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Archive - Feb 2012

Date

February 4th

Whole-Exome Sequencing ID’s Cause of Metabolic Disease

Sequencing a patient’s entire genome to discover the source of his or her disease is not routine – yet. But geneticists are getting close. A case report, published February 2, 2012 in the American Journal of Human Genetics, shows how researchers can combine a simple blood test with an “executive summary” scan of the genome to diagnose a type of severe metabolic disease. Researchers at Emory University School of Medicine and Sanford-Burnham Medical Research Institute used “whole-exome sequencing” to find the mutations causing a glycosylation disorder in a boy born in 2004. Mutations in the gene (called DDOST) that is responsible for the boy’s disease had not been previously seen in other cases of glycosylation disorders. Whole-exome sequencing is a cheaper, faster, but still efficient strategy for reading the parts of the genome scientists believe are the most important for diagnosing disease. The report illustrates how whole-exome sequencing, which was first offered commercially for clinical diagnosis in 2011, is entering medical practice. Emory Genetics Laboratory is now gearing up to start offering whole-exome sequencing as a clinical diagnostic service. It is estimated that most disease-causing mutations (around 85 percent) are found within the regions of the genome that encode proteins, the workhorse machinery of the cell. Whole-exome sequencing reads only the parts of the human genome that encode proteins, leaving the other 99 percent of the genome unread. The boy in the case report was identified by Dr. Hudson Freeze and his colleagues. Dr. Freeze is director of the Genetic Disease Program at Sanford-Burnham Medical Research Institute. A team led by Dr. Madhuri Hegde, associate professor of human genetics at Emory University School of Medicine and director of the Emory Genetics Laboratory, identified the gene responsible.

February 3rd

New Technology Tackles Treatment-Resistant Cancers

Free-flowing cancer cells have been mapped with unprecedented accuracy in the bloodstream of patients with prostate, breast, and pancreatic cancer, using a brand-new approach, in an attempt to assess and control the disease as it spreads in real time through the body, and to solve the problem of predicting response and resistance to therapies. In comparison to a previous generation of systems, the researchers state their test showed a significantly greater number of high-definition circulating tumor cells (HD-CTCs), in a higher proportion of patients, by using a computing-intensive method that enables them to look at millions of normal cells and find the rare cancer cells among them. Their results, published on February 3, 2012, in Physical Biology, could help reveal the mechanisms behind the spread of solid tumours from one organ or tissue to another – mechanisms that have, until now, remained a mystery. Dr Jorge Nieva, an oncologist at Billings Clinic (Billings, Montana) leading the study, said: "This technology will allow scientists to move away from mouse and cell culture systems and speed the delivery of cures for cancer in people. This is the technology we have been waiting for to solve the problem of resistance to chemotherapy drugs." Senior technology author of the study, Professor Peter Kuhn, said: "In the future, our fluid biopsy can effectively become the companion to the patient for life. If we can assess the disease in real time, we can make quantitative treatment decisions in real time.

New RNA-Based Therapeutic Strategies for Controlling Gene Expression

Small RNA-based nucleic acid drugs represent a promising new class of therapeutic agents for silencing abnormal or overactive disease-causing genes, and researchers have discovered new mechanisms by which RNA drugs can control gene activity. A comprehensive review article in Nucleic Acid Therapeutics, a peer-reviewed journal published by Mary Ann Liebert, Inc., details these advances. Short strands of nucleic acids, called small RNAs, can be used for targeted gene silencing, making them attractive drug candidates. These small RNAs block gene expression through multiple RNA interference (RNAi) pathways, including two newly discovered pathways in which small RNAs bind to Argonaute proteins or other forms of RNA present in the cell nucleus, such as long non-coding RNAs and pre-mRNA. Dr. Keith T. Gagnon and Dr. David R. Corey, University of Texas Southwestern Medical Center, in Dallas, Texas, review common features shared by RNAi pathways for controlling gene expression and focus in detail on the potential for Argonaute-RNA complexes in gene regulation and other exciting new options for targeting emerging forms of non-coding RNAs and pre-mRNAs in the review. "The field of RNA-mediated control of gene expression is rapidly evolving and the article by Gagnon and Corey provides a highly informative and up-to-date review of this exciting and often surprising area of biomedical research. We are delighted to publish this important review for the field," says Co-Editor-in-Chief Dr. Bruce A. Sullenger, Duke Translational Research Institute, Duke University Medical Center, Durham, North Carolina. [Press release] [Nucleic Acid Therapeutics artcle]

