Study Rationale:
Alpha-synuclein toxicity is caused by progressive accumulation of this protein in cells. Alpha-synuclein protein aggregation is helped along by impaired lysosomes, which are responsible for degrading cellular waste. The enzyme glucocerebrosidase (GCase) — which plays a role in lysosomes — malfunctions in people with GBA mutations. Recent studies have shown that increased GCase levels can counteract the formation of alpha-synuclein protein aggregates in models of Parkinson’s disease.
Hypothesis:
We devised a strategy to increase GCase levels in the brain based on a gene therapy approach.
Study Design:
We will employ the AAV-BR1 therapeutic virus, which is able to specifically infect only the brain vasculature. With this approach, an increased amount of GCase will be produced and released from the vasculature to the brain parenchyma and uptaken into cells to reduce alpha-syunuclein aggregation.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This approach may provide protection from alpha-synuclein toxicity.
Next Steps for Development:
Intravascular injection of a therapeutic virus is a convenient approach with minimal side effects in a clinical setting. If supported by the positive outcome of this project, we will extend this approach to other models physiologically closer to humans.