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Genetic Medicine

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News Article | May 17, 2017
Site: www.sciencedaily.com

Weekly doses of glucocorticoid steroids, such as prednisone, help speed recovery in muscle injuries, reports a new Northwestern Medicine study. The weekly steroids also repaired muscles damaged by muscular dystrophy. The studies were conducted in mice, with broad implications for humans. One of the major problems of using steroids such as prednisone is they cause muscle wasting and weakness when taken long term. This is a significant problem for people who take steroids for many chronic conditions, and can often result in patients having to stop steroid treatments. But the new study in mice showed weekly doses -- rather than daily ones -- promote muscle repair. "We don't have human data yet, but these findings strongly suggest some alternative ways of giving a very commonly used drug in a manner that doesn't harm, but in fact helps muscle," said lead investigator Dr. Elizabeth McNally, the Elizabeth J. Ward Professor of Genetic Medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. McNally also is the director of the Center for Genetic Medicine at Feinberg. The study was published online in May in the Journal of Clinical Investigation. The study showed prednisone directs the production of annexins, proteins that stimulate muscle healing. Giving weekly doses of prednisone also stimulated a molecule called KLF15, which is associated with improved muscle performance. Daily doses of prednisone, however, reduced KLF15, leading to muscle wasting. In the study, normal mice with a muscle injury received steroids just before injury and for two weeks after the injury. Mice receiving two weekly doses of steroids after the injury performed better on treadmill testing and had stronger muscle than mice receiving a placebo. Mice that received daily steroids for two weeks after the muscle injury performed poorly on the treadmill and in muscle strength studies, compared to placebo-treated mice. Scientists also tested the drug in a mouse model of muscular dystrophy, since prednisone is normally given for this disease. Mice with muscular dystrophy that received weekly prednisone were stronger and performed better on the treadmill than those getting a placebo. When prednisone was given every day, the muscles atrophied and wasted. McNally initiated the research because she wanted to understand how prednisone -- which is given to treat individuals with a form of muscular dystrophy called Duchenne Muscular Dystrophy -- prolongs patients' ability to walk independently and stay out of a wheelchair. "It's been known that long-term daily treatment with prednisone also has the side effect of causing muscle wasting in many people," McNally said. "So it has always been something of a medical curiosity that it is also used chronically to treat conditions like myositis (muscle inflammation) and Duchenne Muscular Dystrophy. " While years of being on the steroids cause growth suppression, osteoporosis and other bad side effects, boys with Duchenne Muscular Dystrophy walk two to three years longer if they take steroids. Boys get the disease because it is on the X chromosome, and males have only one X chromosome. "A typical boy with Duchenne Muscular Dystrophy goes into a wheelchair at age 10; if he takes steroids, it's age 13," McNally said. "So in muscular dystrophy, there is definitely a benefit, but it's a double-edged sword with all the side effects." For the study, McNally and colleagues used high-resolution imaging to view the muscle's ability to repair itself. This technique uses a laser to poke a hole in muscle cells. Then the muscle cell is observed in real time as it reseals the hole, a natural repair process. Next, the scientists tested to see if steroids could boost the repair process. "The steroids made muscle heal faster," McNally said. "We were like, 'Wow!' It accelerated the repair in the muscle cells." For the second part of the study, scientists tested steroids in mice. They damaged the leg muscles in mice and noticed the mice receiving the steroids recovered more rapidly from injury. "We showed steroid treatment, when given weekly, improves muscle performance," McNally said. Her work also implies normal muscle injury would improve more quickly by taking a weekly dose of steroids such as prednisone. In the future, McNally would like to test steroids in humans and is considering studying it in forms of muscular dystrophy in which steroids would not normally be given, like Becker Muscular Dystrophy or Limb Girdle Muscular Dystrophy. Steroid treatment is not usually offered for these diseases since the side effects are thought to outweigh any potential benefit.


