They found that in mice in which they had removed the c-Maf gene in the nerve cells, touch sensation is impaired. This similarly applies to human carriers of a mutant c-Maf gene. People with such a mutation suffer already at a young age from cataracts, a clouding of the lens which typically affects the elderly. The patients, as demonstrated by Professor Carmen Birchmeier and Dr. Hagen Wende in collaboration with Professor Gary Lewin and Dr. Stefan Lechner, have difficulty holding objects such as a sheet of paper as a consequence of this mutation.

Professor Birchmeier, a developmental biologist, commented on the findings of her research group: "c-Maf is an important gene for the development of the peripheral nerve cells." The gene controls the development of neurons that detect touch, the mechanosensory neurons. Previously, c-Maf was known as a key regulator of lens development.

Furthermore, the gene is also active in the dorsal root ganglia, an aggregate of nerve cells next to the spinal cord in which the cell bodies of mechanosensory neurons are localized. The nerve cells form long axons, which terminate in the skin in touch corpuscles or at hair shafts. These axons detect mechanical stimuli, which in turn are converted into electrical signals and transmitted to the brain. When you stroke your fingers over a surface, its structure triggers high-frequency vibrations in the finger, to which specific touch receptors, the Pacinian corpuscles, respond.

In mice with deactivated c-Maf gene only few Pacinian corpuscles are formed, and moreover these few are not intact. The mice are therefore unable to recognize high-frequency vibrations. The same is true for a Swiss family with an inherited mutant c-Maf gene. The consequence is that the affected patients develop cataracts at an early age and have an impaired sense of touch.

More information: Science Express, 16 February 2012. DOI:10.1126/science.1214314

Provided by Helmholtz Association of German Research Centres (news : web)

Continue reading here:
The molecular basis of touch sensation: New function of a well-known gene identified

02-11-2011 18:43 The new drug Kalydeco is being hailed as a breakthrough in the treatment of cystic fibrosis, targeting the underlying genetic cause of the disease decreasing the symptoms. Dr. Jon LaPook reports.

Read the rest here:
Breakthrough in cystic fibrosis treatment - Video

ScienceDaily (Feb. 21, 2012) — A gene known to control lens development in mice and humans is also crucial for the development of neurons responsible for mechanosensory function, as neurobiologists of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have now discovered. They found that in mice in which they had removed the c-Maf gene in the nerve cells, touch sensation is impaired.

This similarly applies to human carriers of a mutant c-Maf gene. People with such a mutation suffer already at a young age from cataracts, a clouding of the lens which typically affects the elderly. The patients, as demonstrated by Professor Carmen Birchmeier and Dr. Hagen Wende in collaboration with Professor Gary Lewin and Dr. Stefan Lechner, have difficulty holding objects such as a sheet of paper as a consequence of this mutation.

Professor Birchmeier, a developmental biologist, commented on the findings of her research group: "c-Maf is an important gene for the development of the peripheral nerve cells." The gene controls the development of neurons that detect touch, the mechanosensory neurons. Previously, c-Maf was known as a key regulator of lens development.

Furthermore, the gene is also active in the dorsal root ganglia, an aggregate of nerve cells next to the spinal cord in which the cell bodies of mechanosensory neurons are localized. The nerve cells form long axons, which terminate in the skin in touch corpuscles or at hair shafts. These axons detect mechanical stimuli, which in turn are converted into electrical signals and transmitted to the brain. When you stroke your fingers over a surface, its structure triggers high-frequency vibrations in the finger, to which specific touch receptors, the Pacinian corpuscles, respond.

In mice with deactivated c-Maf gene only few Pacinian corpuscles are formed, and moreover these few are not intact. The mice are therefore unable to recognize high-frequency vibrations. The same is true for a Swiss family with an inherited mutant c-Maf gene. The consequence is that the affected patients develop cataracts at an early age and have an impaired sense of touch.

Recommend this story on Facebook, Twitter,
and Google +1:

Other bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by Helmholtz Association of German Research Centres.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

H. Wende, S. G. Lechner, C. Cheret, S. Bourane, M. E. Kolanczyk, A. Pattyn, K. Reuter, F. L. Munier, P. Carroll, G. R. Lewin, C. Birchmeier. The Transcription Factor c-Maf Controls Touch Receptor Development and Function. Science, 2012; DOI: 10.1126/science.1214314

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Read this article:
Molecular basis of touch sensation: Researchers identify new function of a well-known gene

UK firm Oxford Nanopore has unveiled two new products that could revolutionise gene sequencing for science and medicine: a new DNA sequencer that could be able to handle a complete human genome in as little as 15 minutes, and a USB thumb drive that can read DNA directly from blood and in some cases with no sample preparation.

The two products were presented last week at a conference in Florida. The company says its nanopore 'strand sequencing' technique means that the four biochemical letters of DNA can be read more quickly and less expensively than by other established companies in the field.

The first product – GridION – is the size of a DVD player, and consists of an array of proprietary protein nanopores embedded in a robust polymer membrane. Individual strands of DNA are passed through a tiny hole in a cell membrane, known as a nanopore, allowing each GridION node to deliver tens of gigabytes of sequence data per 24 hour period.

Related Articles on Techworld

Nodes may be clustered to increase the number of nanopore experiments being conducted at any one time, if a faster time-to-result is required. For example, a 20-node installation using an 8,000 nanopore configuration would be expected to deliver a complete human genome in 15 minutes.

Meanwhile, the miniaturised MinION device is the size of a USB memory stick, and is designed for portable analysis of single molecules. Oxford Nanopore said the device's low cost, portability and ease of use are designed to make DNA sequencing universally accessible.

“The exquisite science behind nanopore sensing has taken nearly two decades to reach this point; a truly disruptive single molecule analysis technique, designed alongside new electronics to be a universal sequencing system,” said said Dr Gordon Sanghera, CEO of Oxford Nanopore. “GridION and MinION are poised to deliver a completely new range of benefits to researchers and clinicians.”

Oxford Nanopore intends to commercialise GridION and MinION directly to customers within 2012. A single MinION is expected to retail at less than $900 (£567), and a new model of versatile pricing schemes will be introduced for the GridION system, designed to deliver a price per base that is as competitive as other leading systems.

The DNA sequencing machines currently on the market, made by US companies Illumina and Life Technologies, are much bigger and take far longer. Life Technologies recently made a splash with its announcement of a machine that could read a whole human genome – 3bn DNA letters – for just $1,000 in less than a day.

“Oxford Nanopore’s technology platform is truly disruptive and game-changing and is poised to deliver new applications and general benefits to science and medicine,” said Alan Aubrey, chief executive of IP Group, which owns 21.5 percent of Oxford Nanopore. “The significance of this technology introduction is, in computing terms, analogous to moving from the mainframe to the laptop.”

Potential applications include screening genetic material, prenatal screening for genetic defects and diagnostic tests aimed at identifying genetic mutations that have applicability in agricultural, environmental and medical markets, according to Aubrey.

See the rest here:
Oxford Nanopore unveils minature DNA sequencer

04-01-2012 14:37 Chronic inflammation and the chemical silencing of tumor-suppressing genes each play roles in development and progression of colorectal cancer. Research published in Nature Medicine led by MD Anderson Provost Raymond DuBois, MD, Ph.D., connects the two factors by showing the inflammatory small molecule PGE2 silences genes via DNA methylation. http://www.nature.com

See the original post here:
Inflammation Shuts Down Cancer-Fighting Genes - Video

Sleepless elite ... Margaret Thatcher was said to get by on four hours sleep a night.

