In a study published in the January 31, 2014 issue of Science, an international team led by scientists at the University of California, San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.

Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP -- the largest such cohort assembled to date. The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.

"After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an 'HSP-ome,' a map that included all of the new and previously described causes," said senior author Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UC San Diego.

The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers were also interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis.

"Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments," said Gleeson.

"I believe this study is important for the neurodegenerative research community," said co-lead author Gaia Novarino, PhD, a post-doctoral scholar in Gleeson's lab. "But more broadly, it offers an illustrative example of how, by utilizing genomics in specific patient populations, and then building an 'interactome,' we greatly expand knowledge around unknown causes of disease."

"This is very exciting since identifying the biological processes in neurological disorders is the first step toward the development of new treatments," agreed co-lead author Ali G. Fenstermaker. "We identified several promising targets for development of new treatments."

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The above story is based on materials provided by University of California, San Diego Health Sciences. Note: Materials may be edited for content and length.

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New genetic forms of neurodegeneration discovered

PUBLIC RELEASE DATE:

30-Jan-2014

Contact: Scott LaFee slafee@ucsd.edu 619-543-6163 University of California - San Diego

In a study published in the January 31, 2014 issue of Science, an international team led by scientists at the University of California, San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.

Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP the largest such cohort assembled to date. The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.

"After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an 'HSP-ome,' a map that included all of the new and previously described causes," said senior author Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UC San Diego.

The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers were also interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis.

"Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments," said Gleeson.

"I believe this study is important for the neurodegenerative research community," said co-lead author Gaia Novarino, PhD, a post-doctoral scholar in Gleeson's lab. "But more broadly, it offers an illustrative example of how, by utilizing genomics in specific patient populations, and then building an 'interactome,' we greatly expand knowledge around unknown causes of disease."

"This is very exciting since identifying the biological processes in neurological disorders is the first step toward the development of new treatments," agreed co-lead author Ali G. Fenstermaker. "We identified several promising targets for development of new treatments."

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Scientists discover new genetic forms of neurodegeneration

PUBLIC RELEASE DATE:

30-Jan-2014

Contact: Donna Dubuc Donna.M.Dubuc@Dartmouth.edu 603-653-3615 The Geisel School of Medicine at Dartmouth

(Lebanon, NH, 1/30/14) Dartmouth researchers developed a new biological pathway-based computational model, called the Pathway-based Human Phenotype Network (PHPN), to identify underlying genetic connections between different diseases as reported in BioDataMining this week. The PHPN mines the data present in large publicly available disease datasets to find shared SNPs, genes, or pathways and expresses them in a visual form.

"The PHPN offers a bird's eye view of the diseases and phenotype's relationships at the systems level," said Christian Darabos, PhD, post-doctoral fellow, Institute for Quantitative Biomedical Sciences (iQBS), Dartmouth College.

The PHPN uses information in human disease networks in conjunction with network science tools to show clusters of related disorders sharing common genetic backgrounds. It does so without the typical clinical classification of disease, in which all heart disease or all cancers are grouped together, based on clinical presentation. Dartmouth geneticists instead rely on the information contained in the PHPN's topology to automatically classify traits and diseases by their shared genetic mechanisms, such as common genes or pathways. PHPN explores the connections between the layers of the networks to find patterns and relationships.

"The intuitive network representation of the knowledge mined from several large-scale datasets makes the information accessible to anyone. It lies at the crossroads of computational genetics, systems biology, information theory, and network science," Darabos said.

PHPN supports the integration of genomic and phenotypic data to uncover significant links between traits, attributes, and disease. This offer tremendous potential in identifying risk factors for certain diseases. At the same time, it can reveal important targets for therapeutic intervention.

"As a proof of concept, the PHPN has proven capable of identifying well documented interactions, and many novel links that remain to be explored in depth," said Darabos.

The PHPN reveals biological connections between seemingly disparate displays of genetic properties and offers a unique view of the architecture of disease.

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Dartmouth researchers develop new tool to identify genetic risk factors

Anne Roberts of Moorhead

Anne Roberts of Moorhead talks about her decision to have her breasts removed after being diagnosed with the gene that made her a high risk for developing breast cancer. David Samson / The Forum

Sanford medical lab scientist Tylise Graff looks at tumor tissue from a breast cancer sample which helps determine the course of treatment. David Samson / The Forum

Would you consider genetic testing?

FARGO Anne Roberts considers herself a breast cancer previvor.

After learning that she inherited a gene that placed her at very high risk and knowing her family history was riddled with cancer she opted for preventive surgery, a double mastectomy.

My surgeon explained to me it wasnt a matter of if, she said. I was going to get cancer. It was a question of when.

Roberts was 55 when she had the surgery four years ago the same age her older sister first developed breast cancer, and the age of her paternal grandmother when she died of cancer.

Genetic testing revealed the Moorhead woman had an 87 percent chance of developing breast cancer. Preemptive surgery reduced her risk by 90 percent.

