Using a Virally Encoded, Single-chain Antibody as a Noninvasive Gene Therapy for Parkinson’s Disease

Study Rationale: The main pathological hallmarks of Parkinson’s disease (PD) are the degeneration of dopamine-producing brain cells and the accumulation of protein aggregates containing misfolded alpha-synuclein protein. The toxic misfolded alpha-synuclein propagates throughout the brain, spreading the pathology and triggering neuronal degeneration. In a previous study funded by MJFF, we generated mini-antibodies targeting the pathological alpha-synuclein protein. We then used viral vectors that facilitate delivery of these mini-antibodies to the brain following intravenous injection. This treatment blocks the development of motor symptoms and the appearance alpha-synuclein aggregates in a mouse model of PD.

Hypothesis: We hypothesize that the secreted mini-antibodies can target intracellular alpha-synuclein and reduce the inflammation associated with PD. We will also determine whether this custom-designed viral delivery vector can infect human brain cells.

Study Design: We will expose cohorts of mice to preformed alpha-synuclein fibrils and then inject the animals with our viruses to induce the production of mini-antibodies against the toxic synuclein. We will collect tissues and fluids from the treated animals and analyze them using a battery of tests to monitor inflammation and to determine the presence and location of alpha-synuclein aggregates and mini-antibodies. We will also examine the capacity of these viruses to infect isolated human brain cells.

Impact on Diagnosis/Treatment of Parkinson’s disease: Our results should allow us to determine the mode of action of our mini-antibodies in a preclinical mouse model of PD and to assess whether our custom-designed viruses are also effective on human brain cells.

Next Steps for Development: If successful, our approach should pave the way for testing anti-Parkinson strategies in nonhuman primate models of PD, a desirable prelude to human clinical trials.