Category Archives: Gene Medicine

Genome sequencing holds great potential for diagnosing diseases, finding treatments and ultimately cutting medical costs, experts say, but insurance companies are leery of covering the still-new procedure, preventing it so far from becoming a routine part of medical care.

Boston-based Partners HealthCare is one of just two systems in the country to offer full genome sequencing for clinical patients. The out-of-pocket cost of unlocking your full genetic code, though, is steep: $9,000.

Cost is a barrier, said Heidi Rehm, chief laboratory director at the Partners Center for Personalized Genetic Medicine in Cambridge.

The lab started offering full genome sequencing last August using blood samples to extract information from DNA but it has done the complex analysis for fewer than half a dozen patients since then. Insurance companies didnt cover the costs for any of those patients, Rehm said.

For patients suffering from a range of diseases, from cancer to hearing loss, sequencing can help identify the gene causing the problem and help doctors determine which treatments will be most effective. Genetic sequencing can also tell patients if theyre at risk of developing certain conditions later in life.

The challenge for scientists like Rehm is to prove that this kind of analysis is useful not just for sick patients but for healthy ones.

Can I say every patient should get their genome sequenced? We just dont have the collective evidence and the studies to prove that today, Rehm said. So the insurers are not going to cover everything today.

Insurance companies do pay for some genetic tests those that test specifically for a patients risk of developing breast cancer, for example but theyre still evaluating the benefit of full genome sequencing, which involves much more data and analysis.

We dont have a lot of information yet to make sweeping decisions, said Dr. Neil Minkoff, medical director for the Massachusetts Association of Health Plans. We tend to look at the individual patient or individual physicians request. Its still early in our experience with it.

The states three largest insurers, Blue Cross Blue Shield, Harvard Pilgrim Health Care and Tufts Health Plan, did not respond to requests for comment.

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Gene screen eyes mainstream

PUBLIC RELEASE DATE:

6-Feb-2014

Contact: Charli Scouller c.scouller@qmul.ac.uk 07-709-825-741 Queen Mary, University of London

The study, published in The American Journal of Human Genetics, detected and identified a new disease gene (ERCC6L2). In its normal form, the gene plays a key role in protecting DNA from damaging agents, but when the gene is mutated the cell is not able to protect itself in the normal way.

The research findings suggest that the gene defect and the subsequent DNA damage was the underlying cause of bone marrow failure among the study participants.

Bone marrow failure is a term used for a group of life threatening disorders associated with an inability of the bone marrow to make an adequate number of mature blood cells.

Patients were recruited from all over the world to join an international bone marrow failure registry and researchers used new DNA sequencing technologies to study cases of bone marrow failure with similar clinical features. These included bone marrow failure associated with neurological abnormalities (learning defects and developmental delay), and patients whose parents were first cousins.

The findings mean it is now possible to carry out a reliable genetic test (including antenatal testing) in these families and get an accurate diagnosis. In the long term, with further research, the findings could lead to the development of new treatment for this specific gene defect.

Professor Inderjeet Dokal, Chair of Paediatrics and Child Health at Queen Mary University of London, comments:

"New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure. This is a promising finding which we hope one day could lead to finding an effective treatment for this type of gene defect. Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.

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New disease gene discovery sheds light on cause of bone marrow failure

Days before she ended her pregnancy, Joselin Linder was thrilled to imagine herself as a parent. She was 37, newly-married, and though her baby-to-be wasnt planned, it was soon deeply desired. Maybe its that I played with dolls until I was so old I had to play with them in my closet, she says. But it seemed inevitable that I would one day be a mother.

Linder is not a mother today, more than a year later, because she had an abortion at 10 weeks. She still wanted the childwanted to call it George, perhapsbut she feared she would pass along the disease that killed her father in mid-life, practically fusing his organs and ballooning his body. She and her sister Hilary inherited the same unnamed illness, but as with most of the thousands of inheritable diseases known to science, there is no cureexcept for stopping the affected bloodline.

Its an agonizing form of prevention the Linder sisters have turned to four times combined. Theyve had three abortions, and in 2009, Hilary and her husband paid $20,000 out of pocket for a round of in vitro fertilization aimed at creating an unaffected embryo. The gene has killed five people in the Linder family, and it now threatens the sisters themselves. But if they have their way, it will die out in their generation.

I think thats a big deal, says Joselin, who lives in Brooklyn, N.Y. I think weve done something amazing with this particular gene.

