My daughter has rheumatoid arthritis, and I had been president of the Clinical Immunologists Society from 2009 to 2010, and the first good drug for juvenile rheumatoid arthritisthat came out. I was invited to give the Japanese scientist Tadamitsu Kishimoto the presidential award for inventing the drug.

Then in 2012, Emily Whitehead was literally dying from CRS, she had multiple organ failures. And her labs came back and IL-6 levels were 1000x normal. It turns out the drug I was looking at for my daughter, it blocks IL-6 levels. I called the physician and I said, listen theres something actionable here, since its in your formulary to give it to her off-label.

And she gave her the appropriate dose for rheumatoid arthritis. It was miraculous. She woke up very rapidly.

Now its co-labeled. When the FDA approvedKymriah, it was co-labeled. It kind of saved the field.

How were you feeling during this time? Did you have any idea what was happening to her?

No, not until we got the cytokine levels, and then it was really clear. The cytokine levels go up and it exactly coincided. Then we retroactively checked out adults and they had adverse reactions and it easy to see. We hadnt been on the lookout because it wasnt in our mouse models.

And it appeared with those who got cured. Its one of the first on-target toxicities seen in cancer, a toxicity that happens when you get better. All the toxicities from chemotherapy are off-target: like leukopenia or hair loss.

I had a physician who had a fever of 106, I saw him on a fever when he was starting to get CRS. When the nurse came in and it said 106, they thought the thermometer must be broken. On Monday, I saw him, and said how are you feeling and he said fine. And I looked at the thermometer and histemperature was still 102.

People will willingly tolerate on-target toxicity thats very different from chemotherapy if they know it helps get them better. Thats a new principle in cancer therapy.

You had these early CART results almost at the same time that Doudna publishes the first CRISPR papers, then still in bacteria. When did you first start thinking about combining the two?

Yeah, it was published inSciencein 2012 and thats when Emily Whitehead got treated. Its an amazing thing.

Thats something so orthogonal. You think how in the heck can that ever benefit CART cells? but my lab had done the first edited cells in patients, published in 2012. And we used zinc-fingered nucleases, which were the predecessors to CRISPR. It knocked out one gene at a time, but we showed it was safe.

I was already into gene editing because it could make T cells resistant to HIV. So it was pretty obvious that there were candidates in T cells that you can knock out. And almost every lab started working on some with CRISPR, cause it was much easier.

We were the first to get full approval by the FDA, so we worked on it from 2012, had all the preclinical data by 2016, and then it takes a while to develop a lot of new assays for this as we were very cautious to optimize safety and it took longer than we wanted, but in the end, we learned a tremendous amount.

So what did we learn?

First of all our patients had advanced metastatic cancer and had had a lot of chemotherapy. The first patient had had 3 bone marrow transplants.

One thing is feasibility: could you really do all the complex engineering? So we found out we could. feasibility was passed.

Another was the fact that cas9 came out of bacteria, forms of strep and staph. Everyone has pre-existing immunity to Cas9 and we had experience from the first trial with Sangamo[with zinc-finger nucleases] where some patients had a very high fever. In that case, we had used adenoviruses, and it turned out our patients had very high levels of baseline immune response to adenoviruses, so we were worried that would happen with CRISPR, and it did not happen.

It did not have any toxicity. If it had, it would have really set the field back. If there was animmune response to cas9 and CRISPR, there couldve been a real barrier to the field.

And then, the cells survived in the patients. The furthest on, it was 9 months. The cells had a very high level of survival. In the previous trials, the cells survived less than 7 days. In our case, the half-life was 85 days. We dont know the mechanism yet.

And we found very big precision in the molecular scissors, and that was a good thing for the field. You could cut 3 different genes on 3 different chromosomes and have such high fidelity.

It [CRISPR] is living up to the hype. Its going to fix all these diseases.

Whats the potential in CAR-T, specifically?

Well theres many many genes that you can add. There are many genes that knocking outwill make the cells work better. We started with the cell receptor. There are many, I think, academics and biotechs doing this now and it should make the cells more potent and less toxic.

And more broadly, what else are you looking at for the future of CART? The week before your paper, there were the results from MD Anderson on natural killer cells.

Different cell types, natural killer cells, stem cells putting CAR molecules into stem cells, macrophages. One of my graduate students started a company to do CAR macrophages and macrophages actually eat tumor cells, as opposed to T cells that punch holes in them.

