An experimental drug designed to silence a gene strongly linked to Parkinson’s disease has shown encouraging effects in a first-in-human clinical trial, according to a study published in Nature Medicine.
The drug, known as BIIB094, targets LRRK2, the most common genetic contributor to Parkinson’s disease; variants in LRRK2 are known to increase the risk of developing the neurodegenerative disorder, which affects nearly 10 million people worldwide.
Scientists have long believed that lowering the activity of the LRRK2 protein could help slow or modify the disease, but turning that idea into a viable therapy has remained a challenge, said co-author of the study Danielle Larson, MD, ’15, ’18 GME, assistant professor in the Ken & Ruth Davee Department of Neurology’s Division of Movement Disorders.
“This was a multi-center clinical trial looking at an antisense oligonucleotide therapy for LRRK2-specific Parkinson’s disease,” Larson said. “The main goal was to examine the safety of delivering this therapy to patients, with the hope that if it proved safe, future studies could evaluate whether it might slow disease progression.”
The study tested whether BIIB094 could safely reduce LRRK2 levels in people with Parkinson’s disease. The results suggest it can be done without serious safety concerns, Larson said.
In the randomized, placebo-controlled trial, 82 participants with Parkinson’s disease were enrolled across two study segments. In the first, 40 participants received a single dose of BIIB094 or placebo. In the second, 42 participants received four doses of the drug or placebo, administered every four weeks. The therapy was delivered intrathecally: directly into the cerebrospinal fluid through a lumbar puncture.
Participants in the second section were stratified based on whether they carried a known LRRK2 genetic variant.
Across both parts of the trial, the treatment was generally well tolerated. While adverse events were common, they were mostly mild to moderate and did not limit dosing. No serious adverse events related to BIIB094 were reported, according to the study.
Beyond safety, the study provided strong evidence that BIIB094 hit its intended biological target. Analysis of cerebrospinal fluid showed that levels of LRRK2 protein fell by as much as 59 percent in treated participants.
These reductions were observed regardless of whether patients carried a known LRRK2 mutation, suggesting the therapy could potentially affect a broader group of Parkinson’s patients, not just those with a genetic diagnosis, Larson said.
“The antisense oligonucleotide was designed specifically to reduce LRRK2 expression,” Larson said. “Because overactivity of this protein kinase is thought to be part of the problem in Parkinson’s disease, reducing LRRK2 levels could be protective and potentially modify the disease.”
The new findings hint at a possible mechanism by which LRRK2-targeting therapies could influence the underlying disease process, rather than simply addressing symptoms, Larson said.
However, Larson cautioned that the trial was not designed to assess clinical benefits such as changes in movement, cognition or disease progression. Larger and longer studies will be needed to determine whether reducing LRRK2 levels translates into meaningful improvements for patients.
“The next step would be a phase 2 study with a larger group of patients,” Larson said. “Instead of focusing only on safety, those trials would look at efficacy, whether the therapy can slow disease progression using motor assessments and standard Parkinson’s rating scales.”
The findings mark an important step toward targeted treatments that address the root biology of Parkinson’s disease and underscore the potential of BIIB094 and other precision-medicine approaches, Larson said.
“This is one of the first antisense oligonucleotide, or ASO, therapies in Parkinson’s disease to have safety and tolerability data,” Larson said. “It really paves the way for other ASO-based treatments to be developed, potentially targeting different biological pathways.”
The study was funded by Biogen.