Now, the kind of genetic screening and counseling that has long been common in treating cancer and assessing prenatal or childhood risk of inheriting disease is spreading to primary care at Sanford Health clinics under a new $125 million initiative in genetic medicine.

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Genetic screening spreads to primary care at Sanford clinics

FARGO Medical science has developed genetic tests for 2,000 diseases that are available for clinical use.

Some, such as prenatal screens to test for Down syndrome and other congenital disorders, have been in use for years.

But in many cases, experts said, limited scientific information is available to evaluate tests, and medical providers and payers are struggling with how to navigate an expanding field of medicine.

Health insurers often are the gatekeepers in deciding whether to pay for genetic tests. Early diagnosis and treatment can improve patients outcomes and be more cost-effective, but payers want scientific guidance.

Theyre struggling with this too, is my belief, said Dr. Claire Neely, medical director of the Institute for Clinical Systems Improvement, a Minnesota group that advises member health systems and insurers.

They want to do the right thing for their patients, she said.

Sanford Healths recently announced initiative to bring genetic medicine and counseling into the primary care setting, in combination with research and education, should generate useful information, Neely said.

I would call it increasing genetic literacy in primary care, she said. I think that is an important piece.

Experts, including those with the Centers for Disease Control and Prevention, say valid and useful tests are available for certain hereditary breast and ovarian cancer, as well as a hereditary form of colon cancer, two well-established examples.

But those tests are not widely used, partly because of limited research on how to get useful tests in the clinic, and others have only limited scientific information to evaluate their effectiveness, a CDC report concluded.

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Health insurers struggle with whether to pay for genetic tests

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Newswise A new study conservatively estimates that one in five women with ovarian cancer has inherited genetic mutations that increase the risk of the disease, according to research at Washington University School of Medicine in St. Louis.

Most women in the study would have been unaware of a genetic predisposition to ovarian cancer because they didnt have strong family histories that suggested it.

The research, published Jan. 22 in Nature Communications, is the first large-scale analysis of the combined contributions of inherited and acquired mutations in a major cancer type. The inherited mutations by themselves are unlikely to cause ovarian cancer but may conspire with other genetic changes acquired over a womans lifetime to tip the balance toward cancer, the researchers said.

Earlier studies that have looked at inherited susceptibility to ovarian cancer have focused on women with known family histories of the disease. For the current study, however, the researchers studied 429 women with ovarian cancer that appeared to develop sporadically, meaning the women did not have known family histories of the disease.

Using advanced genomic analysis, we found that 20 percent of women with ovarian cancer had inherited mutations in a gene pathway known to be important in inherited breast and ovarian cancer. That number seems pretty high, explained senior author Li Ding, PhD, assistant director at The Genome Institute at the School of Medicine and a research member of Siteman Cancer Center. This tells us that we need to find better ways to screen women for ovarian cancer, even if they dont have family histories of the disease.

Ovarian cancer strikes an estimated 22,000 women annually. Its symptoms are nonspecific and include bloating, pelvic pain and frequently feeling the need to urinate. Most women arent diagnosed until the cancer has spread, leading to a poor five-year survival rate of 43 percent.

Women with ovarian cancer in the study did not have known family histories of breast or ovarian cancer or rare cancer syndromes, all of which can increase the odds of developing ovarian tumors. The women ranged in age from 26 to 89, and 90 percent were Caucasian.

The researchers, including Washington University first authors Krishna Kanchi, Kimberly Johnson, PhD, and Charles Lu, PhD, performed a genetic analysis of each womans tumor and her own DNA, taken from a skin sample. By comparing the genetic sequences side-by-side, they identified the acquired mutations in individual tumor samples. In addition, by comparing the patients DNA samples with the DNA of 557 women who did not have ovarian cancer and served as controls, the researchers found inherited mutations.

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Study Shows 1 in 5 Women with Ovarian Cancer Has Inherited Predisposition

PUBLIC RELEASE DATE:

21-Jan-2014

Contact: Karen Teber km463@georgetown.edu Georgetown University Medical Center

WASHINGTON Genetic counseling delivered over the telephone is as effective as face-to-face counseling, finds the largest randomized study to date comparing the two methods. The multi-center study, led by researchers at Georgetown Lombardi Comprehensive Cancer Center, was reported today in the Journal of Clinical Oncology.

The landscape of genetic testing has broadened to include a range of diseases, and demand for testing and counseling has greatly increased because of direct-to-consumer marketing, says the study's lead investigator, Marc Schwartz, PhD, co-leader of Georgetown Lombardi's Cancer Prevention and Control Program.

"It's important that all people interested in testing have access to thorough information so they can consider the implications of test results and interpret them in the context of family history," says Schwartz, who is also co-leader of the Fisher Center for Familial Cancer Research at Georgetown. "Counseling on the phone reduces costs and expands genetic counseling and testing access to rural areas, where counseling isn't always available."