News Article | May 16, 2017
Site: www.eurekalert.org

Steroids thought to waste muscles surprisingly turn out to be beneficial in weekly doses CHICAGO --- Weekly doses of glucocorticoid steroids, such as prednisone, help speed recovery in muscle injuries, reports a new Northwestern Medicine study. The weekly steroids also repaired muscles damaged by muscular dystrophy. The studies were conducted in mice, with broad implications for humans. One of the major problems of using steroids such as prednisone is they cause muscle wasting and weakness when taken long term. This is a significant problem for people who take steroids for many chronic conditions, and can often result in patients having to stop steroid treatments. But the new study in mice showed weekly doses -- rather than daily ones -- promote muscle repair. "We don't have human data yet, but these findings strongly suggest some alternative ways of giving a very commonly used drug in a manner that doesn't harm, but in fact helps muscle," said lead investigator Dr. Elizabeth McNally, the Elizabeth J. Ward Professor of Genetic Medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. McNally also is the director of the Center for Genetic Medicine at Feinberg. The study was published online in May in the Journal of Clinical Investigation. The study showed prednisone directs the production of annexins, proteins that stimulate muscle healing. Giving weekly doses of prednisone also stimulated a molecule called KLF15, which is associated with improved muscle performance. Daily doses of prednisone, however, reduced KLF15, leading to muscle wasting. In the study, normal mice with a muscle injury received steroids just before injury and for two weeks after the injury. Mice receiving two weekly doses of steroids after the injury performed better on treadmill testing and had stronger muscle than mice receiving a placebo. Mice that received daily steroids for two weeks after the muscle injury performed poorly on the treadmill and in muscle strength studies, compared to placebo-treated mice. Scientists also tested the drug in a mouse model of muscular dystrophy, since prednisone is normally given for this disease. Mice with muscular dystrophy that received weekly prednisone were stronger and performed better on the treadmill than those getting a placebo. When prednisone was given every day, the muscles atrophied and wasted. McNally initiated the research because she wanted to understand how prednisone -- which is given to treat individuals with a form of muscular dystrophy called Duchenne Muscular Dystrophy -- prolongs patients' ability to walk independently and stay out of a wheelchair. "It's been known that long-term daily treatment with prednisone also has the side effect of causing muscle wasting in many people," McNally said. "So it has always been something of a medical curiosity that it is also used chronically to treat conditions like myositis (muscle inflammation) and Duchenne Muscular Dystrophy. " While years of being on the steroids cause growth suppression, osteoporosis and other bad side effects, boys with Duchenne Muscular Dystrophy walk two to three years longer if they take steroids. Boys get the disease because it is on the X chromosome, and males have only one X chromosome. "A typical boy with Duchenne Muscular Dystrophy goes into a wheelchair at age 10; if he takes steroids, it's age 13," McNally said. "So in muscular dystrophy, there is definitely a benefit, but it's a double-edged sword with all the side effects." For the study, McNally and colleagues used high-resolution imaging to view the muscle's ability to repair itself. This technique uses a laser to poke a hole in muscle cells. Then the muscle cell is observed in real time as it reseals the hole, a natural repair process. Next, the scientists tested to see if steroids could boost the repair process. "The steroids made muscle heal faster," McNally said. "We were like, 'Wow!' It accelerated the repair in the muscle cells." For the second part of the study, scientists tested steroids in mice. They damaged the leg muscles in mice and noticed the mice receiving the steroids recovered more rapidly from injury. "We showed steroid treatment, when given weekly, improves muscle performance," McNally said. Her work also implies normal muscle injury would improve more quickly by taking a weekly dose of steroids such as prednisone. In the future, McNally would like to test steroids in humans and is considering studying it in forms of muscular dystrophy in which steroids would not normally be given, like Becker Muscular Dystrophy or Limb Girdle Muscular Dystrophy. Steroid treatment is not usually offered for these diseases since the side effects are thought to outweigh any potential benefit. The study was funded in part by National Institutes of Health grants NIH U54 AR052646 and NIH RO1 NS047726, the Muscular Dystrophy Association, Parent Project Muscular Dystrophy and the American Heart Association.


News Article | May 8, 2017
Site: www.businesswire.com

NEWTOWN SQUARE, Pa.--(BUSINESS WIRE)--XyloCor Therapeutics Inc., a privately held biotech company, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to its lead product candidate XC001 (AdVEGF-All6A+), a cardiovascular angiogenic gene therapy. XC001 is a one-time treatment being investigated for improving exercise tolerance in patients who have chronic angina that is refractory to standard medical therapy and not amenable to conventional revascularization procedures such as coronary artery bypass surgery and percutaneous coronary intervention and stents. “Achieving Fast Track status validates the need for XC001, which has the potential to be a unique treatment for this serious condition with high unmet need - chronic, refractory angina,” said Al Gianchetti, President and Chief Executive Officer of XyloCor. “This designation is supported by strong scientific evidence for XC001 and clinical validation of this mechanism of action in refractory angina. This important designation is intended to contribute to an expedited development and regulatory review process, which can get the drug sooner to patients who can benefit from it.” The FDA Fast Track designation is designed to facilitate the development and expedite the review of new drugs and vaccines intended to treat or prevent serious conditions and that demonstrate the potential to address an unmet medical need. XC001 is a novel gene therapy that promotes angiogenesis, the formation of new vessels that can provide arterial blood flow to myocardial regions with inadequate blood supply. Enhancing myocardial blood flow with therapeutic angiogenesis is intended to relieve myocardial ischemia, improve regional and global left ventricular performance, alleviate angina symptoms and disability and potentially improve prognosis. “There are many patients in the United States with refractory angina and there are no available treatment options,” said Magnus Ohman, Professor of Medicine, The Kent and Siri Rawson Director, Duke Program for Advanced Coronary Disease, Duke University School of Medicine. “These patients have significant limitations in terms of their daily activities because of the chest pain associated with their ischemic disease and XC001 could be an important new option for them.” An IND for XC001 is open with the FDA and XyloCor intends to commence clinical trials upon funding. XyloCor Therapeutics is a private biopharmaceutical company developing novel gene therapy for people with unmet medical need from advanced coronary artery disease. XyloCor is focused on developing its lead product, XC001, for patients with refractory angina with no treatment options and its secondary product, XC002, for patients with cardiac tissue damage from heart attacks. XyloCor was founded by Dr. Ronald Crystal and Dr. Todd Rosengart, who both sit on XyloCor’s advisory board. Dr. Crystal is the Bruce Webster Professor and Chairman, Department of Genetic Medicine, Weill Cornell Medicine and Director of the Belfer Gene Therapy Core Facility. Dr. Rosengart is Professor and Chairman, DeBakey Bard Chair of Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine. XyloCor has a licensing agreement with Cornell University granting the company worldwide rights to develop, manufacture and commercialize XC001. With a strong scientific foundation, compelling preclinical and clinical evidence and an experienced team, XyloCor is poised for success and to help patients lead better, healthier lives. For more information, visit www.xylocor.com.