The Linders story is personal, of course, but its also a public milestone. Its the first known example of genetic medicine not only identifying a deadly new mutationakin to the next Huntingtons or Cystic Fibrosisbut of a family banding together to stop a disease before it cuts a path through society itself. It illustrates the promise of genomic medicine, which may one day stop disease as we know it, but also the soul-troubling questions that arise when people have a hand in their own evolution.

America is experiencing a boom in biological fortune-telling. Doctors can now scan the genes of a fetus using only a drop of the mothers blood, testing for hundreds of known mutations, including Down syndrome. Soon theyll be able to detect a growing list of rare mutationsalmost none of them treatableand predict an embryos risk of more common ailments like diabetes, cancer, and heart disease. By that point, millions of pregnant women will be offered a God-like view of their child-to-be and a decision much like the Linders, a decision as miraculous as it is unnerving: When is a life worth living?

The family gene, as Joselin calls it, surfaced in the late 1980s, when her father William came home from a family trip complaining of swollen legs and strange fatigue. He waved it off as jet lag, but the swelling spread and the fatigue deepened. He was 40, vibrant and fit, a busy doctor in Columbus, Ohio. But within a couple years he was forced into semi-retirement, hardly able to take the stairs.

Im very, very sick, he told Joselin, who was then 17, and surprised to see her father start to cry. In the years that followed, his body filled with a creamy white fluid, which doctors pumped out by the liter. He got rounder, but lighter, his muscles withering even as something in his belly grew.

He moved into Brigham and Womens Hospital, a Harvard-affiliated facility in Boston, where he confounded some of the countrys best doctors. In his records, which Joselin shared with NBC News, a series of gobsmacked specialists noted puzzling resultsan occult malignancysomething brewing. None could come up with a diagnosis, however, let alone a cure.

William Linder died a medical mystery in September of 1996, his autopsy revealing a body both starved and bloated. The cause of death was officially unknown. His daughters visited him often, right to the end, shuffling ICU visits into their college schedules. They never suspected that they were getting a preview of their own genetic destiny.

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To Catch a Killer Gene: Sisters Race to Stop Mystery Disease

PUBLIC RELEASE DATE:

4-Feb-2014

Contact: Lisa Newbern lisa.newbern@emory.edu 404-727-7709 Emory Health Sciences

Following another's gaze or looking in the direction someone is pointing, two examples of receptive joint attention, is significantly heritable according to new study results from researchers at the Yerkes National Primate Research Center, Emory University. Determining such communicative cues are significantly heritable means variation in this ability has a genetic basis, which led the researchers to the vasopressin receptor gene, known for its role in social bonding.

The study results, which are published in Scientific Reports, give researchers insight into the biology of disorders in which receptive joint attention is compromised, such as autism spectrum disorders (ASD), and may ultimately lead to new diagnosis and treatment strategies.

According to Yerkes researchers Larry Young, PhD, and Bill Hopkins, PhD, co-authors of the study, receptive joint attention is important for developing complex cognitive processes, including language and theory of mind, and poor joint attention abilities may be a core feature in children with or at risk of developing ASD.

Young is division chief of Behavioral Neuroscience and Psychiatric Disorders at Yerkes, director of the Center for Translational Social Neuroscience (CTSN) at Emory and William P. Timmie Professor in the Emory University School of Medicine Department of Psychiatry and Behavioral Sciences. Yerkes researcher Hopkins is also a core faculty member in the Neuroscience Institute of Georgia State University and newly named science director of the Iowa Primate Learning Sanctuary.

Young and Hopkins led a collaborative team of researchers from Yerkes, the CTSN, the Neuroscience Institute at Georgia State University and the University of Texas M.D. Anderson Cancer Center. They studied chimpanzees to determine the extent to which the animals follow gaze or pointing by a human.

"We used chimpanzees in this behavioral study because their receptive joint attention abilities are well documented and their closeness to humans makes the study results the most likely to be generalizable to humans," says Hopkins.

Young's previous research in which he showed the vasopressin receptor gene was necessary for remembering individuals (or social memories) and for social bonding in male rodents was key to designing the current study. According to Young, variation in the length of a stretch of repetitive DNA, known as junk DNA, in the control region of the vasopressin receptor gene predicted if a male prairie vole was likely to form monogamous bonds with a mate. Human-based studies suggest that a similar repetitive element, referred to as RS3, in the control region of the human vasopressin receptor gene predicts romantic relationship quality and generosity.

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Gene that influences receptive joint attention in chimpanzees gives insight into autism

Researchers used blood platelets and bone marrow cells to deliver potentially curative gene therapy to mouse models of the human genetic disorder Hurler syndrome -- an often fatal condition that causes organ damage and other medical complications.

