Silverstein Foundation in Partnership with The Michael J. Fox Foundation

Our partnership with The Michael J. Fox Foundation has created an unprecedented pipeline of research in Parkinson’s with GBA.  The RFA that was distributed in 2018 generated an incredible response, with 92 proposals being submitted from around the globe for consideration.  Together with MJFF, we will be funding up to 20 of these programs, including programs in basic science, novel therapeutics, and biomarkers. Recipients funded thus far include:

GBA Biology

These projects aim to nominate therapeutic targets by learning more about the role of GCase and its impact of GBA mutations.

  • Cincinnati Children’s Hospital Medical Center scientists are studying how GBA mutations may lead to inflammation, which is also seen in Parkinson’s disease.
  • Researchers at Canada’s Dalhousie University are investigating a class of cellular fats called sphingolipids, which are impacted by GBA mutations, and their role in misfolding of the protein alpha-synuclein, a hallmark of Parkinson’s disease.
  • Grantees from the Icahn School of Medicine at Mount Sinai are using gene-editing (CRISPR) technologies to modulate the expression of GBA and other genes in an effort to identify other risk factors that influence Parkinson’s risk with a GBA mutation.
  • A team at Belgium’s KU Leuven research university is validating a novel target in the GCase pathway. GBA mutations lead to build-up of the lipid glucosylceramide, which may lead to cellular dysfunction. This project is studying a glucosylceramide transporter, which could be a target to regulate cell functions.
  • Researchers at the University of Auckland will use computer programs to identify genes controlled by the DNA switches in the GBA gene then investigate how these switches affect cells and contribute to Parkinson’s disease.
  • Researchers at the University of Keil in Germany are looking for the site of interaction between GCase and the protein LIMP-2, which transports GCase to the lysosome. That site could be a target for therapies that would stabilize GCase, enhance its activity and correct lysosomal dysfunction.
  • University of Maryland, Baltimore scientists are using induced pluripotent stem cells to examine the cellular effects of GBA mutations and if reversing some of those effects can protect dopamine cells.
  • Université de Montréal researchers are studying the role of GCase in autoimmune mechanisms after observing that GCase expression in immune cells influences this response.
  • University of Pittsburgh researchers will work to connect deficits in GCase with another leading genetic target: LRRK2. This work could explore the potential of LRRK2 inhibitors (currently in clinical trials) for a broader Parkinson’s population.
  • Scientists at the Weizmann Institute of Science in Israel are applying advanced RNA sequencing and proteomics analysis to brain tissue samples from people with idiopathic Parkinson’s, those with GBA-associated Parkinson’s and control volunteers to identify GBA-specific pathology.

GBA Biomarkers
Two projects are looking for objective tests that could help in patient care and in research, by aiding in subject selection and therapeutic impact assessment.

  • Grantees at the Feinstein Institute for Medical Research at Northwestern will follow Parkinson’s patients with and without GBA mutations over 18 months to assess progression as measured through clinical examinations and MRI scans in an effort to develop an imaging biomarker.
  • University of British Columbia scientists are looking for predictive biomarkers. Mutation carriers with PD and without the disease will undergo clinical evaluations, keyboard typing tests, blood tests, and MRI and PET scans.

GBA Therapies
Grantees are taking varied approaches to correct or counteract the effects of lower GCase activity.

  • Rheostat Therapeutics is testing activators of TRPML1. Experiments showed activation of this ion channel can fix lysosomal malfunctions, which are associated with GBA mutations.
  • A team at Simon Fraser University is using its novel way to rapidly test many thousands of compounds to identify those that can increase GCase in living cells and then testing those that show promise in different Parkinson’s models.
  • Scientists at Temple University are testing compounds to improve lysosomal function and increase GCase levels in fibroblasts from GBA PD patients.
  • Vall d’Hebron Research Institute researchers in Barcelona are testing in Parkinson’s models drug compounds from Gain Therapeutics that aim to stabilize GCase and recover its activity.