News Article | April 18, 2017
Site: www.businesswire.com

ALISO VIEJO, Calif.--(BUSINESS WIRE)--Ambry Genetics Corporation (Ambry) is calling on psychiatrists, psychologists and behavioral specialists to encourage their patients with autism, along with their family members, to sign up for a new study conducted through Ambry’s data sharing program, AmbryShare. With this program, Ambry is taking a step towards discovering possible associations between genes and autism, so clinicians can provide their patients with targeted treatments and therapies much earlier in life. “What’s unique about AmbryShare’s approach is that we collect genetic information from clinics and families from all over the world to answer questions that can’t be answered with just a handful of patients,” said Brigette Tippin Davis, PhD, Ambry’s Director of Emerging Genetic Medicine. “The great thing about Ambry partnerships is that we are building connections between research institutions and empowering them to develop new approaches to treating patients with autism based on genetic profiles.” So far, dozens of behavioral clinics and other medical offices have contributed to AmbryShare studies by encouraging participation from their patients. Ambry strives to enroll more than 10,000 patients from clinics nationally and internationally. “Genetic testing would allow us to personalize treatment from a genetic profile and optimize it together with our rich behavioral data,” said Dennis Dixon, PhD, Chief Strategy Officer at Center for Autism and Related Disorders (CARD). “I really value working with Ambry, knowing this data will have an impact on treatment for our patients and then will still be available for other researchers to access to answer additional research questions. As we each put more samples in, it increases the overall likelihood that we’re going to find something that really makes a difference.” One in 64 children in the United States is diagnosed with an autism spectrum disorder (ASD), which can impact social interaction, communication and behavior. Genetic testing can help identify an underlying cause in up to 40% of autism spectrum disorders. Some genetic causes include chromosome microdeletions/microduplications, fragile X syndrome, Angelman syndrome, and tuberous sclerosis. New gene discovery can allow clinicians to determine their patient’s course of treatment and the gene-disease relationship associated with their individual case of autism. Through the recruitment of a massive cohort, more data will be collected to discover more genes, develop medical management plans and enact preventive strategies. “The scientists need the data to be out there,” said Charles Dunlop, Ambry’s President and Chairman. “We need to know what these diseases are actually doing, what causes them, what gene mutations are associated with them so we can move forward as an industry and move onto the next phase where there is no disease of any kind. A phase where pharmaceutical researchers know exactly what to do, or exactly what problems they’re trying to solve at a minutiae level—that’s when the cures come.” In 2016, Mayo Clinic and University of Utah collaborated with Ambry on a new research study of more than 60,000 patients to help refine breast cancer risk estimates from predisposition genes that are either previously lacking data or have limited data. The study, “Breast cancer risks associated with mutations in cancer predisposition genes identified by clinical genetic testing of 60,000 breast cancer patients” represented the largest genetic study of women with hereditary breast cancer. The large amount of data was able to provide researchers with new information about genes that contributed to breast cancer risk. Ambry wants to provide researchers with the same capabilities for autism. Since 2001, Ambry has been dedicated to scientific research to help empower the scientific community and refine clinician management guidelines so patients may receive tailored medical management. AmbryShare’s initial launch in 2016 provided scientific researchers and clinicians with the largest open, de-identified database of hereditary breast and ovarian cancer cohorts with the goal of achieving a greater understanding of human disease. For more information and to enroll in the AmbryShare autism study, visit the AmbryShare portal here. Ambry Genetics is both College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified. Ambry leads in clinical genetic diagnostics and genetics software solutions, combining both to offer the most comprehensive testing menu in the industry. Ambry has established a reputation for sharing data while safeguarding patient privacy, unparalleled service, and responsibly applying new technologies to the clinical molecular diagnostics market. For more information about Ambry Genetics, visit www.ambrygen.com. About the Center for Autism and Related Disorders (CARD) CARD treats individuals of all ages who are diagnosed with autism spectrum disorder (ASD) at treatment centers around the globe. CARD was founded in 1990 by leading autism expert and clinical psychologist Doreen Granpeesheh, PhD, BCBA-D. CARD treats individuals with ASD using the principles of applied behavior analysis (ABA), which is empirically proven to be the most effective method for treating individuals with ASD and recommended by the American Academy of Pediatrics and the US Surgeon General. CARD employs a dedicated team of over 3,000 individuals across the nation and internationally. For more information, visit www.centerforautism.com or call (855) 345-2273.