While this study was conducted with women considering testing for mutations in the breast or ovarian cancer genes BRCA1 and/or BRCA2, the findings "may extend to genetic counseling for other hereditary cancers and complex conditions in adults such as heart disease," says co-author Beth N. Peshkin, MS, CGC, a professor of oncology and senior genetic counselor at Georgetown Lombardi.

Researchers at Icahn School of Medicine at Mount Sinai, Vermont Cancer Center, Dana Farber Cancer Institute and the Huntsman Cancer Institute participated in this study, which randomized 669 women to receive telephone or in-person genetic counseling. However, of women approached about participating in the study, about one-third declined because they did not want to receive phone counseling.

"In-person conversations can be intimidating and there's a lot to process," says Angela Smith, of Burlington, Vermont, who participated in study.

Smith's counseling for BRCA mutation testing was done via telephone. She says talking to a genetic counselor from home was comfortable. "I'm a bit introverted so for me, talking about something so personal was easier with the 'protection' of the phone."

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Genetic counseling via telephone as effective as in-person counseling

The importance of genetic counseling
From Hot Topics 2013 - David Valle, MD, Professor, Department of Pediatrics, Johns Hopkins University School of Medicine - What is the importance of genetic ...

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We rely on trillions of bacteria, fungi, archaea and viruses in our mouth, on our skin and in our gut to get through the day and to stay healthy. Scientists had no way to study most of these microbes, which do not seem to want to grow in laboratory cultures. Rapidly improving, low-cost genetic-sequencing technologies are finally making it possible, however. By working with our microbes instead of against them, scientists are coming up with intriguing approaches to tackling persistent diseases and improving our overall health.

A few years ago scientists could only dream of studying large communities of microorganisms, but now such experiments are manageable and affordable, says David Relman, a professor at the Stanford University School of Medicine. This new field of metagenomics is giving scientists profiles of what microbe populations look like in the gut of people who are healthyand in the gut of people who have various conditions and diseases. Armed with these data, scientists are poised to explore the possibility of manipulating the balance of our microbiota as treatments for obesity, inflammatory bowel disease and many other common and uncommon ailments.

For example, researchers have profiled the populations of organisms in people with ulcerative colitis, which forms ulcers in the colon and is linked to changes in the gut's flora. Building on the results, this summer pharmaceutical giant Johnson & Johnson (J&J) announced a $6.5-million deal with Second Genome, a microbiome start-up, to develop treatments. Current approaches, which center on anti-inflammatory drugs, immunosuppressant medications and surgery, are often unsuccessful. A therapy that directly alters the microbiome would potentially create fewer side effects and fend off other infections down the road.

The J&J deal is a watershed, says Rita Colwell, who holds health appointments at the University of Maryland and Johns Hopkins University. There's a moment for any new biotechnology that's critically important: when it moves from being an area of academic interest to one that companies are founded on, she notes. And then there is the next step: when the big pharma money arrives.

The new treatments would be a big improvement over current attempts to improve the microbiome, which consist mainly of fecal transplants and probioticslive bacterial cultures in supplements or foods such as yogurt. Fecal transplants have alleviated Clostridium difficile, a tough, often drug-resistant, toxin-producing bacterial infection, but the practice can require multiple transplants, and not all patients are cured. Probiotics have generated only weak evidence for positively changing the gut. Both treatments amount to throwing a bunch of organisms at the gut and seeing what sticks.

Metagenomics is more specific, providing precise genetic profiles of what organisms are in the gut and offering the possibility of deducing how they might be interactingwith one another and with us.

One of the biggest challenges of metagenomics is how to handle the onslaught of data. Now that scientists can rapidly sequence entire swaths of microbial communities, they need to figure out what the information means for our health. Biologists are teaming up with mathematicians to develop new methods of analyzing the DNA fragments they collect from our body. Physicians will then need to understand what changes occur in an individual's microbiomeand whyto protect or improve health.

For example, many people routinely carry Escherichia coli bacteria without getting sick. Relman likens the hope of curating better gut microbiota to maintaining a healthy ecosystem, one that will keep nasty creatures such as the intestinal equivalent of invasive weeds at bay.

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Genetic Cures for the Gut

A noninvasive screening method could provide expectant parents with unprecedented and comprehensive fetal genetic data, but it also presents new ethical quandaries

Image: Thinkstock/iStock

Todays genetic technologies are not yet a crystal ball for seeing a childs future, but doctors are closer than ever to routinely glimpsing the full genetic blueprints of a fetus just months after sperm meets egg. That genomic reconstruction would reveal future disease risk and genetic traits even as early as the first trimester of pregnancy. Fetal screening could theoretically detect every hint of disease-associated mutations or disease-carrier status in a fetuss genomesometimes outpacing geneticists knowledge of how to interpret such information. It could also reveal nonmedical markers for eye color or athletic prowess.

