MJFF launches program to expedite development of LRRK2-targeted therapies and biomarkers for Parkinson’s disease

The Michael J. Fox Foundation (MJFF) is embarking on a major new initiative to rapidly expedite development of therapeutic strategies targeting LRRK2. Called the LRRK2 Investigative Therapeutics Exchange (LITE), the program, which will include tens of millions of dollars of grant support, focuses on bridging basic science advances to industry-led drug development. The program has already attracted more than 30 academic and clinical collaborators as well as more than a dozen companies expressing interest.

LRRK2 is a gene that makes a protein that helps control different activities inside our cells, like how they communicate and clean up waste. Mutations in the LRRK2 gene were first linked to PD 20 years ago, and they are now understood to be the most common causes of inherited PD. The mutations hyperactivate LRRK2, triggering cellular dysfunction that leads to PD. Researchers are looking for strategies to reduce LRRK2 hyperactivity, which would help the four percent of people with inherited LRRK2 mutations. Research also suggests LRRK2 therapies could have much broader use, helping people without mutations as well.

"We're building a translational research engine that diversifies ways to target LRRK2, improving confidence and clarity in the most promising approaches to targeting the pathway. This program will make therapeutic development faster and more informed while 'de-risking' industry investment," said Shalini Padmanabhan, PhD, MJFF's head of translational research.

Several PD drugs targeting LRRK2 are currently in clinical trials, and several other strategies to target LRRK2 have been identified and await further evaluation. The LITE program will focus both on supporting therapeutic approaches as well as identifying LRRK2-specific biomarkers, which could measure the effect of potential LRRK2-based treatments.

LITE will be led by Dario Alessi, PhD, a global leader in the study of kinases, a class of cellular proteins that includes LRRK2. Alessi runs a lab focused on kinase research at the University of Dundee in the United Kingdom, and directs the Dundee Signal Transduction Therapy Unit, a collaboration between leading researchers in the University of Dundee's School of Life Sciences and global pharmaceutical companies. Alessi, the winner of the 2023 Robert A. Pritzker Prize for Leadership in Parkinson's Research, also leads a project focusing on LRRK2 signaling pathways as part of the Aligning Science Across Parkinson's (ASAP) Collaborative Research Network (CRN), creating a point of collaboration across organizations as he continues to build on this work in the space.

"LRRK2 presents key opportunities to the field, both for better understanding Parkinson's and for treating it," Alessi said. "The LITE initiative gives us a chance to clarify key points of understanding and use that knowledge to inform drug development."

Esther Sammler, MD, PhD, a neurologist at University of Dundee who also has LRRK2 expertise, will work as co-principal investigator for LITE, focusing on efforts to identify critical biomarkers for testing LRRK2-targeted therapies in clinical trials. University of Dundee UK's Paul Davies, PhD, and Francesca Tonelli, PhD, will join them as part of the study's leadership. The team will work with numerous academic and industry collaborators to support their success.

Several existing initiatives will contribute to and support the LITE program, including ASAP's supported programs: the Collaborative Research Network, the Parkinson's Progression Markers Initiatives (PPMI) and the Global Parkinson's Genetics Program (GP2).

"By building a cohesive, collaborative approach to discovery and development, LITE expedites efforts to leverage the enormous potential of LRRK2-targeted therapies," said Todd Sherer, PhD, chief mission officer at MJFF. "Through the initiative, we see the potential for transformative advances in understanding Parkinson's, intervening in the disease process and, we hope, stopping Parkinson's disease in its tracks."

• David Kumbroch

  Senior Science Writer