Gene Therapy Found to Prevent Parkinson’s Disease in Rats

Researchers at the University of Pittsburgh School of Medicine and the VA Pittsburgh Healthcare System in Pennsylvania recently revealed that a gene therapy strategy targeting a key protein in Parkinson’s disease pathology – alpha-synuclein – can prevent disease development in a rat model. The study is entitled “shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model” and was published in the Journal of Clinical Investigation.

Parkinson’s disease is a progressive neurodegenerative disorder that develops gradually. As the disease progresses, the symptoms worsen from a barely noticeable tremor in the hands to serious difficulties in speaking, locomotion, coordination and balance. The dopaminergic neurons, which play an important role in voluntary movement and behavioral processes (like mood, stress, reward, addiction), are particularly vulnerable to the disease. There is currently no cure for Parkinson’s, and it is estimated that four to six million people worldwide suffer from the disease.

Parkinson’s disease is caused by aggregates or deposits of a protein called alpha-synuclein within neurons (Lewy bodies). Alpha-synuclein is encoded by the SCNA gene and its exact function is not clear, although it is thought to play a role in the communication between brain cells. Parkinson’s disease has also been linked to a dysfunction of mitochondria, the powerhouses of the cell that produce energy for the body.

“Until now, these have been pursued largely as separate lines of research in Parkinson’s disease,” explained the study’s senior author Dr. Edward A. Burton in a news release. “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.”

Rotenone is a naturally occurring pesticide that is a potent inhibitor of the mitochondrial function, and exposure to it has been associated with an increased risk of developing Parkinson’s disease. Rotenone-exposed rats experience systemic mitochondrial defects and develop specific neuropathology, including alpha-synuclein aggregation and degeneration of dopaminergic neurons. These animals are therefore useful models for the study of Parkinson’s pathogenesis.

In the study, the team blocked the expression of alpha-synuclein in the rat’s brain by using a harmless virus called AAV2 engineered to deliver into the neurons a short hairpin RNA (shRNA) targeting the Snca RNA, thereby inhibiting alpha-synuclein expression. Animals were then exposed to rotenone.

“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 the study’s co-author Dr. J. Timothy Greenamyre. “We found that our gene therapy prevented those symptoms from appearing, which is very exciting.”

Researchers found that their gene therapy protected dopamine neurons from rotenone effects, resulting in a substantial improvement in terms of motor function and decreased degeneration of dopaminergic neurons. In contrast, animals that were untreated or received a control virus with no shRNA against SNCA developed progressive motor deficits with the loss of dopamine neurons.

The team concluded that gene therapy aimed at reducing alpha-synuclein production has a neuroprotective effect and successfully prevented the development of Parkinson’s disease in a rat model. The team’s next goal is to identify the molecular pathways by which alpha-synuclein affects the mitochondrial function and develop potential drug therapies targeting such mechanisms.

The authors believe that their gene therapy strategy may be applicable in humans. “The viral vector AAV2 has been used safely in Parkinson’s disease patients in clinical trials, so the gene therapy approach might be feasible,” said Dr. Burton. “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,” added Dr. Greenamyre.