There will be different cell types and there will be many more ways to edit cells. The prime editing and base editing. All different new variations.

Youve talked about how people used to think the immuno-oncology, if it ever worked, would nevertheless be a boutique treatment. Despite all the advancements, Novartis and Gilead still have not met the sales they once hoped to grab from their CART treatments. Are you confident CART will ever be widely accessible?

Oh yeah, Novartis sales are going up. They had a hiccup launching.

Back in 96 or 97, when Genentech launched Herceptin, their commercial antibody, they couldnt meet the demand either and then they scaled up and learned how to do better cultures. So right now Novartis is using tech invented in my lab in the 1990s culture tech thats complex and requires a lot of labor, so the most expensive part is human labor. A lot can be made robotic. The scale problem will be much easier.

Thats an engineering problem that will become a thing of the past. The manufacturing problem will get a lot cheaper. Here in the US, we have a huge problem with how drugs are priced. We have a problem with pricing. Thats a political issue.

But in cell therapy, its just kind of the growth things you see in a new industry. Itll get worked out.

This article has been updated to reflect that Jim Riley conducted work on CAR in HIV.

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Carl June on CRISPR, CART and how the Vietnam War dropped him into medicine - Endpoints News

Medical Research and Innovation at Ohio State – Columbus Monthly

From a cancer vaccine to gene insertion for those with Parkinson's, local researchers are breaking through.

Research is big business at Ohio State University, with medical funding currently exceeding a quarter of a billion dollars, according to Peter Mohler, vice dean for research at OSUs College of Medicine. Ohio State gets grants from the National Institutes of Health and other sources such as other government agencies, nonprofit foundations and industry contracts.

Funding for OSUs College of Medicine, alone, now includes some $268.5 million. What follows are some of the latest breakthroughs.

An Anticancer Vaccine

A new anticancer vaccine, called B-Vaxx, is still in the early stages of being tested but initial studies are promising. The first-ever human trial at Ohio State led by researcher Pravin Kaumaya, a professor in the college of medicines department of obstetrics and gynecology, showed that patients with metastatic or recurrent solid tumors that overexpress the HER-2 protein had a stronger immune response than they did to current treatments.

This means that B-Vaxx may be more effective in killing tumor cells in many types of aggressive breast, gastroesophageal, endometrial, ovarian, colorectal and lung cancers. Although more research and clinical trials are needed, the bottom line on this first report is that scientists have concluded that the vaccine induced patient antibodies that showed potent antitumor activity.

Hope for Parkinsons

Dr. Krystof Bankiewicz, a researcher specializing in neurodegenerative disorders, and Dr. Russell Lonser, chair of OSUs department of neurological surgery, have been working with transformational gene therapy to develop cures for Parkinsons and other neurodegenerative diseases.

A one-step solution for Parkinsons could be the insertion of a non-pathogenic virus thats been modified to do only one thing: deliver the missing gene to a specific region of the brain.

The missing gene, if implemented, stops the progression of Parkinsons. Administering it, however, is a complex procedure. An MRI scanner is used to directly implant it in the brain.

Six clinical trials regarding the gene therapy and its effects on neurodegenerative diseasesincluding Parkinsons, Alzheimers, Huntingtons and moreare underway at Ohio State. In fact, the clinical trials for pediatric patients have been so successful that registration of the therapy has been fast-tracked with the U.S. Food and Drug Administration. There is hope that the drug will be approved this year for use in children.

Brain Stimulation

A small 2018 study at Ohio State implanted electrodes into the frontal cortex of Alzheimers patients and programmed a pacemaker to deliver deep brain stimulation. DBS has already proven to be helpful for patients with Parkinsons, epilepsy and obsessive-compulsive disorder. And, it is currently being studied for addiction, chronic pain, multiple sclerosis, traumatic brain injury and more.

Two of three people showed statistical improvement, says Dr. Douglas Scharre, professor of neurology and clinical psychology at OSUs Center for Cognitive and Memory Disorders and its Center for Neuromodulation. One patient was able to plan an outing and handle money, make plans for an event and cook a simple meal. These may seem like minor improvements, but if the patient cant do it, the caregiver has to.

