Last week scientists gathered at The Michael J. Fox Foundation (MJFF) office in New York to discuss progress toward slowing or stopping Parkinson's progression. Representatives from nine companies and 14 academic institutions attended our annual LRRK2 Summit to share advances and challenges that will inform future strategy around a leading Parkinson's drug target: LRRK2.
Mutations in the gene that makes the LRRK2 protein are a cause of Parkinson's, affecting about two percent of the overall disease population. These genetic changes lead to greater activity of the LRRK2 protein, which scientists think may be harmful to cells.
Interest is growing around this target because a study published last year showed people with Parkinson's without a LRRK2 mutation also showed greater LRRK2 activity. This finding means therapies against this target may work for a broader patient population.
"LRRK2 has been a priority target for some time, but the last year has seen leaps in our understanding of its role in disease and in development of new therapies," said MJFF Director of Research Programs, Marco Baptista, PhD, who leads our LRRK2 portfolio. "This summit allows us to gather experts around the world working on LRRK2 to share successes and problem solve and continue momentum toward new treatments."
Here we share five takeaways from the LRRK2 Summit.
1. More Therapies Are in Testing
Because LRRK2 is overactive in people with Parkinson's, therapies in development aim to lower its activity. Last year at our Parkinson's Disease Therapeutics Conference, Denali Therapeutics shared positive results from its first-in-human trials of a LRRK2 inhibitor. Based on the recent findings of higher LRRK2 activity in the greater Parkinson's population, Denali now is testing its drug in patients with and without a LRRK2 mutation.
At the recent summit, pharmaceutical company Biogen shared plans to move its LRRK2-targeting therapy, a different approach called an antisense oligonucleotide, into human trials. Another company, GlaxoSmithKline, has previously shared it is also close to clinical testing. MJFF funded early work on these projects and organized the LRRK2 Safety Initiative that showed lowering LRRK2 levels was safe to test in humans, allowing these studies to begin.
Scientists, too, are looking at other approaches targeting the LRRK2 pathway. Diverse strategies are critical given the risk of failure in drug development. For example, MJFF-funded researchers have showed that LRRK2 modifies other proteins called Rabs. Targeting the Rab pathways could offset issues caused by too much LRRK2 activity.
2. Need More People to Undergo Genetic Testing
Even as we learn more about the role of LRRK2 in the broader Parkinson's population, we still need mutation carriers to better understand this protein and test LRRK2 therapies. We also need to know if people do not have a LRRK2 mutation, so we can explore protein activity in that population. At the summit, researchers discussed strategies to engage people in genetic research, including providing genetic counseling to help volunteers interpret results. We're currently exploring ways to test people without Parkinson's who may be carriers of these mutations.
Participants with Parkinson's disease in the MJFF-sponsored Fox Insight study, through a collaboration with consumer genetics company 23andMe, can receive access to the 23andMe Health + Ancestry Service at no cost and add their genetic information to the study. Eligible participants can also receive complimentary genetic counseling from Indiana University. Visit www.foxinsight.org to learn more.
3. Learning More about LRRK2 Structure
Some summit attendees are working to define the protein structure of LRRK2. A more nuanced understanding of the nooks and crannies of the protein can help develop drugs that can target LRRK2 better, like knowing a lock so you can make a key. Given the value of knowing the protein structure, partners are taking varied approaches to answer this question. As one summit attendee put it, "Throw the kitchen sink at the problem."
Even NASA and the International Space Station have worked on it. MJFF has helped send the LRRK2 protein to space to try to grow crystals (which scientists study to define the structure) under microgravity. Another group at the University of California San Diego are usingcutting-edge imaging techniques to understand the structure. Those MJFF-funded researchers are working on papers to share their findings.
4. Need Better Measures and Tools
Another role of MJFF is to provide research tools to enable studies and to look for better disease measures. For example, in 2018, we launched eight antibodies to interrogate the Rab pathway. Summit attendees presented Foundation staff with a wish list of additional laboratory models and tools that would help them study LRRK2 and test new treatments. Our staff will prioritize needs and work with contract research organizations to create and distribute new tools.
We also are working on better measures of the LRRK2 pathway, which can help assess the impact of new therapies and potentially measure disease progression. Summit attendees discussed work toward LRRK2 biomarkers. Our landmark study the Parkinson's Progression Markers Initiative is measuring some leads -- such as one fatty acid found in urine -- to explore their utility as measures of LRRK2 activity.
5. Collaboration Is Advancing Therapeutic Development
A theme of our annual summit is collaboration -- sharing methods and results and troubleshooting together. Partnerships continue outside the office, too. Companies are working with academic labs to screen libraries of drug compounds for potential therapies against different targets in the LRRK2 pathway. Companies, too, are lending their drug compounds to help academics develop better tests to measure LRRK2 and therapeutic impact. Better tests will help all groups create and assess new treatments. Collaboration is key to progress, and the summit serves as a touchpoint to update on those partnerships and foster new ones.