FUS-meditated delivery of the neurorestorative gene therapy, rAAV9.SIRT3-myc as a disease-modifying strategy in Parkinson’s disease

Parkinson’s (PD) is a progressive neurodegenerative movement disorder that impacts multiple brain regions and currently lacks effective disease-modifying therapies. We have previously shown that direct brain (intra-nigral) infusion of recombinant adeno-associated virus expressing Sirtuin 3 (rAAV.SIRT3-myc) has neurorestorative and neuroprotective effects in preclinical models of PD1,2. These effects are mediated through restoration of mitochondrial health. However, while these studies show promise, the invasiveness of brain surgery limits clinical applicability, particularly in elderly populations. The current study evaluated a non-invasive alternative using magnetic resonance-guided-focused ultrasound (MR-g-FUS) to transiently permeabilize the blood-brain barrier (BBB), enabling targeted delivery of rAAV.SIRT3-myc to affected brain regions. We hypothesized that MR-g-FUS–mediated delivery of rAAV.SIRT3-myc would exert disease-modifying effects in a rat model of PD virally overexpressing mutant (A53T) α-synuclein. The aims of this study were to optimise the dose of AAV.SIRT3-myc for MR-g-FUS mediated delivery, and evaluate therapeutic efficacy, target engagement and biodistribution of SIRT3-myc. The findings of this study will inform the development of a clinically translatable, first in class, mitochondria-enhancing gene therapy strategy for PD.