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Tuesday, June 16, 2015

Gene therapy prevents Parkinson's disease in animal model, says Pitt study


PITTSBURGH, June 15, 2015 - Gene therapy to reduce production of a brain protein successfully prevented development of Parkinson's disease in an animal study, according to researchers at the University of Pittsburgh School of Medicine. The findings, published online today in the Journal of Clinical Investigation, could lead to new understanding of how genetic and environmental factors converge to cause the disease, and the development of effective treatments to prevent disease progression.
Scientists have observed dysfunction of mitochondria, which make energy for cells, in Parkinson's disease, as well as Lewy bodies, which are characteristic clumps of the cellular protein α-synuclein within neurons, said principal investigator Edward A. Burton, M.D., D.Phil., associate professor of neurology, Pitt School of Medicine.
"Until now, these have been pursued largely as separate lines of research in Parkinson's disease," Dr. Burton said. "Our data show that mitochondria and α-synuclein can interact in a damaging way in vulnerable cells, and that targeting α-synuclein might be an effective strategy for treatment."
The team wanted to see what would happen if they knocked out the production of α-synuclein in the brain's substantia nigra, home to the dopamine-producing cells that are lost as Parkinson's disease progresses. To do so, they used a harmless virus called AAV2 engineered to transport into the neuron a small piece of genetic code that blocks production of α-synuclein. They delivered the gene therapy to the brains of rats and then exposed the animals to the pesticide rotenone, which inhibits mitochondrial function.
"Our previous work established that rotenone exposure in rats reproduces many features of Parkinson's disease that we see in humans, including movement problems, Lewy bodies, loss of dopamine neurons and mitochondrial dysfunction," explained co-investigator J. Timothy Greenamyre, M.D., Ph.D., Love Family Professor of Neurology, and director of the Pittsburgh Institute for Neurodegenerative Diseases at Pitt. "We found that our gene therapy prevented those symptoms from appearing, which is very exciting."
Each side of the brain controls the opposite side of the body. The left sides of rats that received gene therapy to the right side of the brain did not become stiff and slow, while their right sides did. The researchers determined that dopamine neurons on the treated side of the brain were protected from rotenone, accounting for the substantial improvement in movement symptoms. In contrast, untreated animals and animals that received a control virus that does not reduce α-synuclein production, developed progressive Parkinsonism and loss of dopamine neurons.
In next steps, the researchers plan to unravel the molecular pathways that enable α-synuclein levels to influence mitochondrial function and develop drugs that can target the underlying mechanisms.
"The viral vector AAV2 has been used safely in Parkinson's disease patients in clinical trials, so the gene therapy approach might be feasible," Dr. Burton said. "We think targeting α-synuclein has great potential to protect the brain from neurodegeneration in Parkinson's disease." 
"We hope to be able to translate this general approach of reducing α-synuclein into human clinical trials soon," Dr. Greenamyre added.
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The team included Alevtina Zharikov, Ph.D., Jason R. Cannon, Ph.D., Victor Tapias, Ph.D., Qing Bai, Ph.D., Max Horowitz, M.D., Ph.D., Vipul Shah, M.D., Amina El Ayadi, Ph.D., and Teresa G. Hastings, Ph.D., all of the University of Pittsburgh.
The project was funded by the U. S. Department of Veterans Affairs grant 1I01BX000548; National Institutes of Health grants ES022644, NS059806, ES018058, ES020718, ES019879 and ES020327; the Blechman Foundation; the Parkinson's Chapter of Greater Pittsburgh; the JPB Foundation; the American Parkinson Disease Association; the Parkinson's Unity Walk; and a gift from Mr. and Mrs. Henry Fisher. 
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu.
Contact: Ashley Trentrock 
Phone: 412-586-9776 

http://health.einnews.com/article/270950207/iwn0b1kWg5LFo0L5

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