Therese Rein once told a journalist that her husband slept about three hours a night.

By this time, Kevin Rudd had already branded himself '24-7 Kevin' and in doing so joined history's long line of short-sleepers: Margaret Thatcher (four hours), Winston Churchill (five), Bill Clinton (five to six), Leonardo Da Vinci (five), Napoleon Bonaparte (three to four), Madonna (four), Silvio Berlusconi (two), P Diddy (less than four), Martha Stewart (two to four) and Donald Trump (three to four).

Some politicians and celebrities have bragged about how little sleep they need - the implication being they are tougher, more productive and more suitable for leadership because of it.

Advertisement: Story continues below

Is there such a thing as a 'sleepless elite' - a segment of the human population that performs equally well on a few hours sleep?

And if so, is Kevin Rudd a genetic freak, or just sleep-deprived like the rest of us?

Two of Australia's leading sleep experts agree that, like all human behaviours, there is variation in how much sleep people need.

And while genes almost certainly play a role, they say, recent newspaper reports that scientists have discovered a "Thatcher gene" are misleading.

"There are some who need less sleep, but scientists cannot explain completely why," Nick Glozier, Associate Professor of Psychological and Sleep Medicine at the University of Sydney, said.

"In terms of how many people are actually these super short sleepers ... about five per cent of the adult population of Australia sleep like that," he said.

Self-reporting of performance after sleep deprivation is unreliable, which makes it difficult to judge how many people fit into this sleepless elite, Professor Glozier said.

"You can't turn around to pilots and surgeons and say, 'How do you think you're doing after this amount of sleep?', because actually they are probably the worst person to ask," Professor Glozier said.

"For instance, if Kevin Rudd says he thinks he's doing well; he probably isn't the best judge of that."

Others may sleep only four hours at night, but compensate by taking power naps during the day, Professor Glozier said.

"If you look at Maggie Thatcher - she had cat naps."

Professor Leon Lack, a sleep expert at Flinders University in South Australia, said that many of history's short-sleepers probably restricted their REM (Rapid Eye Movement) sleep, which, rather than making a person sleepy often has a "manic" or "energising" effect.

"In rats, for example... it results in increased eating behaviour, increased fighting, increased sexual activity.

"One of the effects of REM sleep loss is people become more emotionally labile, which means more emotionally variable. So they will tend to go through more swings, of exhilaration, but also quicker to anger," Professor Lack said.

As for that genetically-blessed minority who can sleep four hours and be sharp and in a good mood; scientists have only a limited understanding of why they are this way.

Scientists in Germany recently found that one gene, called ABCC9, could partly explain why some people seem able to operate on little sleep, but Professor Glozier said if scientists had really discovered a "Thatcher gene" then managers would surely be recruiting for it.

"You can imagine how valuable that [the "Thatcher gene"] might be. If you're going to run some merchant bank where your traders are expected to work 18 hours... I know what I'd be considering."

Continued here:
Quest for a Thatcher gene

Sleepless elite ... Margaret Thatcher was said to get by on four hours sleep a night.

Therese Rein once told a journalist that her husband slept about three hours a night.

By this time, Kevin Rudd had already branded himself '24-7 Kevin' and in doing so joined history's long line of short-sleepers: Margaret Thatcher (four hours), Winston Churchill (five), Bill Clinton (five to six), Leonardo Da Vinci (five), Napoleon Bonaparte (three to four), Madonna (four), Silvio Berlusconi (two), P Diddy (less than four), Martha Stewart (two to four) and Donald Trump (three to four).

Some politicians and celebrities have bragged about how little sleep they need - the implication being they are tougher, more productive and more suitable for leadership because of it.

Advertisement: Story continues below

Is there such a thing as a 'sleepless elite' - a segment of the human population that performs equally well on a few hours sleep?

And if so, is Kevin Rudd a genetic freak, or just sleep-deprived like the rest of us?

Two of Australia's leading sleep experts agree that, like all human behaviours, there is variation in how much sleep people need.

And while genes almost certainly play a role, they say, recent newspaper reports that scientists have discovered a "Thatcher gene" are misleading.

"There are some who need less sleep, but scientists cannot explain completely why," Nick Glozier, Associate Professor of Psychological and Sleep Medicine at the University of Sydney, said.

"In terms of how many people are actually these super short sleepers ... about five per cent of the adult population of Australia sleep like that," he said.

Self-reporting of performance after sleep deprivation is unreliable, which makes it difficult to judge how many people fit into this sleepless elite, Professor Glozier said.

"You can't turn around to pilots and surgeons and say, 'How do you think you're doing after this amount of sleep?', because actually they are probably the worst person to ask," Professor Glozier said.

"For instance, if Kevin Rudd says he thinks he's doing well; he probably isn't the best judge of that."

Others may sleep only four hours at night, but compensate by taking power naps during the day, Professor Glozier said.

"If you look at Maggie Thatcher - she had cat naps."

Professor Leon Lack, a sleep expert at Flinders University in South Australia, said that many of history's short-sleepers probably restricted their REM (Rapid Eye Movement) sleep, which, rather than making a person sleepy often has a "manic" or "energising" effect.

"In rats, for example... it results in increased eating behaviour, increased fighting, increased sexual activity.

"One of the effects of REM sleep loss is people become more emotionally labile, which means more emotionally variable. So they will tend to go through more swings, of exhilaration, but also quicker to anger," Professor Lack said.

As for that genetically-blessed minority who can sleep four hours and be sharp and in a good mood; scientists have only a limited understanding of why they are this way.

Scientists in Germany recently found that one gene, called ABCC9, could partly explain why some people seem able to operate on little sleep, but Professor Glozier said if scientists had really discovered a "Thatcher gene" then managers would surely be recruiting for it.

"You can imagine how valuable that [the "Thatcher gene"] might be. If you're going to run some merchant bank where your traders are expected to work 18 hours... I know what I'd be considering."

Visit link:
Sleepless elite: quest for the Thatcher gene

SUNDAY, Feb. 19 (HealthDay News) -- A new animal study suggests that a genetic mutation could put certain people at higher risk for becoming obese if they eat high-fat diets.

At the moment, the practical uses of the research seem to be limited, but physicians could conceivably test people for the mutation and recommend that they avoid certain kinds of diets, said study co-author Dr. Gozoh Tsujimoto, a professor at Kyoto University's department of genomic drug discovery science in Japan. It may also be possible, Tsujimoto said, to eventually give people drugs to combat the effects of the mutation.

If that happens, there would be "a new avenue for personalized health care," Tsujimoto said.

Scientists have been busy studying genetic links to obesity that could make some people more prone to gain extra weight. Two-thirds of Americans are either overweight or obese, the U.S. Centers for Disease Control and Prevention estimates. Excess pounds contribute to a variety of diseases, including heart disease and cancer.

In the new study, researchers looked at the component of the body's internal communication system that plays a role in the regulation of appetite and the production of fat cells.

The investigators found that mice that didn't have the component were 10 percent fatter than other mice when all were fed a high-fat diet. Mice without the component also developed higher intolerance to glucose.

Research conducted in animals does not always translate into humans, and much more research is needed. However, the researchers found that Europeans with the genetic mutation, known as GPR120, were more likely to be obese.

"Our study for the first time demonstrated the gene responsible for diet-induced obesity," Tsujimoto said.

According to Tsujimoto, more than 3 percent of Europeans have the trait. The next step for researchers is to study its prevalence in Japanese, Korean and Chinese people.