Advances in fetal cell research, coupled with the ever-dropping price of whole genome sequencing, presage the possibility of making such scans commonplace. Two years ago researchers devised two tests that could reveal a fetuss complete genetic profile. Separate research groups sequenced complete fetal genomes after gathering traces of fetal DNA in a blood sample from a pregnant woman or by taking that blood in combination with a drop of saliva from the father. Those largely noninvasive screenings could be carried out early in pregnancy, without the small risks of miscarriage inherent in withdrawing placental tissue or amniotic fluid to hunt for a chromosomal condition such as Down syndrome. The technology is all there to do this, says Lisa Soleymani Lehmann, the director of the Center for Bioethics at Brigham and Womens Hospital. Part of the issue is cost and part of the issue is the ethical controversy, which is limiting the uptake of thisnot knowing how to deal with the uncertainty of this information or how to interpret this massive amount of data.

Indeed, whole genome sequencing could provide parents with an avalanche of unexpected and perhaps confusing data. Instead of targeted tests for a few dozen genes, future sequencing techniques could provide parents with three billion base pairs of data. The key issues inherent in any genome sequence work would plague fetal sequencing as wellnamely, there is no guarantee that genetic mutations will actually result in a specific disease. And grappling with information suggesting that certain conditions may emerge in adulthood, or studying mutations with unclear significance, could be fraught with risks and challengesimpacting parents decision threshold for deciding to terminate a pregnancy or influencing how they rear their child.

Despite the ambiguities, parents should still be able to obtain fetal genome information after receiving genetic counseling, Lehmann and her co-authors argue in an article in the January 16 edition of The New England Journal of Medicine. That information could better inform expectant parents and enhance their ability to plan for the childs future. Parents may emphasize diet and exercise more for a child at heightened risk of diabetes, for instance.

Whereas current prenatal tests are diagnostictelling parents about the definitive presence of diseaseprenatal whole genome sequencing would reveal susceptibility genes for issues including heart conditions, diabetes or obesity. Such a shift would drastically alter prenatal care and decision-making. Put another way, where doctors have been reluctant in the past to provide parents with genetic information for an untreatable illness, the complete genomic profile, revealed long before the fetus is born, would present genetic variants that could serve a purpose more predictive than diagnostic.

Lehmann and her colleagues are not the only ones watching the advances in prenatal screening with an arguably wary but hopeful eye. I believe that most of us think this is still a little ways out before we are seeing significant adoption of this as an option in prenatal testing, says Sandra Darilek, a certified genetic counselor and spokesperson for the National Society of Genetic Counselors. A group of bioethicists affiliated with the National Institutes of Health also penned an analysis in 2012 forecasting a future that included such scans. They called both for further recommendations about what data parents should ask for and advised that children should have the right to be told about adult-onset diseases as adults, rather than during childhood. Two years later no formal recommendations have been released by genetic societies outlining what diseases should be revealed to prospective parents, and there are still no clear answers about where a childs rights to be protected from such data end and a parents prerogative to obtain, and perhaps act on it, begin.

Whereas adults can choose to undergo genome sequencing, an unborn child cannot consent to screening its genes. Still, such concerns should not keep parents from obtaining data they want to see about their fetus, Lehmann says. Parents have a right to this information, and there may be significant benefits to the child of a parent having this information. And more genetic counselors and electronic educational resources will be needed to help guide expectant parents through such sequencing decisions, she says.

Enthusiasm for arming parents with such broad genetic profiles has stoked concern in some circles that screenings would prompt a quest for so-called perfect babies, free of any genetic abnormalities or possessing desirable traits of beauty, intelligence or athleticism. But many parents would forgo whole genome sequencing, Lehmann and her colleagues argue, adding that such concerns should not justify withholding information about genetic markers for future illness. This isnt something physicians should be deciding, Lehmann says. If parents want to have this kind of information, their voices need to be heard.

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What Fetal Genome Screening Could Mean for Babies and Parents

St. Louis, MO (PRWEB) January 17, 2014

Also called individualized or customized medicine, personalized medicine is an innovative subcategory of medicine that the FDA has recognized as topic of focus for treating diseases such as mesothelioma cancer. According to Harvard Medical Schools Partners Healthcare Center for Personalized Genetic Medicine (PCPGM), personalized medicine is the ability to determine an individual's unique molecular characteristics and to use those genetic distinctions to:

Individualized diagnosis, treatment, and prevention are crucial to the fight against mesothelioma and other types of cancers, said Neil Maune, partner at MRHFM. With the FDAs support, we hope that more funding and wide-spread information about personalized medicine for patients will be accessible in the United States.

In a 61-page report titled "Paving the Way for Personalized Medicine: FDA's Role" that was published on the FDAs website in October 2013, the organization states that it plans to help further personalized medicine by focusing on advanced regulatory science. Thanks to this commitment, a number of breakthroughs in genetic research have made it possible for researchers to target specific genetic mutations, which will help lead them to new and more effective mesothelioma treatments. While a traditional approach to mesothelioma treatment may very well be effective in some cases, researchers say that if treatment is more individualized based on the patients unique, specific traits, it will fulfill its purpose to better diagnose an individual's disease, reduce adverse reactions, and increase the chances of a positive outcome following treatment. You can find more information on mesothelioma treatment options at http://www.mesotheliomabook.com.