Scientists from Cincinnati Children's Hospital Medical Center and the National Institute of Neurological Disorders and Stroke (NINDS) report their unique strategy for treating the disease the week of Feb. 3-7 in Proceedings of the National Academy of Sciences (PNAS).

Researchers were able to genetically insert into the cells a gene that produces a critical lysosomal enzyme (called IDUA) and then inject the engineered cells into mice to treat the disorder. Follow up tests showed the treatment resulted in a complete metabolic correction of the disease, according to the authors.

"Our findings demonstrate a unique and somewhat surprising delivery pathway for lysosomal enzymes," said Dao Pan, PhD, corresponding author and researcher in the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's. "We show proof of concept that platelets and megakaryocytes are capable of generating and storing fully functional lysosomal enzymes, which can lead to their targeted and efficient delivery to vital tissues where they are needed."

The mice tested in the study modeled human Hurler syndrome, a subset of disease known as mucopolysaccharidosis type I (MPS I), one of the most common types of lysosomal storage diseases. MPS I is a lysosomal storage disease in which people do not make an enzyme called lysosomal alpha-L-iduronidase (IDUA).

IDUA helps break down sugar molecules found throughout the body, often in mucus and fluids around joints, according to the National Library of Medicine/National Institutes of Health. Without IDUA, sugar molecules build up and cause organ damage. Depending on severity, the syndrome can also cause deafness, abnormal bone growth, heart valve problems, joint disease, intellectual disabilities and death.

Enzyme replacement therapy can be used to treat the disease, but it is only temporary and not curative. Bone marrow transplant using hematopoietic stem cells also has been tested on some patients with mixed results. The transplant procedure can carry severe risks and does not always work.

Pan and her colleagues -- including Roscoe O. Brady, MD, a researcher at NINDS -- report that using platelets and megakaryocytes for gene therapy is effective and could reduce the risk of activating cancer-causing oncogenes in hematopoietic stem cells.

The authors said tests showed that human megakaryocytic cells were capable of overexpressing IDUA, revealing their capacity for potential therapeutic benefit. While engineering megakaryocytes and platelets for infusion into their mouse models of Hurler, the scientists report they were able to release IDUA directly into amply sized extracellular spaces or inside micro-particles as the cells matured or activated. The cells were able to produce and package large amounts of functional IDUA and retained the capacity to cross-correct patient cells.

After infusing mouse models of Hurler with the genetically modified cells, researchers said this led to long-term normalization of IDUA levels in the animal's blood with versatile delivery routes and on-target preferential distribution to the liver and spleen. The treatment led to a complete metabolic correction of MPS I in most peripheral organs of the mice.

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Gene therapy may be possible cure for Hurler syndrome: Mouse Study

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Newswise PHILADELPHIA All creatures great and small, including fruitflies, need sleep. Researchers have surmised that sleep in any species -- is necessary for repairing proteins, consolidating memories, and removing wastes from cells. But, really, sleep is still a great mystery.

The timing of when we sleep versus are awake is controlled by cells in tune with circadian rhythms of light and dark. Most of the molecular components of that internal clock have been worked out. On the other hand, how much we sleep is regulated by another process called sleep homeostasis, however little is known about its molecular basis.

In a study published in eLIFE, Amita Sehgal, PhD, professor of Neuroscience at the Perelman School of Medicine, University of Pennsylvania, and colleagues, report a new protein involved in the homeostatic regulation of sleep in the fruitfly, Drosophila. Sehgal is also an investigator with the Howard Hughes Medical Institute (HHMI).

The researchers conducted a screen of mutant flies to identify short-sleeping individuals and found one, which they dubbed redeye. These mutants show a severe reduction in the amount of time they slumber, sleeping only half as long as normal flies. While the redeye mutants were able to fall asleep, they would wake again in only a few minutes.

The team found that the redeye gene encodes a subunit of the nicotinic acetylcholine receptor. This type of acetylcholine receptor consists of multiple protein subunits, which form an ion channel in the cell membrane, and, as the name implies, also binds to nicotine. Although acetylcholine signaling -- and cigarette smoking -- typically promote wakefulness, the particular subunit studied in the eLIFE paper is required for sleep in Drosophila.

Levels of the redeye protein in the fly oscillate with the cycles of light and dark and peak at times of daily sleep. Normally, the redeye protein is expressed at times of increasing sleep need in the fly, right around the afternoon siesta and at the time of night-time sleep. From this, the team concluded that the redeye protein promotes sleep and is a marker for sleepiness suggesting that redeye signals an acute need for sleep, and then helps to maintain sleep once it is underway.