What can be done with the knowledge from the study?

Tsujimoto said physicians could advise people with the trait to avoid high-fat diets. A test is available to detect the trait and it costs about $200 in Japan, Tsujimoto said.

While medications could potentially be developed that would reverse the effects of the genetic trait, there are no such drugs now, Tsujimoto added.

Ruth Loos, director of Genetics of Obesity and Related Metabolic Traits at Mount Sinai School of Medicine in New York City, said "these findings provide another piece of what turns out to be the very large puzzle that describes the causes of obesity."

Consistent findings in mice and humans have put the trait "more firmly on the obesity map and provides a new starting point for more research into the function of this gene," said Loos.

"This is only the beginning of likely many years of research to disentangle the physiological mechanisms that lie behind the link between this gene and obesity risk," she said. "It is only when we understand the physiology and biology better that one can start thinking of developing a drug."

The study appears online Feb. 19 in the journal Nature.

More information

For more on obesity, visit the U.S. National Library of Medicine.

Read more here:
Gene Might Boost Risk for Obesity

The study, published in the international science and medicine journal PLoS One, was led by Winthrop Professor Alan Harvey from UWA's School of Anatomy, Physiology and Human Biology, and Associate Professor Jennifer Rodger, NHMRC Research Fellow in Experimental and Regenerative Neurosciences at UWA's School of Animal Biology.  The research was funded primarily by the WA Neurotrauma Research Program.

Professor Harvey said gene therapy was a relatively new strategy that attempted to help injured brain cells survive and regrow.

"Our previous work has shown that when growth-promoting genes are introduced into injured brain cells for long periods of time (up to nine months), the cells' capacity for survival and regeneration is significantly increased," he said.

"We have now shown that these same neurons have also changed shape in response to persistent over-expression of the growth factors.  Importantly, it is not just neurons containing the introduced growth-promoting gene that are affected, but neighbouring "bystander" neurons."

Professor Harvey said neural morphology was very important in determining how a cell communicated with other cells and formed the circuits that allowed the brain to function.

"Any changes in morphology are therefore likely to alter the way neurons receive and transmit information.  These changes may be beneficial but could also interfere with normal brain circuits, reducing the benefits of improved survival and regeneration."

Professor Harvey said the results were significant for those involved in designing gene therapy-based protocols to treat brain and spinal cord injury and degeneration.

"These new results suggest that we may need to be careful about the types of genes we use in neurotherapy and how long we continue the therapy.  While it may be beneficial for these genes to move around and cause changes in other cells, we need to be able to switch them off once the change has taken place."

Provided by University of Western Australia

Read the original post:
Neurons change shape after gene therapy

Dilated cardiomyopathy, a common cause of heart failure, can be attributed to defects in any of more than 40 different genes. A new study reveals that defects in the gene that encodes the human body’s largest protein, the muscle protein titin, are responsible for more cases of the disease than are caused by all other known mutations.

In a study of nearly 800 people, researchers found unique mutations that truncate titin in 22% of people with dilated cardiomyopathy. Researchers have had a difficult time learning exactly how Titin mutations lead to the disease because of the high expense and technical difficulty in sequencing the unusually large gene.

“It wasn’t that we weren’t aware that titin caused disease—we were. The problem was that the technology was not sufficiently robust to allow comprehensive analysis of that gene in a large collection of patients.”
Christine E. Seidman

In dilated cardiomyopathy, the heart blows up like a balloon. The stretched-out walls of muscle aren’t able to contract effectively, so the heart starts to fail at its job of pumping blood around the body. Deprived of oxygen and nutrients, the patient gets short of breath easily and retains fluid. Eventually, the only option is a heart transplant.

Dilated cardiomyopathy tends to run in families, so Christine Seidman, a Howard Hughes Medical Institute (HHMI) investigator at Brigham and Women’s Hospital in Boston, and her team have looked for—and found—several genes associated with the disease. But still, “we weren’t getting very far,” she says. Every gene was a step forward, but each gene still only accounted for a small percentage of cases of dilated cardiomyopathy. “We had the sense that maybe we’re missing something,” Seidman says. “We took a step back a few years ago to say, ‘What are we missing?’”

Seidman and her colleagues realized that, over the years, they had found several hints that problems with the titin protein could cause dilated cardiomyopathy. Titin is part of the sarcomere, the unit of muscle that contracts. Titin helps assemble the sarcomere as the heart muscle grows and also plays a role in muscle contractions.

But no one had ever organized a big study on titin. “It wasn’t that we weren’t aware that titin caused disease—we were,” Seidman says. “The problem was that the technology was not sufficiently robust to allow comprehensive analysis of that gene in a large collection of patients.”

The problem, in short, was that titin is enormous and sequencing was expensive. The protein is the longest humans make, some 33,000 amino acids stuck end to end. By comparison, the motor protein myosin has about 2,000 amino acids and Lamin A/C, a nuclear membrane protein that is also associated with dilated cardiomyopathy, only has about 675 amino acids. It was just too expensive to sequence big genes in a big group of people, so researchers had passed it over.

In the last decade, the technology has changed. Next-generation sequencing techniques have made it relatively cheap and easy to sequence long stretches of DNA fast. In a study published February 16, 2012, in The New England Journal of Medicine, Seidman and her colleagues sequenced the gene TTN, which codes for titin, in 312 people with dilated cardiomyopathy. They found 72 mutations that made incomplete forms of titin. Together, these explained about a quarter of the cases of dilated cardiomyopathy that run in families and weren’t caused by something else, like cardiovascular disease. That’s more than all the other genes they’d found put together.

Seidman, her husband Jon Seidman, and their colleagues at Harvard Medical School started out with a smaller group, 92 people with dilated cardiomyopathy who came to Brigham and Women’s Hospital. When they began their study, the team expected to find that TTN was yet another gene that accounted for a small number of cases of the disease. They were shocked by what they found: 28 percent of the people had dramatic mutations in the DNA encoding titin, the kind that mean the protein wouldn’t be fully made.

When they did their initial analysis of that data, Seidman recalls, “we said, ‘this is too good to be true.’ “That’s why we went and got more cohorts.” They then sequenced the TTN gene in 71 people with dilated cardiomyopathy from Imperial College in the UK who had been evaluated for heart transplants—they were, on average, much sicker than the Boston patients—and 149 other people with dilated cardiomyopathy from the University of Colorado and the University of Trieste in Italy. The team also sequenced the gene in 231 people with another form of cardiomyopathy recruited at the Mayo Clinic and 249 controls who did not have cardiomyopathy. Stuart Cook at Imperial College, Luisa Mestroni and Matthew Taylor at the University of Colorado, and Michael Ackerman at the Mayo Clinic led the efforts at the collaborating institutions. The data from that larger analysis confirmed what their initial study had hinted: mutations in the TTN gene are the most common known genetic cause of dilated cardiomyopathy.

Seidman hopes someday doctors will use this information to identify people who are likely to develop dilated cardiomyopathy before they get sick. As sequencing continues to get cheaper, it should eventually be possible for individuals to find out if they have a mutation associated with dilated cardiomyopathy. Then they could start taking drugs that make the heart’s work easier by lowering blood pressure, for example.

As scientists figure out how dilated cardiomyopathy develops, they may also be able to figure out how to keep the heart muscle from changing shape in the first place. Those days are far off, but this research is a step in the right direction, Seidman says. “It allows us to focus on what we don’t know yet,” she says. Discovering the role of mutations in titin is like finding one important piece of a jigsaw puzzle. “There are still a lot more pieces in the box that we need to sort through, but that’s a big deal.”