This individual approach to treatment will also minimize or eliminate the need to participate in experimental treatments and ease patient fears based on the idea that a personalized treatment path offers more promise than a one-size-fits-all approach to treating mesothelioma.

The law firm of MRHFM focuses exclusively on mesothelioma cases and works to educate the public about the mesothelioma industry and advancements in treatment for mesothelioma cancer. The law firm advocates for mesothelioma research also offers a free book about mesothelioma titled 100 Questions & Answers About Mesothelioma that is available for request online at http://www.mesotheliomabook.com.

About Maune Raichle Hartley French & Mudd, LLC Maune Raichle Hartley French & Mudd, LLC is a mesothelioma law firm based in St. Louis, MO. With offices across the country, their size and exclusive focus on mesothelioma cases allows them to represent clients through the process as quickly as possible and maximize their clients recovery. The attorneys at MRHFM have represented thousands of victims exposed to asbestos. The firm has 29 attorneys across the country, 16 investigators, 7 client service managers, and additional support staff including paralegals and legal assistants. For more information about Maune Raichle Hartley French & Mudd, LLC, visit http://www.mesotheliomabook.com.

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MRHFM and the FDA Support Personalized Medicine for Mesothelioma

The Section of Genetic Medicine was created in May 2005 to both build research infrastructure in genetics within the Department of Medicine and to focus translational efforts related to genetics. I am proud to have been chosen to lead this new section. My expertise is in quantitative human genetics with a long-standing research program focused on understanding the genetic component to complex phenotypes, including diabetes (MODY, type 1 diabetes and type 2 diabetes), asthma and related phenotypes, psychiatric disorders (autism, bipolar disorder, obsessive-compulsive disorders, Tourettes Syndrome, and schizophrenia) and speech disorders such as stuttering. Yves Lussier M.D., a talented physician scientist with substantial expertise in medical informatics and bioinformatics, joined the section in January 2006 and is already building his research program. Among his research interests are systems medicine and phenomics. In the summer of 2006, two new faculty will join our section with diverse but complementary research interests in genetic and genomic science.

Among the first of the initiatives in which the Section of Genetic Medicine has contributed in is beginning the Translational Research Initiative of the Department of Medicine (TRIDOM ) sample collections. Protocols have been approved for sample collections in Department of Medicine outpatient clinics, and initial efforts are underway in several of the clinics to collect samples. The early efforts have been very rewarding nearly 70% of patients offered the opportunity to participate in the studies have agreed to do so! If we can continue to achieve high participation rates as we increase the number of clinics in which samples are collected, we will indeed have a very rich sample resource for Department of Medicine scientists to tap for their research needs. Look for more information about TRIDOM protocols and other resources available through the Section of Genetic Medicine on this website in the future.

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Genetic Medicine - The University of Chicago Department of ...

Durham, NC (PRWEB) January 14, 2014

A new study released in STEM CELLS Translational Medicine indicates that stem cells can be effective in treating a debilitating and sometimes lethal genetic disorder called brittle bone disease.

Brittle bone disease, or osteogenesis imperfecta (OI), is characterized by fragile bones causing some patients to suffer hundreds of fractures over the course of a lifetime. In addition, according to the OI Foundation, other symptoms include muscle weakness, hearing loss, fatigue, joint laxity, curved bones, scoliosis, brittle teeth and short stature. Restrictive pulmonary disease occurs in the more severe cases. Currently there is no cure.

OI can be detected prenatally by ultrasound. In the study reported on in STEM CELLS Translational Medicine, an international team of researchers treated two patients for the disease using mesenchymal stem cells (MSCs) while the infants were still in the womb, followed by stem cell boosts after they were born.

We had previously reported on the prenatal transplantation for the patient with OI type III, which is the most severe form in children who survive the neonatal period, said Cecilia Gtherstrm, Ph.D., of the Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. She and Jerry Chan, M.D., Ph.D., of the Yong Loo Lin School of Medicine and National University of Singapore, and KK Womens and Childrens Hospital, led the study that also included colleagues from the United States, Canada, Taiwan and Australia.

The first eight years after the prenatal transplant, our patient did well and grew at an acceptable rate. However, she then began to experience multiple complications, including fractures, scoliosis and reduction in growth, so the decision was made to give her another MSC infusion. In the two years since, she has not suffered any more fractures and improved her growth.

She was even able to start dance classes, increase her participation in gymnastics at school and play modified indoor hockey, Dr. Gtherstrm added.

The second child, which was experiencing a milder form of OI, received a stem cell transfusion 31 weeks into gestation and did not suffer any new fractures for the remainder of the pregnancy or during infancy. She followed her normal growth pattern just under the third percentile in height until 13 months of age, when she stopped growing. Six months later, the doctors gave her another infusion of stem cells and she resumed growing at her previous rate.

