Category Archives: Gene Medicine

PUBLIC RELEASE DATE:

28-Oct-2014

Contact: Julie Chevrette julie.chevrette@icm-mhi.org 514-376-3330 x2641 Montreal Heart Institute

Montreal, October 28, 2014 The Montreal Heart Institute Research Centre is once again pushing the limits of knowledge in personalized medicine. A meta-analysis combining the results of several pharmacogenomic studies and involving over 40,000 research subjects now makes it possible to demonstrate a different response to statins according to the patient's gene profile. This important contribution of two Montreal researchers from the Montreal Heart Institute (MHI), Dr. Jean-Claude Tardif, Director of the Research Centre and Dr. Marie-Pierre Dub, Director of the Pharmacogenomics Centre, was the subject of a scientific publication released today in the prestigious journal Nature Communications.

"Once again, the Montreal Heart Institute and its team of committed doctors, researchers and professionals stand out as world leaders in the fight against cardiovascular diseases. This research project benefitted from our participation in this international consortium, leveraged by our knowledge and our pharmacogenomic laboratory dedicated to the search for innovative treatments in the fight against heart disease. Today, these advances make it possible to identify a different response to a statin commonly used to reduce LDL-cholesterol (bad cholesterol), according to the individual's gene profile. And for the first time, two genomic regions (loci) have been identified as determining locations for responses to a statin," said Dr. Tardif.

Patients will benefit considerably in the medium and long term from these findings and innovations as the medical practices used to treat heart disease are transformed to allow each patient to receive suitable treatment. This is another of the MHI researchers' tangible contributions to the transformation of medical practices in the treatment of cardiovascular diseases.

Keep in mind that more than 1.3 million Canadians suffer from cardiovascular diseases, which are the world's primary cause of hospitalization and death. These diseases also put the greatest burden on our health system, with health costs nearing $22 billion per year.

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About the Montreal Heart Institute

Founded in 1954 by Dr. Paul David, the Montreal Heart Institute fosters the highest standards of excellence in cardiology through its leadership in clinical and fundamental research, ultra-specialized care, professional training, and prevention. It is part of the vast network of excellence in health established by Universit de Montral and its affiliates.

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The effect of statins influenced by gene profiles

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Newswise PHILADELPHIA A new effort mapping 24-hr patterns of expression for thousands of genes in 12 different mouse organs five years in the making provides important clues about how the role of timing may influence the way drugs work in the body. A study detailing this veritable atlas of gene oscillations, never before described in mammals, is published this week in the Proceedings of the National Academy of Sciences. The research was led by John Hogenesch, PhD, professor of Systems Pharmacology and Translational Therapeutics, in the University of Pennsylvanias Perelman School of Medicine.

The 24-hour rhythms of gene and protein activity govern most biological processes in animal and plant life on Earth. The Penn team found that nearly half of all genes in the mouse genome oscillate on a 24-hour schedule somewhere in the mouse body.

The team didnt stop there. They also determined that the majority of best-selling drugs (based on U.S. sales data from Q1 2013 at Drugs.com) target proteins made from genes whose expression changes daily.

Timing is an important but underappreciated factor in drug efficacy. Many of these drugs have relatively short half lives in the body, notes Hogenesch. The team suggests that the intersection of atlas and drug data can predict which drugs might benefit from timed dosing the essential medicines that directly target the products of rhythmic genes and therefore proteins. This approach is the crux of a growing field called chronotherapy. Whats Under the Lamppost

The genome is under much more clock control than we once thought, explains Michael Hughes, PhD, a former postdoctoral researcher in the Hogenesch lab, who is now an assistant professor of Biology at the University of Missouri-St. Louis. Since only a few organs were studied previously, we were only looking under the lamppost. Now we have the most comprehensive survey to date.

Specifically, the team found that 43 percent of all protein-coding genes showed circadian rhythms in being transcribed into proteins somewhere in the mouse body. The liver was the most rhythmic, having more oscillating genes than any other organ studied. They also found that these oscillations largely occur in an organ-specific manner, with the expression of many oscillating genes peaking during rush hours of transcription (that is, the reading of DNA onto RNA before proteins are made by the cell) preceding dawn and dusk. The non-coding RNAs conserved between mouse and humans show a rhythmic expression in similar proportions as protein-coding genes, helping the researchers to focus on the non-coding genes most likely to be relevant in humans.

