Monthly Archives: February 2017

Using stem cells and gene therapy to treat orcure disease may still sound like science fiction, but a scientific meeting here last week emphasizedall the fronts onwhich it is moving closer and closer to fact.

Were entering a new era in medicine, said Lloyd Minor, MD, dean of the School of Medicine, in his opening remarks at the first annual symposium of the schools new Center for Definitive and Curative Medicine. Stanford researchersare poised to use stem cells and gene therapy to amelioratea wide swath of diseases, from common diagnoses such as diabetes and cancerto rare diseases ofthe brain, blood, skin, immune system and other organs. Ultimately, the goal is to create one-time treatments that can provide lifetime cures; hence the definitive and curative part of the centers name. Stanford is a leader in this branch of medical research, Minor said, addingThis is a vital component of our vision for precision health.

Stanford has a long history of leading basic-science discoveries in stem cell biology, andis now engaged in studyingmany different ways those discoveries couldbenefit patients, saidMaria Grazia Roncarolo, MD, who leads the new center.Our job is to produce clinical data so compelling that industry will pick up the product and take it to the next stage, Roncaraolo told the audience.

Among otherevent highlights:

More coverage of the days events is available in a story from the San Jose Mercury News that describeshowAnthonyOro, MD, PhD, and his colleagues are fighting epidermolysis bullosa, a devastating genetic disease of the skin. Oro closed his talk with a slightly goofy photo of a man getting a spray tan. It got a laugh, but his point was serious: Our goal for the cell therapy of the future is spray-on skin to correct a horrible genetic disease.

Ambitious? Yes. Science fiction? In the future, maybe not.

Previously: One of the most promising minds of his generation: Joseph Wu takes stem cells to heart,Life with epidermolysis bullosa: Pain is my reality, pain is my normaland Rat-grown mouse pancreases reverse diabetes in mice, say researchers Photo of Matthew Porteus courtesy of Stanford Childrens

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Stanford scientists describe stem-cell and gene-therapy advances in scientific symposium - Scope (blog)

February 9, 2017

A newly discovered mutation in the INPP5K gene, which leads to short stature, muscle weakness, intellectual disability, and cataracts, suggests a new type of congenital muscular dystrophy. The research was published in the American Journal of Human Genetics by researchers from the George Washington University (GW), St. George's University of London, and other institutions.

"The average pediatrician may only see one child with a rare disorder in his or her entire career. Even working with a team of specialists, it can sometimes take years for a child to be diagnosed with a specific rare disease," said Chiara Manzini, Ph.D., co-corresponding author for the study and assistant professor in the GW Institute for Neuroscience and in pharmacology & physiology at the GW School of Medicine and Health Sciences. "With a correct diagnosis, families have access to the best care and what to expect as far as the progression of the disease. From a research standpoint, we can develop new, targeted therapies to help these patients."

The research team found five individuals from four families presenting with variable clinical features, including muscular dystrophy, short stature, intellectual disability, and cataracts. While these indicators overlap with related syndromes, dystroglycanopathies and Marinesco-Sjgren syndrome, sequencing revealed a unique mutation in the gene INPP5K in the affected members of each family. This is what led the researchers to believe these individuals are presenting a new type of congenital muscular dystrophy.

Congenital muscular dystrophy is a group of muscular dystrophies characterized by muscle weakness, with its onset at or near birth. The cause is genetic mutations in genes responsible for making the proteins necessary to build and maintain muscles, and sometimes to correctly develop the eyes and the brain. However, the INPP5K gene is unique in that it has a different function than other genes associated with congenital muscular dystrophy. Most genes involved in congenital muscular dystrophy are responsible for maintaining contacts between muscle fibers, while this gene has a function inside the cell and regulates both signaling in response to factors like insulin, and protein trafficking.

"Now that we've identified the genetic mutation, we want to know why the disruption in the gene causes this disorder," said Manzini. "The unique mechanism of this gene could help us develop therapies we have not thought about before, and may move research in a different direction."