Our findings suggest that prenatal transplantation of autologous stem cells in OI appears safe and is of likely clinical benefit and that re-transplantation with same-donor cells is feasible. However, the limited experience to date means that it is not possible to be conclusive, for which further studies are required, Dr. Chan said.

Although the findings are preliminary, this report is encouraging in suggesting that prenatal transplantation may be a safe and effective treatment for this condition, said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.

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Stem Cells Could Prove Effective in Treating Brittle Bone Disease

Alnylam Pharmaceuticals Inc. ( ALNY ) provided an update on its pipeline and its goals for the coming years. The company has progressed well with its 'Alnylam 5x15' program so far, and expects six to seven genetic medicine programs in the clinic by 2015 instead of five genetic medicine programs.

One of the important candidates under Alnylam's 'Alnylam 5x15' program is patisiran (ALN-TTR02), which is being developed for the treatment of transthyretin-mediated amyloidosis (ATTR).

The candidate is currently in the phase III APOLLO study in ATTR patients suffering from familial amyloidotic polyneuropathy (FAP). Patisiran is also in a phase II open-label extension study for the treatment of patients suffering from FAP. Alnylam intends to report data from the open-label extension study once a year with initial data expected later this year.

ALN-TTRsc, another important candidate under Alnylam's 'Alnylam 5x15' program is currently in a phase II study in ATTR patients suffering from familial amyloidotic cardiomyopathy (FAC) or senile systemic amyloidosis (SSA). Results from the phase II study are expected late in the year.

Patients successfully completing the phase II study will be eligible for an open-label extension study which is expected to be initiated in mid-2014. Moreover, Alnylam has plans to initiate a phase III study on ALN-TTRsc in patients suffering from TTR cardiac amyloidosis by year end.

Apart from these candidates, Alnylam also has plans to initiate a phase I study on ALN-AT3 (hemophilia and other rare bleeding disorders) soon with initial results expected by year end. Additionally, the company will file three Investigational New Drug (IND) applications by 2015 for ALN-CC5 (complement-mediated diseases), ALN-AS1 (hepatic porphyrias) and ALN-PCSsc for (hypercholesterolemia). We expect investor focus remain on the Alnylam's pipeline going forward.

Alnylam also said that it will acquire Merck & Co. Inc. 's ( MRK ) wholly owned subsidiary Sirna Therapeutics, Inc. for $175 million in cash and equity. Merck is also expected to receive up to $105 million as developmental and sales milestone payments per product along with single-digit royalties related to certain pre-clinical candidates discovered by Merck. Alnylam will also pay $10 million as milestone payments and single-digit royalties for products covered by Sirna's patent estate.

Moreover, Alnylam has expanded its strategic agreement with Sanofi ( SNY ) for the development and commercialization of candidates for the treatment of rare genetic diseases. As per the new agreement, Alnylam will retain most of the product rights in North America and Western Europe whereas Sanofi will become a major Alnylam shareholder with a stake of approximately 12% for an investment of $700 million.

Alnylam's collaborations with big companies like Merck and Sanofi are encouraging. The deals will not help Alnylam to generate revenues from royalties but it will also take its RNAi technology outside its core focus area.

Alnylam presently carries a Zacks Rank #4 (Sell). Some better-ranked stocks include Actelion Ltd. ( ALIOF ) with a Zacks Rank #1 (Strong Buy).

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Pipeline Update at Alnylam - Analyst Blog

With the highest-profile seller of $99 genetic tests under fire, will public trust in personalised medicine suffer, an ethicist wonders

IT'S 2008. The New Yorker is chronicling a celebrity "spit party", at which notables nicknamed the "Spitterati" eject saliva into tubes to find out their risk of developing illnesses such as diabetes, heart disease and cancer. The firm involved is 23andMe, a direct-to-consumer genetic testing company whose service was named Invention of the Year by Time magazine.

Fast-forward five years. 23andMe receives a demand from the US Food and Drug Administration (FDA) to stop selling its health-related tests pending scientific analysis. In a separate event, a Californian woman, Lisa Casey, files a $5 million class action lawsuit alleging false and misleading advertising. 23andMe suspends sales of its test, putting paid to its target of reaching 1 million customers by the end of 2013. Where did it all go wrong?

In November, after what the FDA describes as years of "diligently working to help [23andMe] comply with regulatory requirements", the agency sent a scathing letter to the firm's CEO Anne Wojcicki. It stated that 23andMe's Personal Genome Service was marketed without approval and broke federal law, since six years after it began selling the kits, the firm still hasn't proved that they work.

Doubts go back a long way. In the year of the spit party, the American Society for Clinical Oncology commissioned a report that concluded the partial type of analysis involved wasn't clinically proven to be effective in cancer care. In 2010 the US Government Accountability Office concluded that "direct-to-consumer genetic tests [involve] misleading test results... further complicated by deceptive marketing".

What 23andMe offered was a $99 test for 250 genetically linked conditions, based on a partial reading of single-nucleotide polymorphisms (SNPs). These are points where the genomes of different individuals vary by a single DNA base pair. There are some 3 billion base pairs in the human genome this test targets only a fraction of them. Different companies sample different SNPs and so return different results for the same person.