Drug targets are even more likely to be under clock control -- 56 of the 100 top-selling drugs and 119 of the 250 World Health Organizations list of essential medicines work on genes with circadian oscillation. Most of these drug targets were not known to be clock-regulated. Many metabolizing enzymes and transporters are too, says Hogenesch. Because this isnt appreciated, few of these drugs have been evaluated for time-of-day dependent efficacy, metabolism, or toxicity.

The study of drug timing has been going on for forty years and has had several successes like chemotherapeutics, short-acting statins, and low-dose aspirin. However, most of these studies were done by trial and error. Now we know which drug targets are under clock control and where and when they cycle in the body. This provides an opportunity for prospective chronotherapy, explains Hogenesch. Benefits of proper drug timing could include better compliance, improved efficacy, fewer drug:drug interactions, and ultimately, better outcomes at lower costs.

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First Atlas of Body Clock Gene Expression Informs Timing of Drug Delivery

The drug erlotinib is highly effective in treating advanced-stage lung cancer patients whose tumors have a particular gene change, but when the same drug is used for patients with early-stage tumors with the same gene change, they actually fare worse than if they took nothing. A study by researchers at The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James) and at Cincinnati Children's Hospital might show why.

Oncologists use erlotinib to treat lung cancers that have a mutation in a gene called epidermal growth factor receptor (EGFR). The gene mutation causes EGFR to run like it has a stuck accelerator, and erlotinib blocks the overactive molecule. The study shows that while erlotinib effectively causes tumors to shrink -- suggesting that the drug is helping -- this drug also increases the aggressiveness of the tumor so that growth is accelerated when therapy ends. This study finds that this is due to a secondary and previously unknown effect of inhibiting EGFR.

The researchers found that when erlotinib blocks EGFR, it activates a second signaling molecule called Notch3. Activation of that pathway leads to increased development of cancer stem cells among the surviving tumor cells and to accelerated tumor growth.

"Our findings might explain why erlotinib in clinical trials seems to worsen survival in patients with early-stage lung cancer," says co-corresponding author David Carbone, MD, PhD, professor of medicine, Division of Medical Oncology at the OSUCCC -- James. "They also suggest that combining an EGFR inhibitor with a Notch inhibitor should overcome the effect."

The study was published in the journal Cancer Research.

Carbone, co-corresponding author Stacey Huppert, of Cincinnati Children's Hospital, and their colleagues conducted the study using several cell lines of non-small-cell lung cancer, the most common form of lung cancer, to learn if inhibiting EGFR enhances the activity of the Notch signaling pathway.

"We found that the activated, mutated EGFR directly inhibits Notch signaling, and that inhibiting EGFR with erlotinib removes this restraint and activates Notch signaling," says Carbone, who is the Barbara J. Bonner Chair in Lung Cancer Research. "It suggests that specific dual targeting might overcome this adverse effect."

The study's key technical findings include:

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The above story is based on materials provided by Ohio State University Wexner Medical Center. Note: Materials may be edited for content and length.

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Why targeted drug doesn't benefit patients with early-stage lung cancer

(HealthDay News) -- A new test that scans all of a person's genes to pinpoint a single mutation can help identify rare genetic disorders in children, a new study shows.

Audrey Lapidus and her husband grew concerned when their son Calvin didn't roll over or crawl by the time he was 10 months old. He also had chronic digestive problems. A series of tests didn't provide any answers.

In desperation, Calvin's parents agreed to have their son become the first person to undergo a powerful new test called exome sequencing at the University of California, Los Angeles.

DNA from Calvin and his parents was placed in a machine that rapidly scanned and compared the three family members' genomes. The machine identified a mutation on the boy's 18th chromosome. He was diagnosed with Pitt-Hopkins Syndrome, a rare genetic disorder that affects only 250 children worldwide, according to researchers.

The diagnosis meant that Calvin's parents could start seeking the best treatment for their son, according to the study published online Oct. 18 in the Journal of the American Medical Association.

"Our study is the first to show that sequencing a child's genome together with his or her parents' dramatically improves geneticists' ability to reach a firm diagnosis in rare disorders," corresponding author Dr. Stan Nelson, vice chair of human genetics and a professor of pathology and laboratory medicine at David Geffen School of Medicine at UCLA, said in a university news release.