In addition, cycling of the redeye protein is independent of the circadian clock in normal day:night cycles, but depends on the sleep homeostat. The team concluded this because redeye protein levels are upregulated in short-sleeping mutants as well as in wild-type animals following sleep deprivation. And, mutant flies had normal circadian rhythms, suggesting that their sleep problems were the result of disrupted sleep/wake homeostasis.

Ultimately the team wants to use the redeye gene to locate sleep homeostat neurons in the brain. We propose that the homeostatic drive to sleep increases levels of the redeye protein, which responds to this drive by promoting sleep, says Sehgal. Identification of molecules that reflect sleep drive could lead to the development of biomarkers for sleep, and may get us closer to revealing the mystery of the sleep homeostat.

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New Fruitfly Sleep Gene Promotes the Need to Sleep

PUBLIC RELEASE DATE:

3-Feb-2014

Contact: Anita Srikameswaran SrikamAV@upmc.edu 412-578-9193 University of Pittsburgh Schools of the Health Sciences

PITTSBURGH, Feb. 3, 2014 Opening up a can of worms is a good way to start hunting for new drugs, recommend researchers from Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine. In a study published today in the Public Library of Science One, they used a primitive worm model to show that a drug typically used to treat agitation in schizophrenia and dementia has potential as a treatment for -1 antitrypsin (AT) deficiency, an inherited disease that causes severe liver scarring.

In the classic form of AT deficiency, which affects 1 in 3,000 live births, a gene mutation leads to production of an abnormal protein, dubbed ATZ, that unlike its normal counterpart is prone to clumping, explained David H. Perlmutter, M.D., physician-in-chief and scientific director, Children's Hospital, and Distinguished Professor and Vira I. Heinz Endowed Chair, Department of Pediatrics, Pitt School of Medicine.

"These protein aggregates accumulate in liver cells and eventually lead to scarring of the organ or to tumor formation," Dr. Perlmutter said. "If we could find a drug that slows or stops this process, we might be able to prevent the need for liver transplantation in these patients."

To find that drug, Dr. Perlmutter's team worked with Pitt's Stephen Pak, Ph.D., assistant professor of pediatrics, and Gary Silverman, M.D., Ph.D., Twenty-five Club Professor of Pediatrics, Cell Biology and Physiology, who developed a model of AT deficiency in Caenorhabditis elegans, or C. elegans, a harmless microscopic worm or nematode typically found in soil. Previous experiments conducted by Drs. Pak and Silverman, in which more than 2,000 compounds were screened, showed that fluphenazine, a drug approved for human use as a mood stabilizer, could reduce ATZ accumulation in the worm, so the team studied it further.

Worms that produce ATZ die sooner than normal ones, which typically have a life span of fewer than 20 days. Those that were exposed to fluphenazine, however, had lower burdens of ATZ and lived more than a day longer that untreated animals. The lifespan of normal worms was unchanged by fluphenazine exposure. The researchers also labeled with fluorescent markers intracellular structures called autophagosomes, which help clear abnormal proteins out of the cell in a process called autophagy. Fluphenazine exposure was associated with a greater presence of autophagosomes, suggesting that increased autophagy led to reduced ATZ accumulation.

Follow-up experiments showed that fluphenazine reduced ATZ accumulation in several mammalian-cell line models of AT deficiency, D. Silverman said.

"We found when we gave this drug for three weeks to mice with the disease, autophagy is activated, the abnormal protein load is diminished, and liver scarring is reversed. It's truly amazing," he said. "And because fluphenazine is already being safely prescribed for other conditions, it should be easier to bring it to clinical trials for AT deficiency."

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Mood-stabilizing drug could treat inherited liver disease, says Pitt/Children's team

Scientists in China have created two monkeys with customized gene mutations. The successful births of the twin macaques, named Ningning and Mingming, may bring researchers closer to being able to recreate such human diseases as Alzheimers and Parkinsons in primates. This would allow scientists to use primates, rather than rodents, as more realistic models of human illness.

To engineer the monkeys, researchers at Nanjing University and Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China, used a new gene-editing technology called Crispr, which allows scientists to insert, delete, or rewrite a specific gene sequence. The technique, which may help usher in a new era of genetic medicine, has previously been used to manipulate the genomes of rats, mice, and zebrafish. But this is reportedly the first time it has been used successfully in primates.

The Chinese researchers altered genes in several fertilized monkey eggs before implanting them in surrogate mothers. (Several surrogates miscarried and some pregnancies are reportedly ongoing.) Newborn Ningning and Mingming have three modified genes: one that regulates metabolism, another that regulates immune cell development, and a third that regulates stem cells and sex determination, according to the MIT Technology Review.