To illustrate this point, in his book Experimental Man, science writer David Ewing Duncan recalled how he received three conflicting assessments of heart attack risk from three different companies. The director of one, deCODEme no longer offering such tests telephoned him from Iceland to urge him to start taking cholesterol-lowering statins. Yet the other two tests one from 23andMe, one from Navigenics, which no longer offers consumer tests had rated him at medium or low risk. Given that some statins carry side effects such as muscle weakness, Duncan might have been ill-advised to follow deCODE's urgent advice.

This is the root of the FDA's concerns. In its letter to 23andMe, it raised the risk that customers could get false information that leads to drastic and misguided medical steps. Wojcicki now says: "We want to work with [the FDA], and we will work with them." But is it too little, too late?

And what of the class action lawsuit, brought by Casey after buying a test? It focuses on the test's accuracy but goes further, targeting what Casey's attorney calls "a very thinly disguised way of getting people to pay [23andMe] to build a DNA database".

By asking customers to fill in surveys about health and lifestyle, 23andMe has been creating a valuable "biobank" for patenting purposes and industry collaboration. The firm has always sought customer consent for use of identifiable data and hasn't disguised its aim. "The long game here is not to make money selling kits, although the kits are essential to get the base level data," says 23andMe board member Patrick Chung. "Once you have the data, [23andMe]... becomes the Google of personalised healthcare."

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Testing times for the consumer genetics revolution

PUBLIC RELEASE DATE:

13-Jan-2014

Contact: Haley Bridger hbridger@broadinstitute.org 617-714-7968 Broad Institute of MIT and Harvard

The most comprehensive genetic study to date of the blood cancer multiple myeloma has revealed that the genetic landscape of the disease may be more complicated than previously thought. Through results published in Cancer Cell today, a team of Broad researchers has shown that an individual patient's tumor can harbor populations of cancer cells equipped with different mutations. These findings could have therapeutic implications for patients in the future.

"What this new work shows us is that when we treat an individual patient with multiple myeloma, it's possible that we're not just looking at one disease, but at many in the same person, there could be cancer cells with different genetic make-ups," said co-senior author Todd Golub, the Broad Institute's Chief Scientific Officer and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute. Golub is also a professor at Harvard Medical School and an investigator at Howard Hughes Medical Institute. "These findings indicate a need to identify the extent of genetic diversity within a tumor as we move toward precision cancer medicine and genome-based diagnostics."

In a detailed study of samples from more than 200 multiple myeloma patients, Golub and colleagues identified frequent mutations in several key genes known to play an important role in cancer including KRAS, NRAS, and BRAF. But they found that many of these telltale mutations were not present in all cancer cells within a tumor instead, they were often found in only a smaller fraction of cells, known as a subclonal population.

Many promising cancer therapies used in treatment today target a specific genetic mutation. This new work suggests that such targeted therapies may have limitations in patients whose tumors are made up of these subclonal populations.

The research team performed follow-up experiments in the lab to explore some of the therapeutic implications, looking specifically at BRAF, a cancer gene for which several inhibitors, or drugs, exist. Previous studies indicated that around four percent of multiple myeloma patients may have mutations in this gene, and a recent report on a single multiple myeloma patient treated with drugs targeting BRAF showed promising results. BRAF inhibitors have also been used to treat patients with melanoma and other forms of cancer. In the lab, however, the research team found evidence that treating a tumor harboring subclonal BRAF mutations with one of these targeted drugs may at best kill a fraction of the cells, and at worst, stimulate another cancer cell subpopulation to grow.

"There's clearly potential for these drugs in some patients with multiple myeloma, but we show that there are also potential problems for others," said co-first author Jens Lohr an associated scientist at the Broad and a medical oncologist at Dana-Farber. "If a patient has a BRAF mutation in less than 100 percent of his cells, or if he has mutations in KRAS or NRAS at the same time, his oncologist would want to think through the potential pitfalls before giving the inhibitor."

Resistance or the ability for tumors to shrink and then grow back has become a major hurdle in treating patients with targeted therapies such as BRAF inhibitors. The new research suggests that subclonal populations could be one of the potential reasons many patients suffer relapse after treatment.

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Multiple myeloma study uncovers genetic diversity within tumors

Genzyme, a Sanofi company (SNY: Quote), and Alnylam Pharmaceuticals, Inc. (ALNY: Quote) Monday said they have significantly expanded their strategic agreement to develop and commercialize treatments for rare genetic diseases. As part of the expanded relationship, Genzyme will invest $700 million to become a major Alnylam shareholder.

Under the new agreement, Genzyme will have significant rights to Alnylam's portfolio of clinical and pre-clinical stage drug candidates.

Alnylam will retain most product rights in North America and Western Europe, and will have significantly expanded development and commercial opportunities for its genetic medicine pipeline through Genzyme's established global infrastructure in rare diseases.