Calvin was the first of more than 800 children included in the study.

"We discovered a genetic cause for the conditions affecting 40 percent of the hundreds of young children who come to UCLA for exome sequencing due to developmental delays or intellectual disabilities," Nelson said.

The findings make a strong case for routine clinical use of exome sequencing in efforts to diagnose children with rare genetic disorders, the researchers said.

Unlike earlier tests that assess one gene at a time, exome sequencing rapidly surveys all of a person's 20,000 genes in order to identify a single mutation. The test focuses on the exome, which are protein-encoding parts of genes that account for only 1 percent of DNA but nearly 85 percent of errors known to cause diseases.

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Gene scan helps diagnose mystery disorders in children

Three UCSF faculty members are among 70 new members and 10 foreign associates of the Institute of Medicine (IOM) announced during the organizations 44th annual meeting announced on Oct. 20.

Eric P. Goosby, MD, professor of medicine and director of the Institute of Global Health Delivery and Diplomacy; Deepak Srivastava, MD, professor of medicine and director of the Gladstone Institute of Cardiovascular Disease; and Ron Vale, PhD, professor of cellular and molecular pharmacology and Howard Hughes Medical Institute investigator are the latest UCSF members, bringing the total number of IOM members elected from UCSF to 92.

These individuals and all UCSF members of the Institute of Medicine represent the breadth of our expertise, ranging from national and international leadership in public health to explorations into the genetic blueprint and smallest functional molecules, saidBruce Wintroub, MD, interim dean of the UCSF School of Medicine. Each of them has greatly contributed to our knowledge of disease and our advancement of human health. I congratulate Doctors Goosby, Srivastava and Vale for their extraordinary accomplishments, and I am grateful that they are part of the UCSF community.

Eric P. Goosby, MD

Goosby has a long career in international HIV/AIDS. He was the CEO and chief medical officer of Pangea Global AIDS Foundation from 2001 to 2009, and previously was the director of National AIDS Policy at the While House under President Clinton and the director of the Ryan White Care Act at the US Department of Health & Human Services.

In his role as the Global AIDS Ambassador, Goosby was the nations senior global health diplomat, advancing the mission to improve and save lives and to foster global sustainability. He oversaw PEPFAR (the Presidents Emergency Plan For AIDS Relief), the largest public health endeavor in history with over $45 billion invested in 10 years.

Deepak Srivastava, MD

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Three UCSF Faculty Elected to Institute of Medicine

PUBLIC RELEASE DATE:

23-Oct-2014

Contact: Kat J. McAlpine katherine.mcalpine@wyss.harvard.edu 617-432-8266 Wyss Institute for Biologically Inspired Engineering at Harvard @wyssinstitute

BOSTON - New achievements in synthetic biology announced today by researchers at the Wyss Institute for Biologically Inspired Engineering, which will allow complex cellular recognition reactions to proceed outside of living cells, will dare scientists to dream big: there could one day be inexpensive, shippable and accurate test kits that use saliva or a drop of blood to identify specific disease or infection a feat that could be accomplished anywhere in the world, within minutes and without laboratory support, just by using a pocketsized paper diagnostic tool.

That once farfetched idea seems within closer reach as a result of two new studies describing the advances, published today in Cell, accomplished through extensive crossteam collaboration between two teams at the Wyss Institute headed by Wyss Core Faculty Members James Collins, Ph.D., and Peng Yin, Ph.D..

"In the last fifteen years, there have been exciting advances in synthetic biology," said Collins, who is also Professor of Biomedical Engineering and Medicine at Boston University, and CoDirector and CoFounder of the Center of Synthetic Biology. "But until now, researchers have been limited in their progress due to the complexity of biological systems and the challenges faced when trying to repurpose them. Synthetic biology has been confined to the laboratory, operating within living cells or in liquidsolution test tubes."

The conventional process can be thought of through an analogy to computer programming. Synthetic gene networks are built to carry out functions, similar to software applications, within a living cell or in a liquid solution, which is considered the "operating system".

"What we have been able to do is to create an in vitro, sterile, abiotic operating system upon which we can rationally design synthetic, biological mechanisms to carry out specific functions," said Collins, senior author of the first study, "PaperBased Synthetic Gene Networks".