News Article | October 26, 2016
Site: www.eurekalert.org

MONTREAL, Oct. 20, 2016 - A Canada-US study led by Luis Barreiro, a professor at the University of Montreal's Department of Pediatrics and researcher at the Sainte-Justine University Hospital Center, has demonstrated that Americans of African descent have a stronger immune response to infection compared to Americans of European descent. The study establishes for the first time this difference in immune responses and shows that it is mostly genetic -- inherited from our ancestors and influenced by a relatively recent natural selection. The study is published today in the scientific journal Cell. The study was conducted among 175 Americans, half of which were of African descent, the other half being of European descent, in collaboration with the University of California, Wayne State University, Cornell University, the University of Minnesota, and Duke University. While the immune system of African Americans responds more strongly, Professor Barreiro is careful to qualify it as better: "The immune system of African Americans responds differently, but we cannot conclude that it is better, since a stronger immune response also has negative effects, including greater susceptibility to autoimmune inflammatory diseases such as Crohn's disease. Too much inflammation can damage organs and leave sequelae. In short, a strong immune response can be beneficial in some areas but a disadvantage in others. The immune system reacts to infection by causing inflammation (redness, heat, swelling, etc.) to neutralize and eliminate the infection. It was already known to scientists that African Americans are more susceptible to autoimmune inflammatory diseases and thus more likely to suffer from tuberculosis or scleroderma, for example. The 175 participants in Professor Barreiro's study provided blood samples, from which were extracted macrophages ¬-- cells of the immune system whose role is to kill pathogens responsible for infection. The research team then infected the macrophages with two kinds of bacteria (Listeria and Salmonella) to observe various immune responses: after 24 hours of infection, the macrophages from African Americans killed the bacteria three times faster. The research team also uncovered the molecular mechanisms acting on the genes responsible for these differences in immune responses. "This is one of the firsts of our study," said Barreiro. People of African and European descent have intermingled over the past centuries, and we are even able to determine which part of an individual's immune system is associated with African ancestry and which part with European ancestry." "Although we found these differences in immune responses between African and European Americans, we are still unable to demonstrate what evolutionary pressures led to the observed differences. One of our hypotheses is that in the prehistoric period, after human populations had migrated out of Africa, they were exposed to fewer pathogens (bacteria, viruses, parasites), which reduced the immune response and thus tissue inflammation. This reduction in the immune response (and inflammation) was most likely an advantage because of the adverse consequences of acute or chronic inflammation, which are major contributors to the development of autoimmune inflammatory diseases." Another hypothesis is that the weaker immune response detected in Europeans is the result of a less vigorous natural selection in an environment in which there were fewer, or at least different, pathogens compared to Africa. Neanderthals also played a role in the immune response to infection. Neanderthals, before disappearing, colonized Europe, but not Africa. In the process, they mixed their genes with African Cro-Magnons, who were spread throughout Europe. The analysis of Barreiro's team shows that about 3% of the genes involved in the differences in immune responses between African and European Americans come from Neanderthals! "There is still much to do. For example, we have not yet studied the immune response to viruses and parasites. In addition, genetics explains only about 30% of the observed differences in immune responses. Our future studies should focus on other factors, emphasizing the influence of the environment and our behaviour. The idea is to find immune mechanisms to help understand why some individuals react differently from others in the presence of certain viruses and bacteria," said Barreiro. Luis Barreiro specializes in the evolution of immune responses and was named one of the "40 under 40" (most promising researchers) published in 2014 by the prestigious journal Cell. The first time he set foot in a laboratory after completing his graduate studies in biotechnology at the University of Lisbon in his native Portugal, he found his vocation. After graduating, he obtained a six-month internship in mycobacterial genetics at the Pasteur Institute in Paris. Within five years he had completed a doctorate in human population genetics. After receiving his Ph.D., Barreiro moved to the United States, where he did a postdoctoral fellowship in functional genomics at the University of Chicago's Department of Human Genetics. Today, the same theme runs through Luis Barreiro's work at the University of Montreal and the Sainte-Justine University Hospital Research Center, which he joined in 2011. He is the holder of the Canadian Research Chair in Functional and Evolutionary Genomics of the Immune System. The main project of his laboratory is to discover and define the genetic bases of the variations underlying the differences in immune responses between individuals and human populations. While Barreiro's team is among the two or three groups in the world interested in immune responses and their genetic basis, it is the only one to explore this issue among different species of primates. http://www. Y. Nedelec, J. Sanz, G. Baharian, Z. A. Szpiech, A. Pacis, A. Dumaine, J.-C. Grenier, A. Freiman, A. J. Sams, S. Hebert, A. Pagé Sabourin, F. Luca, R. Blekhman, R. D. Hernandez, R. Pique-Regi, J. Tung, V. Yotova et L. B. Barreiro published the article "Genetic ancestry and natural selection drive population differences in immune responses to pathogens in human" in the journal Cell on October 2016. This study was funded by the Canadian Institutes of Health Research (Grants 301538 and 232519), the Human Frontiers Science Program (CDA-00025/2012), and the Canada Research Chairs Program (950-228993). Y.N. received a grant from the Network of Applied Genetic Medicine Network (RMGA); A.P.S. received a grant from the Fonds de recherche du Québec-Nature et technologies (FRQNT); and G.B. received a grant from the Fonds de recherche du Québec-Santé (FRQS).