Continued here:
Researchers Identify New Gene Mutations that Cause Heart Disorder

Public release date: 15-Feb-2012
[ | E-mail | Share ]

Contact: Marjorie Montemayor-Quellenberg
mmontemayor-quellenberg@partners.org
617-534-2208
Brigham and Women's Hospital

BOSTON, MA?Mutations in TTN?the largest gene in the human genome?cause idiopathic (unknown cause) dilated cardiomyopathy (DCM), a common form of heart failure, according to a study by Brigham and Women's Hospital (BWH) researchers. The TTN gene encodes a protein that functions as a scaffold for assembly of contractile proteins in muscle cells and also regulates the production of force in cardiac muscle cells.

Because of its enormous size, the TTN gene was, until recently, too difficult to sequence and analyze in large numbers of patients. But with the development of next-generation sequencing technologies, the time was ripe to tackle TTN. Christine Seidman, MD, BWH Cardiovascular Genetics Center director and a team of dedicated scientists at Harvard Medical School; Imperial College, London; University of Colorado; and physicians at BWH took on the challenge to comb through the gigantic gene. Their study unveils how mutated TTN genes can lead to structural deformations in heart muscle fibers, which may then lead to heart muscle disease. The study will be published in the February 16, 2012 issue of The New England Journal of Medicine.

Researchers analyzed genetic samples from 312 people diagnosed with DCM, 231 with another heart muscle disease called hypertrophic cardiomyopathy (HCM), and 249 people without heart disease. They identified 72 mutations in the TTN gene that foreshorten the encoded protein. These shortened titin proteins lack regions involved in regulating force production in heart cells. Many more mutations were found in those with DCM compared to healthy individuals and those with HCM, indicating that TTN gene mutation causes DCM, but rarely causes HCM.

Moreover, the study notes that outcomes of patients with DCM were similar regardless of whether or not a person has a TTN gene mutation. However, among those that did have TTN mutations, adverse events such as cardiac transplantation, implantation of a ventricular assist device, or death occurred earlier in men than women. Seidman believes that the study findings will help improve future diagnosis and treatment of heart diseases.

"Early diagnosis of any disease, including DCM, can allow interventions that may prevent some of the devastating outcomes, such as sudden cardiac death from an arrhythmia or development of heart failure," said Seidman. "By knowing that TTN mutations account for a substantial amount of idiopathic DCM, we now will have the opportunity for early diagnosis in lots of at-risk individuals, and any person who has a family member with idiopathic DCM."

###

This research was supported by funding from Howard Hughes Medical Institute; National Institutes of Health Leducq Foundation; American Heart Association and Muscular Dystrophy Association; UK National Institute for Health Research Cardiovascular Biomedical Research Unit (Royal Brompton and Harefield NHS Foundation Trust & Imperial College), The British Heart Foundation and the MRC UK; and J. Ira and Nicki Harris Family Research Award.

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is the home of the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), http://www.brighamandwomens.org/research, BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $537 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information about BWH, please visit http://www.brighamandwomens.org.

[ | E-mail | Share ]

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Here is the original post:
Mutations in gigantic gene responsible for common heart muscle disease

CAMBRIDGE, Mass.--(BUSINESS WIRE)--

bluebird bio, a world leader in the development of innovative gene therapies for severe genetic disorders, today announced the appointment of David M. Davidson, M.D., to the role of chief medical officer.

“David brings a wealth of gene therapy, rare disease and clinical drug development expertise to bluebird bio during an exciting time in our company’s growth,” said Nick Leschly, chief executive officer of bluebird bio. “Operationally, David’s deep gene therapy and translational medicine experience will help guide bluebird bio’s clinical development efforts and regulatory strategies. With the addition of David to our team, we are well positioned to maximize the high priority opportunities available to us through our broad product platform.”

Prior to joining bluebird bio, Dr. Davidson served as a senior medical director at Genzyme Corporation where he led clinical research for programs in Phases 1 through 4 across a wide range of therapeutic areas for more than a decade. Most recently, Dr. Davidson was the medical leader for Genzyme’s gene therapy and Pompe disease enzyme replacement therapy programs. In addition to Dr. Davidson’s translational medicine experience, he has also worked on a number of commercial products, including Fabrazyme® and Myozyme®/Lumizyme®, and was integral in crafting the new drug application that resulted in the approval of Welchol®. Prior to Genzyme, Dr. Davidson was a medical director at GelTex Pharmaceuticals. Previously, he completed clinical and research fellowships in infectious diseases at the Harvard Longwood Combined Infectious Diseases Program. Dr. Davidson received a B.A. from Columbia University and his M.D. from New York University School of Medicine. In addition, he completed an internal medicine internship, residency training and an endocrinology research fellowship at the University of Chicago Hospitals.

“bluebird bio’s platform has the potential to be truly transformative,” said Dr. Davidson. “It is rare to be presented with an opportunity to develop a novel, clinically validated platform with promising early proof-of-concept data in two indications that can have such a dramatic effect across a broad set of severe genetic diseases. In the next two years, bluebird looks to have its ALD program well into a Phase 2/3 trial and two other programs nearing completion of Phase 1/2 trials for beta-thalassemia and sickle cell disease. I look forward to this exciting challenge and the potential to have a fundamental and meaningful impact on patients and their families.”

About bluebird bio

bluebird bio is developing innovative gene therapies for severe genetic disorders. At the heart of bluebird bio’s product creation efforts is its broadly applicable gene therapy platform for the development of novel treatments for diseases with few or no clinical options. The company’s novel approach uses stem cells harvested from the patient’s bone marrow into which a healthy version of the disease causing gene is inserted. bluebird bio’s approach represents a true paradigm shift in the treatment of severe genetic diseases by eliminating the potential complications associated with donor cell transplantation and presenting a one-time potentially transformative therapy. bluebird bio has two later stage clinical products in development for childhood cerebral adrenoleukodystrophy (CCALD) and beta-thalassemia/sickle cell anemia. Led by a world-class team, bluebird bio is privately held and backed by top-tier life sciences investors, including Third Rock Ventures, TVM Capital, ARCH Venture Partners, Forbion Capital Partners, Easton Capital and Genzyme Ventures. Its operations are located in Cambridge, Mass. and Paris, France. For more information, please visit http://www.bluebirdbio.com.

Read the original:
bluebird bio Appoints David Davidson, M.D., as Chief Medical Officer

WEDNESDAY, Feb. 15 (HealthDay News) -- Researchers have discovered a defective gene that's responsible for more than one-quarter of cases of inherited dilated cardiomyopathy, a serious heart muscle disease that often leads to heart failure by middle age.

In the study, published in the Feb. 16 issue of the New England Journal of Medicine, researchers analyzed the DNA of 312 people with dilated cardiomyopathy, 231 people with another form of heart muscle disease (called hypertrophic cardiomyopathy) and 249 people with healthy hearts.

The study patients with dilated cardiomyopathy had no obvious cause for their disease -- such as alcoholism, heart attacks and other infections -- so the researchers believed there was a genetic origin for the disease in these patients.

About 27 percent of the dilated cardiomyopathy patients had mutations on the TTN gene that shortened the length of the gene.

Only 1 percent of the patients with the other form of cardiomyopathy and 3 percent of patients with healthy hearts had similar mutations, the investigators found.