February 2nd

Alzheimer’s Disease May Spread by “Jumping” from One Brain Region to Another

For decades, researchers have debated whether Alzheimer’s disease starts independently in vulnerable brain regions at different times, or if it begins in one region and then spreads to neuroanatomically connected areas. A new study by Columbia University Medical Center (CUMC) researchers strongly supports the latter, demonstrating that abnormal tau protein, a key feature of the neurofibrillary tangles seen in the brains of those with Alzheimer’s, propagates along linked brain circuits, “jumping” from neuron to neuron. The findings, published February 1, 2012 in the online journal PloS One, open new opportunities for gaining a greater understanding of Alzheimer’s disease and other neurological diseases and for developing therapies to halt its progression, according to senior author Dr. Karen E. Duff, professor of pathology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute. Alzheimer’s disease, the most common form of dementia, is characterized by the accumulation of plaques (composed of amyloid-beta protein) and fibrous tangles (composed of abnormal tau protein) in brain cells called neurons. Postmortem studies of human brains and neuroimaging studies have suggested that the disease, especially the neurofibrillary tangle pathology, begins in the entorhinal cortex, which plays a key role in memory. Then, as Alzheimer’s progresses, the disease appears in anatomically linked higher brain regions. “Earlier research, including functional MRI studies in humans, have also supported this pattern of spread,” said study coauthor Dr. Scott A. Small, professor of neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC.

Potential New Treatment for Leishmaniasis

Researchers at the University of Dundee in the UK have identified fexinidazole as a possible, much-needed, new treatment for the parasitic disease visceral leishmaniasis. Leishmaniasis is named after William Leishman, a Glasgwegian doctor who served with the British Army in India, and who first identified the parasite in the early 1900s. The disease is the second biggest killer in Africa, Asia, and Latin America after malaria, and affects 500,000 people, killing about 50,000-60,000 patients per year. Current drug treatments for the disease are unsatisfactory for reasons such as high cost, drug resistance, or the need for hospitalization. The disease is caused by the bite of a sand fly. Fexinidazole is already in phase 1 clinical trials for a related disease - African sleeping sickness – but a research team at Dundee, including Dr. Susan Wyllie, Professor Alan Fairlamb, and colleagues, has identified it as having potential in treating leishmaniasis. Their research was published February 1, 2012 in Science Translational Medicine, and was funded by the Wellcome Trust. Tests in mice showed that the drug has a greater than 98% rate of suppressing infection of leishmaniasis, comparable to current treatments such as miltefosine and Pentostam. These and other existing treatment options all suffer from disadvantages; they are not always safe, effective, or easy to administer. The only oral drug, miltefosine, cannot be given to women of child-bearing age due to a substantial risk of birth defects; other drugs are costly and have to be given by injection. Thus, there is a continuing need for safe and cost-effective drugs suitable for use in resource-poor settings. Professor Fairlamb said that fexinidazole has the potential to become a safe and effective oral drug therapy for treating the severest form of visceral leishmaniasis.

January 31st

FDA Approves Cystic Fibrosis Drug for Patients with Rare Mutation

On January 31, 2012, the U.S. Food and Drug Administration approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. This represents a breakthrough in the field of personalized medicine. CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations in a gene that encodes the protein CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes. CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation. “Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Dr. Margaret A. Hamburg. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.” The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.