Atrial Fib: The Watchman

Among the 3,000 clinical trials at various stages at Ohio State in recent years has been apilot studylead by Dr. Ahmet Kilic, former OSU associate professor of cardiac surgery, on the efficacy of the Watchman, a tiny parachute-like device which is implanted into the heart to regulate the heartbeat of those who suffer from atrial fibrillation. (Kilic is now director of heart transplantation and mechanical circulatory support at Johns Hopkins Medicine.)

Along with reducing stroke risk, the Watchman allows for remote monitoring of heart function. Watchman patients also forgo the risk of excessive bleeding caused by long-term use of warfarin, such as Coumadin and other blood thinners. The implantnow in more than 100,000 peoplecan eliminate regular blood tests and food-and-drink restrictions that come with warfarin.

Expecting a Daughter?

Researchers at the Wexner Medical Center have found thatthat immune cell samples of women carrying girls produced more proteins called pro-inflammatory cytokines than those carrying boys, resulting in exacerbation of conditions such as asthma, and contributing to fatigue and achiness.

Too many of these cytokinescan really be unhelpful for our bodies functioning, explains Amanda Mitchell, lead author of the study while she was a postdoctoral researcher in the universitys Institute for Behavioral Medicine Research. Women carrying girls exhibited greater inflammatory responses when faced with some sort of immune challenge compared to women carrying boys.

Exercising and doing relaxing activities, such as meditation, are recommended. Also, eating healthy foods, including leafy greens, will better support healthy immune responses. Mitchell is now an assistant professor at the University of Louisvilles department of counseling and human development.

More Sleep EqualsHappier Marriages

According to the Centers for Disease Control and Prevention, 35 percent of Americans get less than seven hours of sleep per night, resulting in increased risk of stress-related inflammation and ensuing chronic illnesses such as cardiovascular disease, diabetes, arthritis and others.

In arecent studyat Ohio States Institute for Behavioral Medicine, married couples were asked to supply blood samples and information regarding hours they slept the previous two nights. They were then asked to resolve a conflict, with blood samples taken after the discussion. Although people who had slept less initially had no more inflammation than usual, there was a greater inflammatory response after the conflict. Furthermore, if both partners got less than seven hours of sleep the previous two nights, they were more likely to become hostile.

Couples using unhealthy resolution tactics had an even greater inflammatory response. In a marriage, sleep patterns often track together, explains Janice Kiecolt-Glaser, the senior author of the study and director of OSUs Institute for Behavioral Medicine Research. If one person is restless, or has chronic problems, that can impact the others sleep. If these problems persist over time, you can get this nasty reverberation within the couple.

Less Stress, Better Health

Dining on a Greek salad may be great, but if youre stressed, it may be no better for you than fish and chips, according to an Ohio State study published inMolecular Psychiatry. In the study, 58 women were given two different types of meals, one high in saturated fat, which has been linked to cardiovascular disease, and another with more heart-healthy, plant-based oil. The meals were similar in terms of calories and grams of fat. While inflammatory responses were predictably lower if the women were not stressed after the healthier meal, if a woman was stressed, it looked like she was eating the saturated fat meal in terms of her [inflammatory] responses, study author Kiecolt-Glaser told National Public Radio.

Even though the stressors were for everyday issues, such as dealing with a sick parent, the stress seemed to boost inflammation, increasing chances for disease and slowing the healing process. Still, more research needs to be done and there are plenty of ways to combat stress, includingdeep-breathing.

Immune Cells and Sex

An Ohio State study done on rats and reported in theJournal of Neurosciencefound that immune mast cells,usually ignored by neuroscientists, appear to play an important role in determining the gender of an animals sexual behavior.

When researchers, led by Kathryn Lenz, assistant professor of behavioral neuroscience, silenced the mast cells in male fetal rats, they found that the adult males were far less interested in having sex with females. In fact, they acted almost like females, according the study.

Newborn female rats whose mast cells were activated with a stimulating chemical did the opposite, showing more traditionally males behaviors. Lenz theorizes that if human development mirrors what was seen in this study, even relatively minor influencessuch as an allergic reaction, injury or inflammation during pregnancycould possibly steer sexual behavior and development.

On the Move: Its All Good

According to Bernadette Melnyk, chief wellness officer and dean of OSUs College of Nursing, researchers at the American College of Sports Medicine have confirmed that physical activity completed in any duration is associated with health benefits and count towards your recommended 150 minutes of weekly activity.