Further analysis of family members' DNA revealed that up to half of the dilated cardiomyopathy patients had first-degree relatives (including parents and siblings) who also had the TTN mutation by age 40, and of those, nearly all (95 percent) had some sign of heart disease, said study co-leader Jonathan Seidman, a professor of genetics at Harvard Medical School.

Seidman's wife, Dr. Christine Seidman, a professor of genetics and a cardiologist at Harvard, was the other study co-leader.

The researchers also estimate that about 20 percent of sporadic cases of the disease, that is, dilated cardiomyopathy that isn't passed down from parents, involve a TTN mutation.

In dilated cardiomyopathy, the chambers of the heart become enlarged, the walls thin and the ability of the heart to pump is impaired. When the heart can't squeeze properly, it can't circulate enough blood, leading to heart failure and landing many people on heart transplant lists.

Prior research has found genetic causes for dilated cardiomyopathy, but collectively those genes account for only about one-fifth of cases, Seidman said.

TTN is a very large gene, which made it difficult to analyze until recently, Seidman explained. The protein that TTN makes contains 30,000 amino acids, while the average protein contains about 1,000 amino acids. Only with the advent of next-generation gene sequencing -- which allows for more genetic data to be analyzed more quickly and for less money -- did it become possible to effectively analyze TTN, he said.

In people with a shortened TTN gene, the protein that's produced causes problems with the filaments inside the muscle fibers that allow the heart to contract.

The few people with healthy hearts who had a similar mutation and didn't have the disease had the shortening on a different location of the gene.

"Not only do they [the people with dilated cardiomyopathy] have the shortened mutation, it has to occur in just the right place," Seidman said.

The analysis also found that men with the TTN mutation are affected more severely than women. "We don't know why," Seidman said, noting that for other causes of heart failure, men also tend to get sicker younger and more severely than women.

To develop dilated cardiomyopathy, children have to inherit just one copy of the mutated TTN gene from a parent, the researchers noted.

Dr. Gordon Tomaselli, president of the American Heart Association and chief of cardiology at Johns Hopkins Medicine in Baltimore, said the study is important for both researchers and patients.

"Of the cases that are inherited [dilated cardiomyopathy], it looks like a substantial proportion are due to mutations in the TTN gene," Tomaselli said.

Currently, genetic tests are available that screen for the other known causes of cardiomyopathy. Soon, possibly within months, expect to see TTN testing added to genetic panels, Tomaselli said.

Although there is no cure for dilated cardiomyopathy, patients who know early on that they are susceptible can take steps to keep their hearts healthier longer, he noted. That may include taking certain heart failure medications, maintaining blood pressure control and other lifestyle changes.

An estimated one-third to one-half of dilated cardiomyopathy cases have a genetic cause, Tomaselli added. The others have an environmental trigger, such as drug or alcohol abuse or infections. For those patients, TTN would likely not play a role in the disease.

More information

The U.S. National Heart, Lung, and Blood Institute has more on cardiomyopathy.

Read the original:
Study Finds Gene Behind Inherited Cases of Enlarged Heart

WEDNESDAY, Feb. 15 (HealthDay News) -- Researchers report that they've discovered the importance of a particular gene in kicking off puberty in humans, a finding that offers insight into how the mysterious process begins and could help children who suffer from a rare disease that prevents the start of puberty.

An analysis of the DNA of a family whose members have suffered from the disease confirmed that the gene is vital because it paves the way for the body to process a hormone known as kisspeptin.

"Without kisspeptin, a human being cannot attain sexual characteristics of his/her gender and child-bearing capacity. Kisspeptin is absolutely required for the start of the puberty process in humans," said study author Dr. A. Kemal Topaloglu, of the department of pediatric endocrinology at Cukurova University in Adana, Turkey.

A mutation in the gene, the researchers found, can cause a rare condition called hypogonadotropic hypogonadism, in which children don't fully enter puberty.

Dr. William F. Crowley Jr., director of the Harvard Reproductive Endocrine Sciences Center at Harvard Medical School, said the condition affects no more than one in 10,000 children, and perhaps even fewer.

"They look like they're 12 years old, even when they're 20. They don't have a growth spurt and tend to be short, and the males don't shave," Crowley said.

In the new study, researchers examined the genetic makeup of a family in which four daughters had the disease. They linked the disease to a mutation in the gene that creates a receptor that processes the kisspeptin hormone.

The hormone can be used to make the brain produce hormones that stimulate the maturation of ovaries and testicles, Topaloglu said. Also, medications that shut down the hormone could be used to treat a condition that causes early puberty, he said, or serve as a contraceptive.

"Such drugs can also be used in the treatment of cancers that are stimulated by sex hormones, the most notably breast and prostate cancers," Topaloglu said.

The research could lead to alternative treatments for the puberty-preventing disease. Currently, hormone therapy is almost always a success when used to treat kids with the condition, but it's more difficult to enable them to have children of their own once they grow up, Topaloglu said.

As for the big question of what causes puberty, Crowley said the new findings help provide another clue. They show how the gene -- one of 19 -- helps turn on the pilot light that powers puberty, he said.

"This is a very rare cause of a very rare condition," he said. "But every piece of this puzzle winds up being very important to putting the whole thing together."

The study appears in the Feb. 16 issue of The New England Journal of Medicine.

More information

For more about puberty and adolescence, try the U.S. National Library of Medicine.

Here is the original post:
Gene Linked to Start of Puberty

For Immediate Release:
Feb. 13, 2012

Newswise — BOSTON—Novel gene abnormalities discovered in a subpopulation of lung and colorectal tumors could potentially identify patients with a good chance of responding to highly specific “targeted” drugs already in use for treating other cancers, scientists report.

The genetic alterations – pieces of two genes fused together - showed up in a massive search of the DNA in stored tumor samples of non-small cell lung cancer and colorectal cancer, said researchers from Dana-Farber Cancer Institute and Foundation Medicine, Inc. These specific genetic abnormalities had not been previously linked to the two cancer types.

Their results were published online by the journal Nature Medicine.
Other cancers with similar genetic alterations often respond to “targeted” drugs s that block overactive proteins called tyrosine kinase inhibitors. This suggests that the same drugs also may be effective against lung and colorectal tumors driven by the newly found gene fusions. Because these drugs are already approved to treat cancer, it should be possible to move rapidly to clinical trials in colorectal and lung cancer, the authors said.

If the trials are successful, physicians could potentially test patients' tumors for the presence of the gene fusions and prescribe a medication matched to those alterations, said Pasi A. Jänne, MD, PhD, a thoracic oncologist at Dana-Farber and co-senior author of the report along with Philip J. Stephens, PhD, and Maureen Cronin, PhD, of Foundation Medicine. Doron Lipson, PhD, is the paper’s first author.
“This is a textbook example of personalized medicine for lung cancer – a genetic alteration found in a subset of patients that we can now look for and use as a means to select particular therapies,” Jänne said.

“In the past, although these targeted drugs were available, they were not chosen for a particular subset, but instead given to everybody,” he explained. “This will increase the likelihood of those therapies being more successful.”

The researchers estimate that less than 1 percent of Caucasians and about 2 percent of Asians with lung cancers carry this alteration – a fusion gene labeled KIF5B-RET. However, they said the finding opens a significant therapeutic opportunity.

“In a common indication like non-small cell lung cancer, identifying even a small subpopulation of individuals with gene fusions who may be responsive to a targeted therapy has the potential for major therapeutic impact,” said Stephens, executive director of cancer genomics at Foundation Medicine. “This joint research with Dana-Farber translates genomic research to the clinic and we expect that it may quickly have a positive impact for patients.”