David Meeker, Genzyme's President and CEO, said, "This collaboration is an important building block for our future. It strengthens our pipeline and provides us with the opportunity to meet the needs of patients with rare diseases around the world through our well-established global organization."

In 2012, Alnylam and Genzyme formed an exclusive alliance to develop and commercialize Alnylam's lead product, patisiran, which is in Phase 3 development for the treatment of transthyretin or TTR-familial amyloid polyneuropathy, a rare life-threatening disease that damages the nervous system.

In the new alliance, Alnylam benefits from Genzyme's proven global capabilities, enabling the firm to accelerate and expand market access for its 'Alnylam 5x15' products.

In the new relationship, Genzyme will obtain expanded rights to patisiran. Under the original agreement from 2012, Genzyme had rights to commercialize patisiran in Japan and the broader Asia-Pacific region where this disease has a disproportionately high prevalence.

Under the expanded agreement, Genzyme will now commercialize patisiran in all territories outside of North America and Western Europe, which are retained by Alnylam for their commercialization.

Secondly, Genzyme will obtain rights to commercialize worldwide three products in Alnylam's pipeline. Genzyme and Alnylam will co-develop and co-commercialize ALN-TTRsc, a product currently in Phase 2 development for the treatment of familial amyloid cardiomyopathy, in North America and Western Europe, while Genzyme commercializes the product in the rest of world.

Genzyme will have the rights to two additional products after the completion of early clinical trials. The firm will be able to choose between full global rights or co-commercialization rights, depending on the product.

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Genzyme Expands Alliance With Alnylam Pharma, To Invest $700 Mln For 12% Stake

Washington, D.C. (PRWEB) January 13, 2014

The Food and Drug Administrations new approach to personalized medicine was sent in motion on November 22, 2013 with its warning letter to 23andme regarding the provision of personal genetic information to customers.

The FDA found that 23andmes offering to be a device that was intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease and that in certain circumstances it could lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing action. Accordingly, the FDA found 23andme in violation of the Federal Food, Drug and Cosmetic Act by marketing its product without acquiring prior approval from the FDA.

Zecola explains that such an approach is misguided for several reasons:

1) The provision of personal genetic information is just that, an information service. The FTC, not the FDA, has jurisdiction over information services in determining whether they are fraudulent. 2) The action is paternalistic and impinges upon personal liberty. The personal genetics companies include disclaimers on their websites and materials saying that their customers should not take action on the personal genetic information but rather should consult with a certified healthcare practitioner before taking any action. 3) The FDAs action, in effect, protects the status quo and undermines the potential for innovation in personalized medicine. 4) The FDA hasnt explained how it could carry out in a timely manner the massive amount of tests that it says is required for the personal genetic firms to provide information to their customers. Its track record suggests that it would take years to analyze and rule upon the upwards of a million tests that are being run by personal genetic firms.

Zecola argues that rather than protecting the status quo from new technology, the Department of Health and Human Services and its subsidiary Food and Drug Administration should be reorganized to better focus on how technology can be used to improve health care.

In essence, the burden should be on the FDA to improve its efficiency to match the exponential growth of technology, rather than constraining the gains from technology to the processing capability of the FDA.

The article is available at http://www.TheFDAandYou.com.

For additional work by the author describing how government should better manage science and technology, see The Major Forces Driving Humanity: Solutions for a Growing Divide (2008). Also see Obama Needs Better Tools to Drive Lasting Change (December 24, 2008).

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Author and Entrepreneur Steven Zecola Highlights the Fallacies of the FDA’s Approach to Personal Genetic Information

Current ratings for: Rare genetic mutation confirmed as a cause of Tourette Syndrome

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Brain researchers say they have confirmed for the first time that a rare genetic mutation can cause some cases of Tourette syndrome, with the fault disrupting production of histamine in the brain.

The New Haven, CT, researchers at the Yale School of Medicine say the histamine effect "is a cause of the tics and other abnormalities of Tourette syndrome." Tics are repetitive movements and vocal sounds, and they are unwanted and involuntary - they cannot be controlled.

Publishing their research on mice in the journal Neuron, the authors raise the question of investigating treatment of Tourette syndrome by drugs that target histamine receptors in the brain.

Drugs with such a mode of action are already being explored by pharmaceutical companies for the treatment of separate brain disorders, schizophrenia and ADHD.

Information from the national gene database about histamine describes the chemical's role - it is a messenger molecule released by nerves, among other functions.

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Rare genetic mutation confirmed as a cause of Tourette Syndrome

USC TREET Seminar Series: Eric Hoffman - Molecular and Clinical Outcome Measures in Rehab Medicine
Eric Hoffman, PhD presents "Molecular and Clinical Outcome Measures in Rehabilitation Medicine: The National Center for Medical Rehabilitation Research in Wa...

By: USC Division of Occupational Science and Occupational Therapy

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USC TREET Seminar Series: Eric Hoffman - Molecular and Clinical Outcome Measures in Rehab Medicine - Video