Traditionally, physical activity recommendations have focused on accumulating moderate-to-vigorous physical activity either in a continuous manner, such as going for a 30-minute run, or in short bouts performed throughout the day, according to theACSM. However, in 2018, thanks to the advent of digital and other activity trackers, the ACSM also recognized that most daily activity is sporadic and is typically performed in bouts that are less than 10 minutes in duration. Any such activity is now associated with favorable health-related outcomes.

Take time each day to get moving, even if only for five minutes, adds Melnyk.

Reprinted fromColumbus Monthly Health 2020.

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Medical Research and Innovation at Ohio State - Columbus Monthly

Fight against Alzheimer’s: Governor’s proposal would map genes of one million – WKBW-TV

(WKBW) New York Governor Andrew Cuomo is proposing a new tool in the fight against Alzheimer's. It's called "SUNY Curing Alzheimer's Health Consortium." Cuomo wants to spend five years mapping one million people both suffering from and at-risk of developing the disease.

"And then we will work with SUNY's research institutions, as well as our other research institutions across the state to develop treatments and therapies," Elizabeth Garvey, Special Counsel and Senior Advisor to Governor Cuomo, said.

Empire State Development life science initiative will lend $20 million in funding to recruit 200,000 people for phase one.

"This looks to be a very ambitious program, but one that is very complimentary to the other programs," Dr. Bruce Troen said. He is Chief of the Division of Geriatrics and Palliative Medicine, as well as the Director of Centers of Excellence for Alzheimer's Disease both at Jacobs School of Medicine and Biomedical Sciences. He also works at the Buffalo VA Medical Center.

"Hopefully this will law the foundation for ongoing investigation," he said. Dr. Troen said this proposal is just a piece of the bigger pie. It's not an immediate answer or a cure.

"New York state in taking the lead has been really doing this at a clinical services standpoint, but now it's helping to plant a stake in the ground to say they also want to support research," he said. Gene mapping can play an important role in determining risk factors. The Governor's Office said at the end of this consortium, the data base will be free to use for further research.

"Knowledge is king here...anticipation and prevention is going to help us," he said.

If approved, the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo will participate.

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Fight against Alzheimer's: Governor's proposal would map genes of one million - WKBW-TV

Adverum Biotechnologies Reports New Interim Data from Cohorts 1 and 2 of OPTIC Phase 1 Trial of ADVM-022 Intravitreal Gene Therapy for Wet AMD at…

DetailsCategory: DNA RNA and CellsPublished on Sunday, 09 February 2020 11:42Hits: 258

-- Robust efficacy with evidence of a dose response ---- 6/6 patients rescue-injection-free in cohort 1, with 3 patients at 52 weeks ---- 4/6 patients rescue-injection-free in cohort 2 (lower dose) at 24 weeks --

REDWOOD CITY, CA, USA I February 08, 2020 IAdverum Biotechnologies, Inc. (Nasdaq: ADVM), a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, today announced new interim clinical data from the OPTIC Phase 1 dose-ranging clinical trial of ADVM-022 intravitreal injection gene therapy. OPTIC includes treatment-experienced patients with wet age-related macular degeneration (AMD). The data are being presented today by David S. Boyer, M.D., senior partner, Retina-Vitreous Associates Medical Group and adjunct clinical professor of ophthalmology with the University of Southern California/Keck School of Medicine in Los Angeles, at the Angiogenesis, Exudation, and Degeneration 2020 Annual Meeting in Miami.

A copy of the presentation is available on the Adverum corporate website under Events and Presentations in the Investors section.

For the first time, data are being presented from patients in cohort 2 (n=6) at 24 weeks following treatment with a single intravitreal injection of a three-fold lower dose of ADVM-022 (2 x 10^11 vg/eye) compared to the cohort 1 dose (6 x 10^11 vg/eye).New data as detailed in the table below include:

OPTIC Phase 1 Clinical Trial Data:

I am very encouraged that this difficult-to-treat patient population enrolled in OPTIC is maintaining vision and anatomical improvements for an extended period of time, said David S. Boyer, M.D., senior partner, Retina-Vitreous Associates Medical Group and adjunct clinical professor of ophthalmology with the University of Southern California/Keck School of Medicine in Los Angeles, California. Additionally, ADVM-022continues to be safe and well tolerated, with ocular inflammation that is manageable with steroid eye drops. Patients with wet AMD and their caregivers carry a significant treatment burden from the current standard-of-care anti-VEGF injections, and real-world vision outcomes are suboptimal due to undertreatment. ADVM-022 as a one-time intravitreal injection therapy could transform the treatment paradigm for patients and their caregivers.