The American Cancer Society projects that 226,160 Americans will be diagnosed with lung cancer in 2012 and 160,340 will die of the disease.

Foundation Medicine scientists identified the novel fusion gene in a DNA tumor sample removed from a 44-year-old man with non-small cell lung cancer (NSCLC) who had never smoked. The hybrid gene is composed of a piece of a cell growth gene, RET, and part of another gene, KIF5B. This abnormal gene combination causes RET to act like a growth switch stuck in the “on” position, spurring uncontrolled cell division.

The company formed a collaboration with Jänne and his Dana-Farber colleagues to follow up the discovery. “We looked for the RET fusion gene in a larger collection of lung tumor samples to determine how common it is, and if it is acting as an oncogene [a gene that drives cancer]” said Jänne. They searched samples from 121 Caucasian patients and 405 Asian patients who had never smoked or had rarely smoked in the past.
The RET fusion gene was detected in 1 of the Caucasian samples (0.8 percent) and 9 of the Asian patient samples (2 percent).

Thyroid cancers containing RET gene hybrids are known to respond to certain targeted drugs that inhibit RET. When Dana-Farber investigators tested three such inhibitors – sorafenib, sunitinib and vandetinib – on cultured cells containing the newly discovered RET mutation, each of the drugs killed those cells, the scientists reported.
Jänne noted that some patients with NSCLC have responded to treatment with these inhibitor drugs. The researchers want to find out whether those patients had RET mutations in their tumors.

The Foundation Medicine scientists also sequenced DNA samples from 40 patients with colorectal cancer. Along with numerous known mutations, the researchers identified a novel gene alteration, C2orf44-ALK, that causes a 90-fold overexpression of the ALK protein leading to cancerous proliferation. Overexpressed ALK is also found in a small percentage of lung cancer cases and can be inhibited by the targeted drug crizotinib. This raises the possibility of using crizotinib to target the C2orf44-ALK fusion gene in colorectal cancer, the researchers said.

In addition to Cronin, Jänne, Lipson and Stephens, the paper’s co-authors were from Sharett Institute of Oncology, Jerusalem; TEVA Pharmaceutical Industries, Petach Tikva, Israel; Samsung Medical Center, Seoul, Korea; Nagoya City University Graduate School of Medical Sciences, Japan; Asan Medical Center, Seoul, Korea; and Albany Medical Center, New York.

The research was funded in part by the Dana-Farber/Harvard Cancer Center Lung Cancer SPORE grant from the National Cancer Institute and the Cammarata Family Foundation Research Fund.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

EDITOR’S NOTE: This video is available online at:
http://resources.dana-farber.org/pr/media/

# # #

Comment/Share

See more here:
Newly Identified Fusion Genes in Lung and Colorectal Cancer May Guide Treatment with "Targeted" Drugs

The researchers used gene therapy in rats to stimulate production of somatostatin, a seizure-stopping chemical that naturally occurs in the brain. The study was published in the February issue of the journal Neuroscience Letters.

More than 3 million people in the United States have epilepsy, according to the Centers for Disease Control and Prevention. This lifelong disease is characterized by uncontrollable seizures and can keep people from living independently or holding jobs, particularly if they do not respond to seizure-controlling medication. Finding novel ways to prevent these seizures could help people with epilepsy live more normal, symptom-free lives, said Dr. Paul Carney, chief of the division of neurology in the UF College of Medicine department of pediatrics and senior author of the study.

“For years people have focused only on treating the disease, not preventing the disease,” Carney said. “The mantra is no seizures, no side effects.”

People with epilepsy tend to have lower levels of the hormone somatostatin, as do people with Alzheimer’s disease. Although somatostatin, which belongs to a group of protein-like molecules called neuropeptides, is present in the brains of people with epilepsy, scientists have shown that its levels decrease during seizures, said Rabia Zafar, the lead author of the paper and a former postdoctoral associate in Carney’s lab.

To test whether they could prevent seizures by bolstering levels of this hormone, the researchers administered a dose of the gene that triggers somatostatin expression. A harmless virus transported the gene safely through the body.

“There is some somatostatin in the brain anyway, because it’s a neuropeptide, but there was a dramatic increase after the injection,” Zafar said.

Boosting somatostatin levels led to weaker and shorter seizures, and none of the subjects that received the injection suffered the highest level of seizure. Better yet, the treatment did not result in unwanted side effects. The only side effect was positive: subjects learned better after the treatment.

“Being able to restore somatostatin up to normal levels allows the brain to heal itself and that is the idea here,” Carney said. “We’re putting something back in that is normally there and allowing the brain to pick it up as part of its normal machinery. We’re not putting in a drug.”

In addition to epilepsy, studies have shown that somatostatin may play a role in aging and neurodegenerative disorders such as Alzheimer’s disease, Carney said. Somatostatin is a neuromodulator, which means it can alter how nerve cells behave.

In this study, the researchers focused on temporal lobe epilepsy, the most common form of the disease. Although medication helps control seizures in most people with this type of epilepsy, about 30 percent of patients do not respond to therapy, Carney said.

“We need better, more effective treatments for a large population of children and adults who don’t respond to conventional treatments,” he said. “Gene therapy, as well as other forms of treatment, are emerging, and there is the hope and promise they will offer more effective and novel treatments for people with drug-resistant epilepsy.”

But the researchers caution that this study is just a first step. Additional research is needed before the technique can be attempted in humans. Researchers are particularly focused on ensuring the treatment does not cause inflammation and discovering the best way to administer it, either be injection to the brain or a less invasive intravenous infusion.

“What effect a compound is going to have partly depends on where in the seizure circuit that new compound or gene is being placed. You could put the same chemical in two places and get two different results,” said Dr. Edward Bertram III, a professor of neurology at the University of Virginia, who was not involved in the study. “That is going to be the issue as they try to develop this: Where should we be putting this to have the best effect? On the promising side, they put (the gene) in a restricted area and had an effect. That is a great first step.”

Provided by University of Florida (news : web)

Originally posted here:
Gene therapy for epilepsy could stop seizures

News | Mind & Brain

Two doses of gene therapy restore vision to three women who were born nearly blind

By Ferris Jabr  | February 8, 2012 |

SIGHT FOR SORE EYES: A second round of gene therapy for blindness worked just as well as the first. Image: Garretttaggs55, Wikimedia Commons

Gene therapy has markedly improved vision in both eyes in three women who were born virtually blind. The patients can now avoid obstacles even in dim light, read large print and recognize people's faces. The operation, researchers predict, should work even better in children and adolescents blinded by the same condition.

The advance, reported in the February 8 issue of Science Translational Medicine, extends earlier work by the same group. Between 2008 and 2011, Jean Bennett of the University of Pennsylvania's Mahoney Institute of Neurological Sciences and her colleagues used gene therapy to treat blindness in 12 adults and children with Leber's congenital amaurosis (LCA), a rare inherited eye disease that destroys vision by killing photoreceptors—light-sensitive cells in the retina at the back of the eye. Typically, afflicted children start life with poor vision, which worsens as more and more photoreceptors die.

The treatment grew out of the understanding that people with the disorder become blind because of genetic mutations in retinal cells. One mutated gene that causes the disorder is named RPE65. An enzyme encoded by RPE65 helps break down a derivative of vitamin A called retinol into a substance that photoreceptors need to detect light and send signals to the brain. Mutant forms of RPE65 prevent the production of this enzyme in a "nursery" layer of cells called the retinal pigment epithelium, which is attached to the retina and nourishes photoreceptors by breaking down retinol, among other cellular services.

