MJFF and Silverstein Foundation Jointly Award $3M Supporting Research into GBA Mutations

Some 10 percent of Parkinson’s patients carry a mutation in the GBA gene, making it the most common genetic risk for this disease. With a goal of learning more about these mutations, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Silverstein Foundation for Parkinson’s with GBA is awarding $3 million in grants.

Specifically, projects chosen aim to shed more light on the effect of glucocerebrosidase beta acid (GBA) mutations, and GBA’s overall function. They also hope to 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,” Todd Sherer, MJFF’s chief executive officer, said in a press release. “This partnership with the Silverstein Foundation streamlined the grant process to more quickly direct funding to these promising projects.”

GBA mutations impede activity of the glucocerebrosidase (GCase) enzyme that breaks down damaged or excess cell parts, such as lipids and cellular proteins. Accumulations of cell parts can be toxic, leading to the cell damage seen in Parkinson’s disease.

While directly associated with GBA gene mutations, GCase hindrance is also found in patients without mutations. That’s why treatments to rouse the enzyme’s activities or imitate its effects may benefit people with Parkinson’s in general, the MJFF said.

MJFF and the Silverstein Foundation winnowed 92 proposals to 16. In the area of GBA biology, the following projects hope to find novel biomarker candidates or treatment targets by studying the role of GCase and effect of GBA mutations:

• Two projects that look at 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 technologies (CRISPR) to alter the expression of GBA and other genes, in the hopes of identifying additional risk factors. Justin Martin O’Sullivan, PhD, at the University of Auckland will use computer technology to identify genes controlled by certain mechanisms within the GBA gene and how these contribute to Parkinson’s disease.
• Two projects are using other technologies to study the cellular effects of GBA mutations. One, led by Ricardo Feldman, PhD, at the University of Maryland, uses induced pluripotent stem cells; the other, led by Anthony Futerman, PhD, at the Weizmann Institute of Science in Israel, is applying advanced RNA sequencing and proteomics analysis to brain tissue samples from those with idiopathic (of unknown cause) Parkinson’s, those with GBA-associated Parkinson’s and healthy volunteers.
• A study led by Manoj Kumar Pandey, PhD, at the Cincinnati Children’s Hospital Medical Center will investigate about how GBA mutations may lead to inflammation, while another led by Michel Desjardins, PhD, at the Université de Montréal, will fuse on the role of GCase in autoimmune mechanisms.
• Research led by Emily M. Rocha, PhD, and J. Timothy Greenamyre, MD, PhD, at the University of Pittsburgh will focus on connecting deficits in GCase with another top genetic target — LRRK2 — while exploring the potential of LRKK inhibitors in Parkinson’s patients.
• Three projects are investigating other cellular players — prospective treatment targets — in the GBA pathway.

In the category of GBA biomarkers, two projects are hoping to aid in subject selection and therapeutic impact assessment through objective measures that may benefit patient care as well as research.

The area of GBA therapies has three projects testing compounds against GCase, and one project — led by researchers at Rheostat Therapeutics — testing to see whether activators of the ion channel TRPML1 can repair lysosomal malfunctions associated with GBA mutations. Lysosomes are special compartments within cells that digest and recycle different types of molecules. 

“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,” said Jonathan Silverstein, founder of the Silverstein Foundation.

The non-profit Silverstein Foundation invests mainly in promising new ways to treat and prevent Parkinson’s disease in GBA mutation carriers. The MJFF is the globe’s largest non-profit founder of Parkinson’s research. It has supported both pre-clinical and clinical work in GBA1 since 2006.