Pittsburgh: 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.
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.