In the initial study, retina specialist and Bennett's co-author Albert Maguire of Penn Medicine injected a harmless virus carrying normal copies of RPE65 into an area of the retinal pigment epithelium, which subsequently began producing the enzyme. In each of the 12 patients, Maguire treated one eye—the one with worse vision. Six patients improved so much they no longer met the criteria for legal blindness.

In the new study, Maguire injected the functional genes into the previously untreated eye in three of the women from the first group. Bennett followed the patients for six months after their surgeries. The women's vision in their previously untreated eye improved as soon as two weeks after the operation: They could navigate an obstacle course, even in dim light, avoiding objects that had tripped them up before, as well as recognize people's faces and read large signs. Bennett showed that not only were the women's eyes much more sensitive to light, their brains were much more responsive to optical input as well. Functional magnetic imaging showed regions of their visual cortices that had remained offline before gene therapy began to light up.

Surprisingly, Bennett reports, the second round of gene therapy further strengthened the brain's response to the initially treated eye as well as the newly treated one. "That wasn't something we had been expecting, but it makes sense because the two eyes act in concert, and some aspects of vision rely on binocularity." In the new paper, the authors suggest that neuroplasticity plays a role: It is possible that regions of the visual cortex responding to the newly flowing channel of information from the second eye bolster activity in areas of the visual cortex responding to the initially treated eye.

An institutional review board required that Bennett work with adults in the follow-up study, but she thinks the therapy will work even better in younger patients who have not lost as many photoreceptors. She says the results "really bode well" for restoring meaningful vision to people with LCA and other forms of inherited blindness.

View original post here:
Sight Seen: Gene Therapy Restores Vision in Both Eyes

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Researchers from Foundation Medicine and the Dana Farber Cancer Institute have demonstrated that Foundation's sequencing-based assay, which it is developing for cancer diagnostics, can identify clinically actionable mutations from tumor samples.

Reporting in Nature Medicine this week, the team tested the assay on 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded biopsy samples and identified at least one potentially clinically actionable alteration in 59 percent of the samples.

Additionally, the test identified two novel gene fusions.

"These findings in aggregate show the potentially large clinical impact of a single multiplex test that requires minimal DNA from FFPE tumor biopsies," the authors wrote in the paper.

The company recently received CLIA certification from the Centers for Medicare and Medicaid Services for its genomic sequencing lab in Cambridge, Mass., and plans to commercialize its test this year.

The test analyzed 2,574 exons from 145 genes that are associated with cancer-related pathways, targeted therapy, or prognosis, plus 37 introns from 14 genes that are frequently rearranged in cancer. Sequencing was done on the Illumina platform to an average 229-fold coverage.

In the 40 colorectal cancer samples, 125 alterations were identified in 21 genes, with 39 out of 40 samples having at least one mutation. Eighty percent of the samples had mutations to TP53, a known tumor suppressor that is mutated in a broad range of cancers, and 67.5 percent of the samples had mutations to APC, a tumor suppressor gene that regulates the growth of polyps.

Twenty one samples had at least one mutation that has been linked to a clinical treatment or is currently being studied in a clinical trial of targeted therapy.

For example, mutations were found in KRAS and BRAF that predict resistance to Eli Lilly's and Bristol-Myers Squibb's Erbitux (cetuximab) or Amgen's Vectibix (panitumumab), and in FBXW7 that predict anti-tubulin resistance.

Additionally, mutations were found in BRCA2 for which there are clinical trials for PARP inhibitors, in GNAS for which there are MEK- and ERK-inhibitor trials, and in PIK3CA for which there are mTOR-inhibitor trials.

The team also detected a novel gene fusion involving ALK, suggesting that ALK inhibitors such as Pfizer's Xalkori (crizotinib) may be effective.

Among the 24 non-small cell lung cancer samples, 72 percent had at least one alteration associated with a current clinical treatment or targeted therapy trial. There were mutations to KRAS, some of which point to EGFR kinase-inhibitor resistance and others that suggest eligibility for PI3K- and MEK-inhibitor trials. Mutations in BRAS suggest eligibility for BRAF-inhibitor trials, and mutations in EGFR suggest that EGFR-inhibitors such as AstraZeneca's Iressa (gefitinib) or Genentech's Tarceva (erlotinib) may be effective.

Two novel mutations were also found. A mutation at low frequency was found in JAK2, which is commonly found in myelodysplastic syndromes, but has not previously been described in solid tumors and suggests that patients with this mutation may be sensitive to JAK2 inhibitors.

Additionally, a novel gene fusion involving RET was identified in a 44-year old 'never smoker.' The team next looked for the fusion in lung cancer samples from 121 Caucasian and 405 Asian patient samples, finding it in 0.8 percent and 2 percent of the samples, respectively. Notably, the samples with the fusion did not have any known driver mutations, suggesting that the fusion may be driving the cancer.

A different RET gene fusion is frequently found in thyroid cancers, and is sensitive to RET inhibitors. A subsequent in vitro analysis found that cells with the novel fusion were also sensitive to a number of RET kinase inhibitors, suggesting that those drugs "should be tested in prospective clinical trials for therapeutic benefit in individuals with NSCLC" with the novel fusion, the authors wrote.

See the rest here:
Foundation Medicine Cancer Dx IDs Clinically Actionable Mutations, Novel Gene Fusions

CAMBRIDGE, Mass.--(BUSINESS WIRE)--

Foundation Medicine, Inc., a molecular information company that brings comprehensive cancer gene analysis to routine clinical care, and Dana-Farber Cancer Institute today announced the Nature Medicine publication of results from their collaborative next-generation sequencing (NGS) study to assay cancer-relevant genes in 24 non-small cell lung cancer (NSCLC) and 40 colorectal cancer (CRC) cases. In this study, 59% of the samples were found to have genomic alterations directly associated with a clinically-available targeted therapeutic or a relevant clinical trial of a targeted therapy. Two novel gene fusions, KIF5B-RET in NSCLC and C2orf44-ALK in CRC, were discovered among the potentially druggable alterations identified in the study. Both of these findings may expand therapeutic options for a subset of cancer patients. This publication demonstrates that using targeted NGS to profile patient tumors for molecular alterations associated with therapeutic responses may have an important clinical impact in cancer treatment.

“In this collaboration, we detected clinically-relevant genomic alterations in more than half of the samples profiled, and, because Foundation Medicine’s NGS assay detects all classes of alterations with clinical-grade sensitivity, this research was able to identify both expected as well as completely novel alterations,” said Maureen Cronin, Ph.D., senior vice president, research & product development of Foundation Medicine and co-author of the study. “The discovery of novel rearrangements and fusions, such as KIF5B-RET and C2orf44-ALK, supports an important role for NGS in the clinical understanding and treatment of cancer.”

“In a common indication like NSCLC, identifying even a small subpopulation of individuals with gene fusions who may be responsive to a targeted therapy has the potential for major therapeutic impact,” said Phil Stephens, Ph.D., executive director, cancer genomics of Foundation Medicine and co-author of the study. “This joint research with Dana-Farber translates genomic research to the clinic and we expect that it may quickly have a positive impact for patients.”

Clinically-relevant alterations, which are defined here as being associated with an available clinical treatment option or ongoing clinical trial investigating a new targeted therapy, were identified in 72% of NSCLC tumor samples and 52.5% of CRC tumor samples.