"Mutations in the inositol phosphatase INPP5K cause a congenital muscular dystrophy syndrome overlapping the dystroglycanopathies and Marinesco-Sjgren Syndrome" was published in The American Journal of Human Genetics.

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Specific genetic errors that trigger congenital heart disease (CHD) in humans can be reproduced reliably in Drosophila melanogaster - the common fruit fly - an initial step toward personalized therapies for patients in the ...

A newly discovered mutation in the INPP5K gene, which leads to short stature, muscle weakness, intellectual disability, and cataracts, suggests a new type of congenital muscular dystrophy. The research was published in the ...

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Researchers find genetic cause of new type of muscular dystrophy - Medical Xpress

February 9, 2017 Credit: NIH

A single blood test and basic information about a patient's medical status can indicate which patients with myelodysplastic syndrome (MDS) are likely to benefit from a stem cell transplant, and the intensity of pre-transplant chemotherapy and/or radiation therapy that is likely to produce the best results, according to new research by scientists at Dana-Farber Cancer Institute and Brigham and Women's Hospital.

In a study published in the New England Journal of Medicine, the investigators report that genetically profiling a patient's blood cells, while factoring in a patient's age and other factors, can predict the patient's response to a stem cell transplant and help doctors select the most effective combination of pre-transplant therapies. The findings are based on an analysis of blood samples from 1,514 patients with MDS, ranging in age from six months to more than 70 years, performed in collaboration with investigators from the Center for International Blood and Marrow Transplant Research.

MDS is a family of diseases in which the bone marrow produces an insufficient supply of healthy blood cells. Treatments vary depending on the specific type of MDS a patient has; donor stem cell transplants are generally used for patients with a high risk of mortality with standard treatments.

"Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself," said the study's lead author, R. Coleman Lindsley, MD, PhD, of Dana-Farber. "As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse."

Researchers have long known that the specific genetic mutations within MDS patients' blood cells are closely related to the course the disease takes. The current study sought to discover whether mutations also can be used to predict how patients will fare following a donor stem cell transplant.

Analysis of the data showed that the single most important characteristic of a patient's MDS was whether their blood cells carried a mutation in the gene TP53. These patients tended to survive for a shorter time after a transplant, and also relapse more quickly, than patients whose cells lacked that mutation. This was true whether patients received standard "conditioning" therapy (which includes chemo- and/or radiation therapy) prior to transplant or received reduced-intensity conditioning, which uses lower doses of these therapies. Based on these results, doctors at Dana-Farber are now working on new strategies to overcome the challenges posed by TP53 mutations in MDS.

In patients 40 years old and over whose MDS didn't carry TP53 mutations, those with mutations in RAS pathway genes or the JAK2 gene tended to have a shorter survival than those without RAS or JAK2 mutations. In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in reduced-intensity conditioning. This suggests that these patients may benefit from higher intensity conditioning regimens, the researchers indicated.

The study also yielded key insights about the biology of MDS in specific groups of patients. Surprisingly, one in 25 patients with MDS between the ages of 18 and 40 were found to have mutations associated with Shwachman-Diamond syndrome (a rare inherited disorder that often affects the bone marrow, pancreas, and skeletal system), but most of them had not previously been diagnosed with it. In each case, the patients' blood cells had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after transplantation.

The researchers also analyzed patients whose MDS arose as a result of previous cancer therapy (therapy-related MDS). They found that TP53 mutations and mutations in PPM1D, a gene that regulates TP53 function, were far more common in these patients than in those whose disease occurred in the absence of previous cancer treatment.

"In deciding whether a stem cell transplant is appropriate for a patient with MDS, it's always necessary to balance the potential benefit with the risk of complications," Lindsley remarked. "Our findings offer physicians a guide - based on the genetic profile of the disease and certain clinical factors - to identifying patients for whom a transplant is appropriate, and the intensity of treatment most likely to be effective."

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A large, nationwide study published in the journal JAMA Oncology found that people who received transplants of cells collected from a donor's bone marrow the original source for blood stem cell transplants, developed decades ...

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Genetic profiling can guide stem cell transplantation for patients with myelodysplastic syndrome - Medical Xpress