Gene therapy for Parkinson’s disease targets α-synuclein

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Inhibiting endogenous α-synuclein expression using gene therapy has been demonstrated to be neuroprotective in a rat model of Parkinson’s disease (PD). The study, published in the Journal of Clinical Investigation, suggests that α-synuclein plays a role in the vulnerability of dopaminergic substantia nigra neurons to mitochondrial dysfunction.

Mitochondrial dysfunction is being increasingly implicated in PD pathogenesis, as is α-synuclein. However, how the two interact in PD is the subject of ongoing debate and discussion. Principal investigator Edward Burton, Associate Professor of Neurology at the University of Pittsburgh School of Medicine (PA, USA) explained, “Until now, these have been pursued largely as separate lines of research in PD.” However, in this study, the 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 authors used the mitochondrial complex I inhibitor rotenone to induce a Parkinson’s-like state in rats. As well as systemic mitochondrial defects, disease-specific hallmarks are also observed, such as movement problems, α-synuclein aggregation and degeneration of dopaminergic neurons.
The gene encoding α-synuclein in the substantia nigra was targeted using adeno-associated virus–mediated delivery of a short hairpin RNA (shRNA). Following α-synuclein knockdown, in rats exposed to rotenone, any motor deficits were remarkably improved. Additionally, nigral dopaminergic neuron and dendrite degeneration was reduced. Co-author J. Timothy Greenamyre, Professor of Neurology, and Director of the Pittsburgh Institute for Neurodegenerative Diseases, described the results as “very exciting.” In control rats, the treatment had no detrimental effects. Taken together, these results indicate that genetic make-up in respect to α-synuclein expression can influence cellular susceptibility to environmental exposures in PD. Neuron

Although α-synuclein is a known hallmark of the disease, these results shed light on the physiological role of the protein and the interaction between its genes and the environment. These data present α-synuclein as a valid future neuroprotective target worthy of further evaluation. The safety and feasibility of inhibiting α-synuclein throughout the adult brain will need to be explored in further translational research. “We think targeting α-synuclein has great potential to protect the brain from neurodegeneration in Parkinson’s disease,” added Burton. Given the safety of the vectors in human trials, the authors see a future for the selective targeting of the SNCA gene with shRNA in future therapeutic evaluations for this degenerative condition. “We hope to be able to translate this general approach of reducing α-synuclein into human clinical trials soon,” concluded Greenamyre.

Source: Zharikov AD, Cannon JR, Tapias V et al. shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model. J. Clin. Invest.. doi:10.1172/JCI64502