News Article | February 3, 2016
Site: www.nature.com

Researchers at the body responsible for monitoring birth defects in Latin America are questioning the size of an apparent surge in the number of Brazilian children born with 'microcephaly' — abnormally small heads and brains. Alarm is growing about a reported rise in suspected cases of the rare condition, which has been tentatively linked to the rapid spread of the Zika virus through the Americas. But Jorge Lopez-Camelo and Ieda Maria Orioli, from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), say that the surge might largely be attributed to the intense search for cases of the birth defect, and misdiagnoses, because of heightened awareness in the wake of the possible link with Zika. This ‘awareness’ effect is well known and inevitable, they say, and must be revealing cases that would have gone unnoticed under normal circumstances. They also say that a high rate of misdiagnoses among reported cases is likely because the diagnostic criteria being used for microcephaly are broad. Lopez-Camelo and Orioli presented their analysis in Portuguese-language reports, and, after Nature’s enquiries, provided an English version of the summary (ECLAMC Report). They say that from the epidemiological data available, it is impossible to establish the true size of the surge in microcephaly, and whether there is any link with the Zika virus. In particular, large 'prospective' studies, in which pregnant women in areas of Brazil experiencing Zika outbreaks are monitored to see how many of their children develop microcephaly are needed, they say. Several research groups in and outside Brazil are already planning such studies, and some have begun. Specialists contacted by Nature emphasize that it is prudent for pregnant women to be cautious — for example, by protecting themselves against mosquito bites — until more is known. The experts agree that the reported size of the microcephaly increase so far is probably inflated — and this chimes with the latest figures from the Brazilian government. On 27 January, it said that of 4,180 suspected cases of microcephaly recorded since October, it has so far confirmed 270 and rejected 462 as false diagnoses. But some disagree with the ECLAMC team's conclusion that the reported surge in recent months can mostly be attributed to an increase in the intensity of the search for cases and misdiagnosis. Thomas Jaenisch, a tropical medicine specialist at the Heidelberg University Hospital in Germany, calls this an “extreme” position and says that it “might also create uncertainty in the media and public discussion in Brazil”. Previously confined to Africa and Asia, Zika virus reached the Americas in 2015, where it is currently causing an unprecedented epidemic in Brazil (see 'Zika in the Americas'). Most people infected with the virus — after being bitten by a mosquito — have no symptoms; the remainder have mild symptoms such as fever, skin rash and headache. But in October, Brazil's health ministry reported an unusual spike in reported cases of microcephaly in the northeastern state of Pernambuco, where the affected children's mothers had been in early pregnancy at around the same time as large Zika outbreaks occurred. The ministry subsequently raised the alarm of a possible link to Zika. This led the World Health Organization and its regional office, the Pan American Health Organization (PAHO), to issue an epidemiological alert on 17 November last year, which called on member states to look out for any similar increase in microcephaly among their populations. Earlier this month, the US Centers for Diseases Control and Prevention issued a travel notice, “out of an abundance of caution”, that advised pregnant women to consider postponing travel to places that have ongoing Zika outbreaks. To investigate the situation, the researchers at ECLAMC turned to its own databases dating back to 1967, as well as the country's Live Birth Information System (SINASC). According to ECLAMC, the average historical prevalence of microcephaly in Brazil is around 2 cases per 10,000 births, although rates in the country's north have typically been higher. The researchers calculate that the maximum number of cases that would have been expected in the northern state of Pernambuco in 2015 is around 45. Yet Pernambuco reported 26 times that number last year. Even if Zika is causing microcephaly, these huge numbers are simply too high to be credible, says the report. As well as the increased diagnoses owing to heightened awareness from the media and governments, Lopez-Camelo also highlights that the diagnostic criteria for microcephaly are relatively unspecific and are casting too wide a net. Brazilian health authorities are treating all fetuses with head circumferences that are more than two standard deviations below the average, and newborns with a head circumference of less than 32 centimetres, as suspected cases. But these criteria will inevitably capture many healthy children within the normal growth range who do not have microcephaly. But head circumference is only a proxy measure, note Lopez-Camelo and Orioli: confirming microcephaly requires a diagnosis of small brain size, and a decreased rate of brain growth. The pair are not alone in drawing attention to the broad diagnostic criteria — a risk assessment published on 21 January by the European Centre for Disease Prevention and Control (ECDC) also noted this and said: “It is expected that many of the suspected cases will be reclassified and discarded.” Helen Dolk, an epidemiologist at the University of Ulster near Belfast, UK, who works on the surveillance of congenital abnormalities, says that the ECLAMC’s conclusion — that the apparent surge could be largely an artefact — is possible in principle. But she stresses that it is impossible to confirm until more data becomes available — and that she is reserving judgement on the portion of the apparent increase that can be attributed to confounding factors. Lavinia Schüler-Faccini, a researcher at the Federal University of Rio Grande do Sul, Brazil, and president of the Brazilian Society of Genetic Medicine, says that she is certain that there has been a substantial increase in microcephaly cases. She notes that physicians began reporting a rise before the increased attention by health authorities, and the media began reporting a spike last November. “My personal impression is that there is an augmentation of cases of microcephaly in Brazil,” she says. “However it is not as huge as the suspected cases referred to the Ministry of Health.” Prospective studies have started and others are planned, she says. And she adds: “All our efforts now are to establish the real level of increase.” Establishing whether there is a link between microcephaly and Zika is particularly important because people living in the Americas lack immunity to the virus. This, combined with the fact that the Aedes mosquitoes that transmit the virus are widespread in the Americas, means that many people will be infected in future, including pregnant women. Zika virus has been found in amniotic fluid, placental or fetal tissues in several cases of nervous system malformations, including microcephaly, in Brazil. Following a World Health Organization press conference on Zika virus on 28 January, the agency said in a statement: “A causal relationship between Zika virus infection and birth defects and neurological syndromes has not been established, but is strongly suspected.” It also said: “The Organization is supporting the scaling up and strengthening of surveillance systems in countries that have reported cases of Zika and of microcephaly and other neurological conditions that may be associated with the virus.”