The infant monkeys are too young for researchers to determine the physiological and behavioral effects of their mutations, but scientists worldwide are already looking to create their own Crispr-modified monkeys. Although mice are giving us tremendous insight into basic brain biology and the biology of the disease, theres still a big gap in between the mouse brain and the monkey brain, Robert Desimone, director of MITs McGovern Brain Institute for Brain Research, told the MIT Technology Review. Not to mention that several drugs that work in mice dont work in humans.

Researchers also hope that the possibility of using genetically-modified monkeys will encourage more companies to boost spending on drugs to treat neurological disorders, reversing a recent trend of large pharmaceutical companies pulling back from such risky research. They also say Crispr may eventually be used for human gene therapy to treat inherited diseases such as cystic fibrosis and sickle-cell anemia. The ability to alter DNA is also being investigated as a way to make people resistant to HIV.

Chinas mutant-monkey breakthrough is controversial among animal rights activists. According to PETA, more than 125,000 primates are kept in U.S. laboratories and used for experiments every year.

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China Creates Monkeys With Custom Gene Mutations

PUBLIC RELEASE DATE:

3-Feb-2014

Contact: Vicki Bendure vicki@bendurepr.com 202-374-9259 Society for Maternal-Fetal Medicine

In a study to be presented on Feb. 6 at 2:45 p.m. CST, at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting, in New Orleans, researchers will report that a variant in SERPINE1, a gene involved in inflammation and blood clotting, is associated with cerebral palsy and death in very preterm babies. This gene has been associated with increased risk of cerebral palsy in one previous study of preterm babies.

Previous genetic studies of very preterm babies have suggested several genetic variations that might predispose to brain injury and developmental problems. However, different studies have had different results.

This study, titled Genetic Predisposition to Adverse Neurodevelopmental Outcome After Early Preterm Birth: A Validation Analysis, was a collaborative effort between the Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units and Neonatal Research Networks.

Researchers evaluated two different populations of very early preterm births (earlier than 32 weeks) with the goal of confirming the same genetic risk factors in both groups. The first population of preterm births was enrolled in a large Neonatal Research Network study, and the other group was of births that were enrolled in a Maternal Fetal Medicine Units Network study of magnesium sulfate before preterm birth for prevention of cerebral palsy.

Results revealed a variant in the gene SERPINE1, a gene involved in inflammation and blood clotting, was associated with cerebral palsy and death after early preterm birth in both populations of preterm babies.

"Preterm birth is the leading cause of childhood brain injury in otherwise normal children. The earlier a baby is born, the higher the risk of brain injury. However, even among the tiniest preemies, some babies develop quite normally, while others have devastating brain injury and life-long disability," said Erin Clark, M.D., the study's author. "The reason for this difference in outcomes is not well understood. Genetics may allow identification of babies at increased risk so that we can target those babies for prevention and treatment strategies. These results add to the evidence that genes may play a role in risk of brain injury and death in preterm babies."

Clark, assistant professor of Maternal Fetal Medicine, University of Utah School of Medicine's Department of Obstetrics and Gynecology, also noted that additional research is necessary to further evaluate genes that may influence risk and to determine how to apply these results to clinical care.

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Study associates gene with cerebral palsy and death in very preterm babies

A joint research team led by an NUI Galwayscientist has found that changes in a little-known gene called ULK4 were observed in individuals with schizophrenia.

A rare risk factor which is associated with mental illnesses like schizophrenia has been identified by a joint research team led by an NUI Galway (NUIG) scientist.

The research team has found that changes in a little-known gene called ULK4 were observed in individuals with schizophrenia.

The findings are published today in the Journal of Cell Science.

Prof Sanbing Shen of NUIGs Regenerative Medicine Institute, who led the research, says that this could contribute to more effective treatment of the condition in time.

The multi-institutional study examined a database of up to 7,000 people, half of whom had schizophrenia and half of whom did not.

Many genetic risk factors have been associated with schizophrenia and other mental illnesses such as bipolar disorder and depression, but Prof Shen and his team were able to characterise how the ULK4 gene functions in the brain.

He and his colleagues found that when levels of ULK4 were decreased, through mutation or deletion, the neuronal (brain) cells tend to function less well.

This leads to reduced synaptic function and other changes that are also known as risk factors of schizophrenia.

Prof Shen said ULK4 is essential for the formation of the nerve fibres which connect the two sides of the brain.

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Risk factor linked to schizophrenia identified by NUI Galway scientist