Funded Studies
Study Rationale:
Mutations in the GBA gene are a known genetic risk factor for Parkinson’s disease and cause reduced stability and activity of the GBA protein. This can contribute to the impairment of cellular pathways fundamental for function of nerve cells, such as those responsible for the clearance of intracellular garbage. GBA levels and/or activity may also be reduced in people with other forms of Parkinson’s disease (cause unknown or other genetic mutations). For these reasons, stabilizing GBA to improve its function may be a promising therapeutic strategy.
Hypothesis:
We can produce small antibody fragments, termed nanobodies, against the GBA protein, which are able to stabilize it and hence increase its activity.
Study Design:
We will use GBA recombinant protein to produce nanobodies and test their efficacy in stabilizing the protein and thus increasing the enzymatic activity in well-established in vitro assays. We will test the recombinant GBA and some pathogenic mutants as well as fibroblasts from people carrying the PD-related GBA mutations and nerve cells obtained from a model carrying the L444P mutation. The promising nanobodies will then be used to produce viral vectors to express the nanobodies in diseased cells or to model more cost-efficient peptides that should have the same stabilizing effect.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Viral vectors and/or peptides based on the GBA nanobodies that are able to stabilize the GBA protein and increase its activity may be used to treat Parkinson’s disease patients carrying GBA mutations, but also those that present other forms of the disease in which GBA activity/stability is reduced.
Next Steps for Development:
Effects of the nanobodies’ expression by viral vectors and mimicking peptides on cellular function will need to be assessed. Safety and tolerability of the therapeutics will be then studied in models. The availability in our lab of models carrying a common PD-related mutation in GBA will allow early in vivo studies on our new therapeutics.
Additional Support:
The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity and the Stop Parkinson Walk as a lead supporter providing funding for this phase of the project.