News Article | March 9, 2016
Site: www.nature.com

Researchers have found Colombia's first cases of birth defects linked to the Zika virus, Nature has learned — which are likely forerunners of a widely anticipated wave of Zika-related birth defects in the country. The discovery is perhaps no surprise: the virus arrived in Colombia last September, and the country is second only to Brazil in terms of the number of people infected with Zika. But Colombian researchers hope that plans put in place to closely monitor pregnant women can help to better establish the magnitude of the threat posed to fetuses by Zika. That is a crucial question that scientists have not so far been able to answer with the data from Brazil. Researchers have diagnosed one newborn with microcephaly — an abnormally small head — and two others with congenital brain abnormalities, says Alfonso Rodriguez-Morales, who chairs the Colombian Collaborative Network on Zika (RECOLZIKA), which made the diagnoses. All three tested positive for the presence of Zika virus. The researchers have submitted a report of their detections to a scientific journal. Rodriguez-Morales, an infectious-diseases epidemiologist at the Technological University of Pereira in western Colombia, says that he expects to see a rise in cases of Zika-linked birth defects starting in two or three months' time. The RECOLZIKA group — a network of researchers and public-health institutions across Colombia — are already investigating a handful of other suspected cases of microcephaly, which have a possible link to Zika. Brazil is the only country so far to report a large surge in newborns with microcephaly that coincides with outbreaks of Zika virus. By the time the alarm over a possible microcephaly link was raised there (in October 2015), Zika infections had already peaked in many parts of the country, because the virus first reached Brazil at the beginning of last year. In Colombia, by contrast, researchers detected the first Zika cases in September, and by December had set up national tracking programmes to monitor pregnant women for signs of infection, and to spot early signs of birth defects in fetuses. Since then, researchers have been waiting attentively to see whether their country might experience a similar rise in birth defects. The true size of Brazil's surge in microcephaly cases is unknown. The country's health ministry says that 5,909 suspected microcephaly cases have been registered since early November, but only 1,687 of them have been investigated so far. Of those, 1,046 have been discarded as false positives, and 641 have been confirmed. (A link with the Zika virus has been confirmed by molecular-lab tests in 82 cases.) Given that Brazil reported only 147 cases of microcephaly in 2014, the reported increase in cases since November suggests a marked rise in the number of babies born with the condition. But the 2014 figure is a “huge underestimate”, says Lavinia Schüler-Faccini, a geneticist who specialises in birth defects at the Federal University of Rio Grande do Sul, Brazil, and president of the Brazilian Society of Genetic Medicine. She says that according to the frequency of microcephaly typically observed in regions around the world, one would expect to see 300–600 cases of severe microcephaly in any given year in Brazil, and around 1,500 less-severe ones. The search for cases of microcephaly in Brazil since October is probably turning up many mild cases that previously went unnoticed — so that the reported surge looks higher than it really is. Still, Schüler-Faccini and other clinicians say there is a real problem. They have observed first-hand a marked increase in the number of unusually severe cases of microcephaly, they say. To be prepared to better interpret any imminent peak in birth defects in Colombia, RECOLZIKA plans to look at historical cases to establish a baseline for the annual numbers of birth defects in different regions. It is also setting up a study to analyse patterns in the distribution of head-circumference measurements recorded in obstetrics units regionally throughout the country, to get a better idea of the local range of normal values. It has also not been possible so far from Brazilian data to quantify the extent to which Zika virus is linked to the rise in microcephaly. The latest data from Brazil's ministry of health show that increased cases of microcephaly and/or congenital malformations of the central nervous system are still concentrated in the northeast — raising questions as to whether other factors, perhaps specific to this region, might also be in play. Clinical evidence leaves little doubt that a link between Zika and microcephaly exists: the virus has been detected in amniotic fluid, in the cerebrospinal fluid of affected babies and in the brains of stillborn fetuses and those aborted after the detection of severe malformations during pregnancy. But there are also many other possible causes of microcephaly, including a group of infections that are collectively called STORCH (syphilis, toxoplasmosis, other infections, rubella, cytomegalovirus infection and herpes simplex), which are known to cause birth defects. Exposure to toxic chemicals and the consumption of alcohol during pregnancy can also cause the condition. “There is a clear need for a full assessment of other detailed causes of microcephaly, such as STORCH, and even non-infectious causes,” says Rodriguez-Morales. Brazil’s health ministry has stated that it is carrying out tests for such causes, but it has not made public how many of the confirmed microcephaly cases are attributable to these. A key question in assessing the scale of the threat that Zika may pose to fetuses is how many pregnant women infected with Zika — in particular during the first trimester, when the fetus is most vulnerable — nonetheless give birth to healthy babies. RECOLZIKA researchers hope to help to answer this through their monitoring programme. The risk posed by Zika may well be lower than that of other diseases that are known to cause microcephaly such as toxoplasmosis and rubella, says Rodriguez-Morales. That is a preliminary estimate, he says, based on back-of-the-envelope calculations of the reported numbers of confirmed cases of microcephaly and congenital disorders, compared to the number of pregnant women in regions experiencing Zika epidemics. But even if its risk does turn out to be low, Zika could still lead to many cases because a large number of pregnant women in the Americas are likely to become infected with the virus. The biggest risk to pregnant women is right now, rather than in the long term. The epidemic is sweeping so quickly through the Americas that much of the population, including young women, will become naturally vaccinated by their exposure to the virus. As population immunity increases, the Zika epidemic is likely to fade quickly, and it will become endemic with only occasional flare ups. In a modelling study posted to the preprint server bioRxiv1 on 29 February, US researchers noted that the risk of prenatal Zika virus exposure “should decrease dramatically following the initial wave of disease, reaching almost undetectable levels”.