Leveraging an innovation for chemistrybased paper diagnostics previously devised by Wyss Institute Core Faculty Member George Whitesides, Ph.D. , the new in vitro operating system is ordinary paper.

"We've harnessed the genetic machinery of cells and embedded them in the fiber matrix of paper, which can then be freeze dried for storage and transport we can now take synthetic biology out of the lab and use it anywhere to better understand our health and the environment," said lead author and Wyss Staff Scientist Keith Pardee, Ph.D.

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Synthetic biology on ordinary paper, results off the page

TUESDAY, Oct. 21, 2014 (HealthDay News) -- About one-fifth of Hispanic women have a genetic variation that offers significant protection against breast cancer risk, according to a new study.

The genetic variant originates from native Americans and reduces breast cancer risk by 40 percent to 80 percent, particularly the more aggressive estrogen receptor-negative forms of the disease, researchers said.

"The effect is quite significant," study senior author Dr. Elad Ziv, a professor of medicine at the University of California, San Francisco, said in a university news release.

"If you have one copy of this variant, which is the case for approximately 20 percent of U.S. Latinas, you are about 40 percent less likely to have breast cancer. If you have two copies, which occurs in approximately 1 percent of the U.S. Latina population, the reduction in risk is on the order of 80 percent," Ziv explained.

The researchers pinpointed the genetic variant after analyzing DNA from 3,140 breast cancer patients in the United States, Mexico and Columbia, as well as from nearly 8,200 women without breast cancer in those same countries.

The team also found that women with the genetic variant have breast tissue that appears less dense on mammograms. Breast tissue that appears more dense on a mammogram is a known risk factor for breast cancer, according to the study published Oct. 20 in the journal Nature Communications.

Hispanic women are at lower risk for breast cancer than women in other ethnic groups. Lifetime risk of the disease is 13 percent for whites, 11 percent for blacks, and less than 10 percent for Hispanics, according to the U.S. National Cancer Institute. The risk is even lower for Hispanic women with native American ancestry.

The newly identified genetic variant is on chromosome 6, near a gene that codes for an estrogen receptor called ESR1. Further research is needed to determine how the genetic variant affects breast cancer risk, the researchers said.

"If we can use these results to better understand how this protects [against] estrogen receptor-negative breast cancer, that would be interesting and important, because right now we have no good way to prevent that type of breast cancer," Ziv said.

-- Robert Preidt

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Gene May Help Shield Hispanic Women From Breast Cancer, Study Says

PUBLIC RELEASE DATE:

20-Oct-2014

Contact: Todd Murphy murphyt@ohsu.edu 503-494-8231 Oregon Health & Science University @ohsunews

Oregon Health & Science University's Vaccine & Gene Therapy Institute (OHSU), has been awarded a $10 million contract from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Kineta, Inc., the University of Washington Center for Innate Immunity and Immune Disease (CIIID), and the Vaccine & Gene Therapy Institute of Florida (VGTI Florida) will collaborate with OHSU as major sub-contractors to develop new vaccine adjuvants that could boost the effectiveness of a wide range of human vaccines for infectious diseases including West Nile Virus, Dengue and Japanese Encephalitis. The work will also provide novel applications for enhancing the immune response against Ebola virus, HIV, and other virus infections. Infectious diseases affect millions of people in developed and developing nations, many with no effective protective vaccines.

Vaccines are the first line of defense against infectious disease and have saved millions of lives over the years. However, some people with weakened immune systems and the elderly lose the ability to respond to vaccines. The effectiveness of vaccines can be improved by the addition of substances called adjuvants that not only enhance the body's immune response to the vaccine but also decrease the dose of the vaccine, allowing the vaccine supply to be extended.

Currently, the Food and Drug Administration has approved only three vaccine adjuvants. This award is part of an NIH push to develop more adjuvants.

"Although vaccines are extremely effective at preventing disease, the elderly and infants, who are the most vulnerable part of our population, are not efficiently protected," said Jay Nelson, Ph.D., professor and director of OHSU's VGTI, who will co-lead work on the NIH contract. "For example, while 80 percent of normal healthy adults are protected with the flu vaccine, more than 40 percent of people over 65 do not develop protective immunity. We have found that the addition of adjuvants to vaccines can better protect older animals from virus infection," Nelson added.