The novel, recurrent KIF5B-RET fusion was identified by the NGS assay in one patient with NSCLC. In subsequent screening, 11 additional RET fusions were identified in 561 lung adenocarcinoma samples from a cohort of never or limited former smokers with NSCLC. In common with known oncogenic alterations in EGFR and EML4-ALK, the KIF5B-RET gene fusion was found more than twice as often in NSCLC samples from individuals of Asian descent (0.8% (1/212) of the Caucasian samples and 2% (9/405) of the Asian patient samples). Additionally, none of the fusion-positive tumors contained alterations in any of the other known oncogenes that drive lung cancer (EGFR, ERBB2, BRAF or KRAS or rearrangements of EML4-ALK or ROS1).Tumors with this fusion were specifically sensitive to targeted drugs that inhibit RET, suggesting that prospective clinical trials of RET-targeted therapeutics may benefit individuals with NSCLC with KIF5B-RET rearrangements.

The second novel finding in the study was a potentially clinically-relevant gene fusion between C2orf44 and ALK identified in one CRC patient. Additional assays suggest this fusion gene yields 90-fold overexpression of anaplastic lymphoma kinase (ALK), the target of crizotinib, a U.S. FDA approved therapy for NSCLC. Given the structure of the rearrangement that generated the C2orf44-ALK fusion, it is unlikely that current clinical detection methods would have detected this alteration. This research thus suggests that a previously unrecognized subset of individuals with CRC may harbor genetic alterations that may make them responsive to ALK-inhibitor treatment.

The assay used for the testing described in this Nature Medicine paper is analytically validated to have a false discovery rate of less than 1% with at least 99% sensitivity for base substitutions occurring with at least 10% frequency.

The paper, “Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies” by Lipson, D. et al. is now available online.

About Foundation Medicine’s Comprehensive Cancer Genomic Test

Foundation Medicine’s comprehensive cancer genomic test uses next-generation sequencing to analyze routine clinical specimens (i.e., small amounts of formalin fixed, paraffin embedded tumor tissue) for all classes of genomic alterations (point mutations, copy number alterations, insertions/deletions, and select rearrangements) in approximately 200 cancer-related genes. The test is optimized for clinical-grade analysis of tumor tissues, overcoming multiple complexities (such as purity, ploidy and clonality) inherent to tumor genomes. Results are designed to serve as a helpful decision-support tool for physicians to evaluate cancer treatment approaches tailored to each patient’s molecular subtype. Each patient report is reviewed and annotated by a molecular oncologist and consists of scientific and medical literature relevant to that patient’s genomic alterations and includes information on targeted therapies and clinical trials supported by scientific and medical research.

About Foundation Medicine

Foundation Medicine is dedicated to improving cancer care through the development of comprehensive cancer diagnostics that will help physicians inform treatment decisions based on an individual patient’s molecular cancer subtype. Foundation Medicine’s first laboratory developed test, based on a next-generation sequencing platform, is designed to accommodate a broad landscape of cancer genome information and a growing repertoire of targeted treatments and clinical research opportunities. Foundation Medicine’s test will assist physicians to make prompt and informed determinations about the best cancer treatments and clinical trial options for each patient, taking into account each patient’s unique cancer-associated alterations alongside publicly available scientific and medical information. The company’s founding advisors are world leaders in genome technology, cancer biology and medical oncology; they, alongside clinicians, biotech and molecular diagnostics industry leaders, are working to harness emerging technologies to develop unparalleled tests that will identify and interpret an ever-growing set of actionable genomic alterations, truly enabling personalized cancer medicine. For more information, please visit the company’s website at http://www.foundationmedicine.com.

Go here to see the original:
Foundation Medicine and Dana-Farber Cancer Institute Identify Novel Genomic Alterations in Lung and Colorectal Cancer

WEDNESDAY, Feb. 8 (HealthDay News) -- As a child, Tami Morehouse had vision problems. She struggled to read the blackboard at school, and homework took hours.

Yet, she made it through high school and college, and became a social worker. Although she was never able to drive, she learned to ride a bike.

But in her 30s, with three young children, her vision took a turn for the worse. "I'd be reading a book and the words faded away," she said.

Morehouse was going blind, the result of Leber congenital amaurosis (LCA), a rare inherited eye disease that causes a progressive loss of vision. "As my kids needed me more and more, I was able to do less and less," Morehouse said.

That changed in 2009, when she was one of 12 people to undergo an experimental treatment using gene therapy in one eye. Now, scientists report even more progress, having successfully treated the second eye of three patients, including Morehouse. The new results are published Feb. 8 in Science Translational Medicine.

LCA is caused by a faulty gene, RPE65, that fails to produce an enzyme needed by the retina, the tissue in the back of the eye that converts light images into nerve signals that get sent to the brain.

Lack of the enzyme causes toxic byproducts to build up in the retinal cells, gradually killing them.

"It's inevitable and progressive, and people watch as they are losing more and more of their vision," said Dr. Jean Bennett, an ophthalmology professor at University of Pennsylvania Perelman School of Medicine and co-leader of the research team that pioneered the treatment. "By the time they're teenagers or young adults, they are severely impaired."

The treatment involved injecting a virus genetically engineered to carry a normal version of gene RPE65 into the retinal cells.

About two weeks later, with the eyes now producing the enzyme, the patients -- adults and children -- saw a marked improvement in their vision.

"They all gained vision in a very meaningful way," said Bennett, also a scientist at Children's Hospital of Philadelphia. "Children can read books, ride their bikes to their friends' houses -- things which they never could do before."

Initially, researchers only injected one eye because of safety concerns, Bennett explained. The fear was that the first injection would prime the immune system to recognize the virus and attack it when it was injected into the second eye. That would cause inflammation in the eye, potentially leading to more vision loss.

But animal studies showed that didn't happen, and so they decided it was safe to try the second eye in adults.

"It's amazing," Morehouse said. "I just feel so different. I used to wake up in the morning, so afraid and so anxious, that I would look over at the alarm clock and see nothing."

Prior to the treatments, she could see light and dark, but most of the world was hazy and gray. By night time, when her eyes were tired, she could see very little.

Today, her vision is still significantly impaired. She needs help finding her way to a table in a restaurant, for example, and reading isn't really possible. Yet, she can tell when someone is approaching, and she can make out a smile.

"Seeing my daughter walk across the basketball court. Seeing my son step up to the plate when he's playing ball -- it's phenomenal," Morehouse said.

Researchers verified that patients could see more by performing functional MRI scans before and after the second eye treatment. The brain imaging showed much more response to visual stimuli after their second eye was done.

At 47, Morehouse was the oldest patient. The prior study taught researchers that children improved the most, probably because their retinal cells had suffered less damage.

Now that researchers have established the procedure is safe in adults, they've started using gene therapy on the second eyes of children with the condition, Bennett said.

Though more research needs to be done and there are "technical" issues to be overcome, "we want to be able to use this approach in developing similar treatments for other more common blinding diseases," she said.

Dr. Richard Lewis, a clinical correspondent for the American Academy of Ophthalmology, called the results "exciting." Not only did the results show that treating the second eye is safe and effective, but that vision in the first eye also appears to improve as well.

"This is setting us up for the next step, which is to take the 5-year-old, the 8-year-old, or even the 6-month-old who has the mutation in this particular gene, and replace the enzyme using gene replacement therapy before permanent damage is done," said Lewis, who is a professor of ophthalmology at Baylor College of Medicine's Cullen Eye Institute in Houston.

More information

The Foundation Fighting Blindness has more on LCA.

Read the original here:
More Success With Gene Therapy for Blindness