News Article | February 21, 2017
Site: www.businesswire.com

ALISO VIEJO, Calif.--(BUSINESS WIRE)--Ambry Genetics (Ambry) has created an online portal to enable more patients and families to participate in research through the AmbryShare program. With this simplified portal, Ambry has streamlined the research consent process to make cohort recruitment easier for clinicians at the time of sample collection for clinical testing. Patients now have the flexibility to e-consent from home, or a mobile device during their office visits. An individual can also enroll themselves and submit a sample to the program independently, whether or not their clinician orders a clinical test at Ambry. The new e-consent portal is one more example of the company’s mission to use AmbryShare to remove the red-tape that has been slowing down scientific progress. The data-sharing program is currently focused on the genomics of autism and prostate cancer, and Ambry is actively seeking research partners for those initiatives. “We've created a simple way for patients to participate in crowd-sourced research,” said Brigette Tippin Davis, PhD, Ambry’s Director of Emerging Genetic Medicine. “If your family is impacted by disease, we are empowering you to make a real difference. AmbryShare freely enables researchers worldwide to put your de-identified genomic DNA to work to find treatments, keeping your privacy protected at the same time.” Since March 2016, Ambry has provided researchers with de-identified aggregated data from whole exome sequencing on a large cohort of affected patients with the intention of aiding and accelerating scientific research at no cost to the public. This data will ultimately help clinicians create more tailored treatments through enhanced understanding of human disease. For more information and to enroll in AmbryShare, visit the AmbryShare portal here. Ambry Genetics is both College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified. Ambry leads in clinical genetic diagnostics and genetics software solutions, combining both to offer the most comprehensive testing menu in the industry. Ambry has established a reputation for sharing data while safeguarding patient privacy, unparalleled service, and responsibly applying new technologies to the clinical molecular diagnostics market. For more information about Ambry Genetics, visit www.ambrygen.com.


