NEW YORK (February 20, 2019) – The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and The Silverstein Foundation for Parkinson’s with GBA announce nearly $3 million in grants to studies investigating glucocerebrosidase beta acid (GBA). Mutations in the GBA gene are the most common genetic risk factors for Parkinson’s, affecting about 10 percent of the more than 6 million people estimated to have the disease. The projects selected through this joint funding program aim to better understand the effect of GBA mutations – and the role of GBA more generally – and advance treatments against this target.

“Defining the GBA pathway and its role in disease, including in patients without a GBA mutation, could point to new therapeutic approaches that may slow or stop Parkinson’s,” said MJFF CEO Todd Sherer, PhD. “This partnership with the Silverstein Foundation streamlined the grant process to more quickly direct funding to these promising projects, speeding their efforts to help Parkinson’s patients.”
Silverstein Foundation Founder Jonathan Silverstein said, “We are very pleased with the collaboration with The Michael J. Fox Foundation and feel confident that the projects chosen will significantly add to the library of knowledge around GBA and propel new treatments for people living with Parkinson’s and, perhaps, individuals at risk for the disease.”
Previous research found that GBA mutations hamper activity of the glucocerebrosidase (GCase) enzyme, a member of the cell’s cleaning crew that degrades damaged or excess cell parts. Build-up of cell parts (e.g., lipids and cellular proteins) can be toxic, resulting in the cell damage seen in Parkinson’s disease. While linked directly to GBA gene mutations, GCase inhibition is also found in Parkinson’s patients without these mutations. Therefore, therapies to heighten the enzyme’s activities or mimic its effects may help a wider Parkinson’s patient base. Three such medications are already in clinical trials.
From the 92 proposals submitted, MJFF and the Silverstein Foundation have selected 16 of the most promising projects to support through their joint funding program. Descriptions of the programs follow.

GBA Biology
These projects aim to define novel biomarker candidates or therapeutic targets by investigating the role of GCase and impact of GBA mutations.
” Two projects are looking for other genetic factors that influence Parkinson’s risk with a GBA mutation. Tim Ahfeldt, PhD, at the Icahn School of Medicine at Mount Sinai is using gene-editing (CRISPR) technologies to modulate the expression of GBA and other genes in an effort to identify other risk factors. Justin Martin O’Sullivan, PhD, at the University of Auckland will use computer programs to identify genes controlled by the DNA switches in the GBA gene and then investigate how these switches affect cells and contribute to Parkinson’s disease.

” Grantees are using other cutting-edge technology to investigate the cellular effects of GBA mutations. Ricardo Feldman, PhD, at the University of Maryland, Baltimore is using induced pluripotent stem cells to examine the cellular effects of GBA mutations and to test if reversing some of those effects can protect dopamine cells. Anthony Futerman, PhD, at the Weizmann Institute of Science in Israel is 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.

” The immune system is a growing area of interest in Parkinson’s research. Manoj Kumar Pandey, PhD, at the Cincinnati Children’s Hospital Medical Center is studying how GBA mutations may lead to inflammation, which is also seen in Parkinson’s disease, and Michel Desjardins, PhD, at the Université de Montréal is studying the role of GCase in autoimmune mechanisms after observing that GCase expression in immune cells influences this response.

” Emily M. Rocha, PhD, and J. Timothy Greenamyre, MD, PhD, at the University of Pittsburgh 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.

” Three projects are investigating other cellular players in the GBA pathway, which may be potential therapeutic targets. Aarnoud Cornelis van der Spoel, PhD, at Canada’s Dalhousie University is investigating a class of cellular fats called sphingolipids that are impacted by GBA mutations. Peter Vangheluwe, PhD, at Belgium’s KU Leuven research university is looking at a transporter of the lipid glucosylceramide, which builds up in response to GBA mutations. And Friederike Zunke, PhD, at the University of Keil in Germany is looking for the site of interaction between GCase and the protein LIMP-2, which transports GCase to the lysosome.

GBA Biomarkers
Two projects are looking for objective measures that could help in patient care and in research, by aiding in subject selection and therapeutic impact assessment.
” David Eidelberg, MD, at the Feinstein Institute for Medical Research 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.

” Michele Matarazzo, MD, at the University of British Columbia is looking for predictive biomarkers. Mutation carriers with PD and without the disease will undergo clinical evaluations, blood tests, and MRI and PET scans.

GBA Therapies
Grantees are taking varied approaches to correct or counteract the effects of lower GCase activity.
” Three grantees are testing compounds against GCase. David Vocadlo, PhD, at Simon Fraser University is rapidly screening thousands of compounds to identify those that can increase GCase and testing leads in Parkinson’s models. Marlene Jacobson, PhD, at Temple University is testing compounds to improve lysosomal function and increase GCase levels in fibroblasts from Parkinson’s patients with GBA mutations. Marta Martinez-Vicente, PhD, at Vall d’Hebron Research Institute in Barcelona is conducting pre-clinical tests of drug compounds from Gain Therapeutics that aim to stabilize GCase and recover its activity.

” Magdalene Moran, PhD, at Rheostat Therapeutics is looking at another target, testing activators of TRPML1. Experiments showed activation of this ion channel can fix lysosomal malfunctions, which are associated with GBA mutations.