Aaron Osborne, MBBS, chief medical officer of Adverum, added, ADVM-022 has demonstrated a robust efficacy signal and evidence of a dose response in the OPTIC Phase 1 trial with data from 12 patients and two doses now available. Patients in cohort 2 received a three-fold lower dose of ADVM-022 than in cohort 1, and 4 of 6 of these patients are rescue injection-free through 24 weeks, whilst all 6 patients in cohort 1 remain rescue free with a median follow up of 50 weeks. OPTIC is progressing well, with the key objectives for cohorts 3 and 4 being to further evaluate dose response and to assess a 6-week prophylactic course of steroid eye drops instead of the 13-day oral steroid prophylaxis used in cohorts 1 and 2. We look forward to presenting clinical data from all four cohorts of OPTIC during this important year in the clinic for our novel gene therapy, ADVM-022.

KOL Discussion Tomorrow:In addition, Adverum will host an event with expert retinal specialists to discuss the OPTIC data presented at Angiogenesis and the potential opportunity for ADVM-022. The discussion will be held on Sunday, February 9, 2020 beginning at 10:00 am EST. The event will be webcast live from Adverums website at http://www.adverum.com in the Investors section under the Events and Presentations page. A replay of the webcast will be archived and available for replay following the event. A copy of the slide presentation will also available on the Adverum corporate website under Events and Presentations in the Investors section.

About the OPTIC Phase 1 Trial of ADVM-022 in Wet AMDThe multi-center, open-label, Phase 1, dose-ranging trial is designed to assess the safety and tolerability of a single intravitreal (IVT) administration of ADVM-022 in patients with wet AMD who are responsive to anti-vascular endothelial growth factor (VEGF) treatment. In cohort 1, patients (n=6) received ADVM-022 at a higher dose of 6 x 10^11 vg/eye and in cohort 2, patients (n=6) received ADVM-022 at a lower dose of 2 x 10^11 vg/eye. In cohort 3, patients (n=9) also are receiving a dose of 2 x 10^11 vg/eye and in cohort 4, patients (n=9) will receive a dose of 6 x 10^11 vg/eye. Patients in cohorts 3 and 4 will receive prophylactic steroid eye drops instead of oral steroids which were used in cohorts 1 and 2. The primary endpoint of the trial is the safety and tolerability of ADVM-022 after a single IVT administration. Secondary endpoints include changes in best-corrected visual acuity (BCVA), measurement of central retinal thickness (CRT), as well as mean number of anti-VEGF rescue injections and percentage of patients needing anti-VEGF rescue injections. Each patient enrolled will be followed for a total of two years.

Eight leading retinal centers acrossthe United States(U.S.) are participating in the OPTIC Phase 1 trial for ADVM-022. For more information on the OPTIC Phase 1 clinical trial of ADVM-022 in wet AMD, please visithttps://clinicaltrials.gov/ct2/show/NCT03748784.

About ADVM-022 Gene TherapyADVM-022 utilizes a propriety vector capsid, AAV.7m8, carrying an aflibercept coding sequence under the control of a proprietary expression cassette. ADVM-022 is administered as a one-time intravitreal injection, designed to deliver long-term efficacy and reduce the burden of frequent anti-VEGF injections, optimize patient compliance and improve vision outcomes for wet AMD and diabetic retinopathy patients.

In recognition of the need for new treatment options for wet AMD, the U.S. Food and Drug Administration granted Fast Track designation for ADVM-022 for the treatment of this disease.

Adverum is currently evaluating ADVM-022 in the OPTIC study, a Phase 1 clinical trial in patients 50 years and older with wet AMD. Additionally, Adverum plans to submit an Investigational New Drug Application for ADVM-022 for the treatment of diabetic retinopathy to the U.S. Food and Drug Administration in the first half of 2020.

About Wet Age-related Macular Degeneration (AMD)Age-related macular degeneration (AMD) is a progressive disease affecting the macula, the region of the retina at the back of the eye responsible for central vision. In patients with wet AMD, an aggressive form of AMD, abnormal blood vessels grow underneath and into the retina. These abnormal blood vessels leak fluid and blood into and beneath the retina, causing vision loss.