News Article | February 17, 2017
Site: www.eurekalert.org

When a child is conceived, he or she receives DNA from both parents. The child's own genome thus consists of a maternal and a paternal genome. However, some genes -- about 100 out of the 20,000 encoded genes-- are exclusively expressed either from the maternal or from the paternal genome, with the other copy of the gene remaining silent. We know that these imprinted genes are more likely to lead to serious genetic diseases, such as Prader-Willi or Angelman syndrome. Researchers at the University of Geneva (UNIGE), Switzerland, have devised a new technique, based on a combination of biology and bioinformatics, to quickly and accurately detect the imprinted genes expressed in each of the cell types that constitute the human organs. This major breakthrough will improve our understanding and diagnosis of genetic diseases. The study can be read in full in the American Journal of Human Genetics. The research team, led by Professor Stylianos Antonarakis from the Department of Genetic Medicine and Development in the Faculty of Medicine at UNIGE, focused on genomic imprinting. This is a set of genes exclusively expressed from the genetic code inherited either from the father (the paternal allele) or from the mother (maternal allele). Why is there so much interest in the identification of the imprinted genes? Because if a deleterious mutation affects the functional allele, it cannot be compensated by the expression of the second silent allele, likely causing a serious genetic disease. The goal, therefore, is to determine the imprinted genes in all cell types of human body tissues that are liable to cause these kind of diseases. Until recently, millions of cells were analysed together without distinction. «We have now developed a new technique with a better resolution, known as Human Single-Cell Allele-Specific Gene Expression," explains Christelle Borel, UNIGE researcher. "The process can be used to simultaneously examine the expression of the two alleles, paternal and maternal, of all known genes in each individual cell. The method is fast and can be carried out on thousands of single cells with the utmost precision using next-generation sequencing technology." The heterogeneity of each tissue of the body is thus analysed in detail while searching for imprinted genes in disease-relevant tissue. The individual's genome is sequenced, as is the genome of both parents, in order to identify the parental origin of the alleles transcribed in the person's single cell. Federico Santoni, first author of the study and researcher at UNIGE and HUG (Geneva University Hospitals) further explains, "We establish the profile of the allelic expression for thousands of genes in each single cell. We then process this data with a novel computational and statistical framework to identify the specific signature of each imprinted gene, enabling us to accurately record them." This new technique redefines the landscape of imprinted genes by examining all cell types, and can be applied to all tissues affected by diseases, such as cardiac and brain tissue. Moreover, the scientists have discovered novel imprinted genes and demonstrated that some were restricted to certain tissues or cell types. This technique focuses on the specific characteristics of each individual by treating each cell as a single entity. This concept, called Single-cell Genomics, is part of an emerging field that is assuming an all-important role at UNIGE, which sees it as the future of medicine that will be personalised rather than generalised. Thanks to the technique pioneered by UNIGE researchers, it will be possible to identify new disease causing genes and to adapt a specific and targeted treatment for individual patients.


INGELHEIM, Germany--(BUSINESS WIRE)--Boehringer Ingelheim today announced a collaboration with Weill Cornell Medicine to identify new treatment approaches for chronic obstructive pulmonary disease (COPD) in order to develop novel treatments that could possibly halt or even reverse the progression of the disease process. The new, three-year collaboration combines Weill Cornell Medicine’s Department of Genetic Medicine’s unique understanding of chronic airway diseases and experience in the investigation of novel therapeutic concepts for airway repair with Boehringer Ingelheim’s expertise in the discovery and development of new therapies for respiratory diseases. This collaboration is the second collaboration between Boehringer Ingelheim and Weill Cornell Medicine, following prior work in inflammatory bowel disease (IBD). Chronic lower respiratory diseases, which include COPD, are the third leading cause of death in the United States, and approximately 15 million Americans have been told by a healthcare provider that they have COPD. It cannot be cured and current treatment approaches focus on bronchodilation, reducing symptoms and preventing exacerbations to decelerate the downward spiral of the disease. The goal is to help patients keep as active as possible and overall, improve their quality of life. “Our continuous search for molecular drivers of chronic obstructive airway diseases has revealed novel repair mechanisms that warrant further investigation of their potential as therapeutic approaches,” said Dr. Ronald G. Crystal, Chairman of Genetic Medicine at Weill Cornell Medicine and lead investigator in the new collaboration. “We will look to further expand our knowledge about progressive airway destruction in close collaboration with Boehringer Ingelheim and focus on promising therapeutic concepts with the potential to slow down or halt progressive airway damage in patients with COPD.” “We are delighted to work with Dr. Crystal at Weill Cornell Medicine, who is one of the leading scientists in severe progressive airway diseases worldwide,” said Dr. Clive R. Wood, Senior Corporate Vice President, Discovery Research at Boehringer Ingelheim. “The scientists at Weill Cornell Medicine and Boehringer Ingelheim will work hand in hand to translate new discoveries into drug discovery and development programs at Boehringer Ingelheim. The new collaboration is an excellent example of our unique partnering approach and our focus on early innovation, underscoring our ambition to develop the next generation of medical treatments for patients with COPD.” Boehringer Ingelheim is combining a focus on cutting-edge science with a long-term view enabling the company to create a stable environment for the development of the next generation of medical breakthroughs. This new project adds another building block in this long-term strategy to improve the lives of patients with high unmet medical needs. Weill Cornell's Office of BioPharma Alliances and Research Collaborations negotiated the three-year collaboration. The office’s mission is to proactively generate, structure and market translational research alliances with industry in order to advance promising research projects that have commercial potential. For more information, contact Larry Schlossman at las2041@med.cornell.edu or at 212-746-6909. For references and notes to editors, please visit:

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