Nelson and other OHSU VGTI scientists will work with Shawn Iadonato, Ph.D., Chief Scientific Officer for Kineta, Inc., a biotechnology company in Seattle, on the development of new adjuvants using the company's innate immune drug development platform.

"Kineta has significant experience in high through-put methods to identify chemical compounds that stimulate the immune system and that are safe and effective. Developing these new adjuvants could change the paradigm for generating lasting immunity to pathogens," said Dr. Iadonato.

Michael Gale, Jr., Ph.D., Professor of Immunology and Director of the CIIID at the University of Washington, will co-lead this project with Nelson. "The identification of new adjuvants will also be important to make vaccines for other diseases such as Ebola virus, influenza A virus, HIV, bacterial infection, and cancer more effective," Gale said.

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OHSU, partners Kineta, UW, VGTI Florida awarded NIH contract to develop vaccine adjuvants

A new kind of genetic test that analyzes all of a persons genes can provide a diagnosis about a quarter of the time for patients whose conditions have baffled doctors, scientists reported Saturday. And for young children with mysterious developmental delays, the test gives a diagnosis more than 40 percent of the time.

The test is called whole-exome sequencing, and it looks at all 20,000 or so genes in the human body. Its not a whole genome sequence because it leaves out DNA thats not classified as a gene. But such tests provide a good map of the so-called protein coding sequences.

It was a relief for Audrey Lapidus of Los Angeles, whose baby son Calvin seemed just fine at first. But at 6 months, an osteopath suggested genetic testing. She said he had some very interesting facial features, Lapidus told NBC News. Other pediatricians rejected the notion.

But then he just wasnt hitting the milestones, she said. He wasnt sitting up or rolling over.

Deep down, I knew something was wrong."

Still, pediatricians and friends alike reassured her. A basic genetic panel came back clear.

Everyone wants to tell you about their nephew who didnt walk until he was 2 and he graduated from Harvard, Lapidus said. I was holding on to those stories.

At the same time, she continued to visit geneticists and neurologists. Deep down, I knew something was wrong, she said.

Calvin became the first child at UCLA to get a whole-exome genetic test at UCLA, in 2012. When it came back, it showed Calvin had Pitt-Hopkins Syndrome, a rare genetic disorder affecting only 250 children worldwide.

Its caused by a single mutation on one gene found on chromosome 18. It causes developmental delays, seizures and, as Calvins osteopath suspected, distinctive facial features, such as thin eyebrows and sunken eyes. Children often never learn to speak or walk without help.

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New Clues: Whole-Gene Scan Analyzes Mystery Illnesses

A new kind of genetic test that analyzes all of a persons genes can provide a diagnosis about a quarter of the time for patients whose conditions have baffled doctors, scientists reported Saturday. And for young children with mysterious developmental delays, the test gives a diagnosis more than 40 percent of the time.

The test is called whole-exome sequencing, and it looks at all 20,000 or so genes in the human body. Its not a whole genome sequence because it leaves out DNA thats not classified as a gene. But such tests provide a good map of the so-called protein coding sequences.

It was a relief for Audrey Lapidus of Los Angeles, whose baby son Calvin seemed just fine at first. But at 6 months, an osteopath suggested genetic testing. She said he had some very interesting facial features, Lapidus told NBC News. Other pediatricians rejected the notion.

But then he just wasnt hitting the milestones, she said. He wasnt sitting up or rolling over.

Deep down, I knew something was wrong."

Still, pediatricians and friends alike reassured her. A basic genetic panel came back clear.

Everyone wants to tell you about their nephew who didnt walk until he was 2 and he graduated from Harvard, Lapidus said. I was holding on to those stories.

At the same time, she continued to visit geneticists and neurologists. Deep down, I knew something was wrong, she said.

Calvin became the first child at UCLA to get a whole-exome genetic test at UCLA, in 2012. When it came back, it showed Calvin had Pitt-Hopkins Syndrome, a rare genetic disorder affecting only 250 children worldwide.

Its caused by a single mutation on one gene found on chromosome 18. It causes developmental delays, seizures and, as Calvins osteopath suspected, distinctive facial features, such as thin eyebrows and sunken eyes. Children often never learn to speak or walk without help.

Read this article:
New Clues for Kids: Whole-Gene Scan Analyzes Mystery Illnesses