Wet AMD is a leading cause of vision loss in patients over 60 years of age, with a prevalence of approximately 1.2 million individuals in the U.S. and 3 million worldwide. The incidence of new cases of wet AMD in the U.S. is approximately 150,000 to 200,000 annually, and this number is expected to grow significantly as the countrys population ages.

The current standard-of-care therapy for wet AMD is anti-VEGF intravitreal injections. These are effective but typically require eye injections every 4-12 weeks in order to maintain vision. Compliance with this regimen can be difficult for patients, caregivers, and healthcare systems, leading to undertreatment and resulting in loss of vision.

About Adverum BiotechnologiesAdverum Biotechnologies (Nasdaq: ADVM) is a clinical-stage gene therapy company targeting unmet medical needs in serious ocular and rare diseases. Adverum is evaluating its novel gene therapy candidate, ADVM-022, as a one-time, intravitreal injection for the treatment of its lead indication, wet age-related macular degeneration. For more information, please visit http://www.adverum.com.

SOURCE: Adverum Biotechnologies

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Adverum Biotechnologies Reports New Interim Data from Cohorts 1 and 2 of OPTIC Phase 1 Trial of ADVM-022 Intravitreal Gene Therapy for Wet AMD at...

Human Mutation Rates Steady Across GroupsExcept in the Amish – The Scientist

The rate of new mutations in the human genome appear to be consistent across diverse populations, except onethe Old Order Amish of Lancaster, Pennsylvania. This group has a lower rate of developing new mutations, according to a study published January 21 in PNAS.The lower mutation rate does not appear to have a genetic component, pointing to a possible role for environmental factors in modifying how fast human genomes accrue new mutations.

It really looks like environmental differences might actually [have] the most significant effect on the number of mutations that you pass on to your offspring, rather than . . . there being some sort of gene causing mutations, says Aylwyn Scally, a geneticist at the University of Cambridge who was not involved in the work. In a larger study than this one, researchers might be better able to detect a genetic contribution if there is one, he says. But still its surprising that it hasnt jumped out, and instead theres this curious effect thats bolstered by their finding about the Amish. Maybe different environments are actually the biggest factor.

Mutation rates are a source of genetic variation within populations. Knowing more about these rates in humans can help researchers better understand disease and evolution. Before this study, mutation rates had really only been looked at in Europeans, and so we wanted to be able to look in a much broader, diverse population, evolutionary geneticist Timothy OConnor of the University of Maryland, a coauthor on the new paper, tells The Scientist.

To this end, he and his colleagues leveraged a dataset of whole genomes from more than 1,400 parent-child trios from the National Heart, Lung, and Blood Institutes TOPMed (Trans-Omics for Precision Medicine) program. The team found that the rate of de novo mutations was similar across populations of African, Latino, and European ancestry. That finding was intriguing because previous work had suggested that populations with high levels of genetic diversity, such as those of African descent, would have higher mutation rates.

Even more unexpected was the mutation rate detected in the 59 Amish families in the cohort. These Amish families are of European descent but have been genetically isolated from other populations since the 1700s and all descended from about 700 individual founders. They had a seven-percent-lower mutation rate compared with the other populations.

We were pretty surprised, says OConnor. Initially the team thought the lower mutation rate had to be an artifact of the sequencing or analysis. We did basically everything we could to try and figure out what kind of artifact would be causing it, and we couldnt find one.

The research team next tried to pinpoint what caused the Amish to have a lower incidence of new mutations. OConnor and his colleagues determined that the lower mutation rates were not heritable, which led the team to speculate that environmental factorssuch as the typical Amish diet and limits on technologymay contribute.

The findings are novel in that the reduced mutation rate hasnt been previously shown with so much sequencing data, says Heather Wheeler, a geneticist at Loyola University Chicago who was not involved in the study. The caveat is that it was still just in one group, and there were only 59 families in the Amish population, she notes. If this is a real effectthe clean-living hypothesis they proposewe definitely want to see it validated in other populations that have similar environments to the Amish.

M.D. Kessler et al., De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population,PNAS,doi:10.1073/pnas.1902766117, 2020.

Abby Olena is a freelance journalist based in Alabama. Find her on Twitter@abbyolena.

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Human Mutation Rates Steady Across GroupsExcept in the Amish - The Scientist