An experimental gene-silencing therapy safely lowered LRRK2 protein levels in an early Parkinson’s trial, but its effect on symptoms remains untested.
An experimental medicine built to silence a gene closely associated with Parkinson’s disease has produced encouraging results in its first clinical test in people, according to a study published in Nature Medicine.
The treatment, called BIIB094, is designed to target LRRK2, the most common genetic contributor to Parkinson’s disease. Variants in LRRK2 are known to raise the risk of developing the neurodegenerative condition, which affects nearly 10 million people around the world.
Researchers have long thought that reducing the activity of the LRRK2 protein might help slow or alter the course of Parkinson’s disease. However, turning that concept into a practical therapy has been difficult, said study coauthor 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.”
Safety came before efficacy
The trial examined whether BIIB094 could lower LRRK2 levels safely in people with Parkinson’s disease. Larson said the results indicate that this can be achieved without major safety concerns.
The randomized, placebo-controlled trial included 82 people with Parkinson’s disease divided across two parts. In the first part, 40 participants received one dose of BIIB094 or placebo. In the second part, 42 participants received four doses of BIIB094 or placebo, given every four weeks. The therapy was administered intrathecally, meaning it was delivered directly into the cerebrospinal fluid through a lumbar puncture.
In the second part of the study, participants were grouped according to whether they carried a known LRRK2 genetic variant.
The treatment was generally well tolerated across both parts of the trial. Adverse events were common, but most were mild to moderate and did not prevent dosing. According to the study, no serious adverse events related to BIIB094 were reported.
LRRK2 levels fell sharply
In addition to its safety findings, the study showed strong evidence that BIIB094 affected the biological target it was designed to reach. Cerebrospinal fluid analysis found that LRRK2 protein levels dropped by as much as 59 percent in treated participants.
Those reductions occurred whether or not patients carried a known LRRK2 mutation, Larson said, suggesting the therapy might eventually be relevant to a wider Parkinson’s population, not only people with a confirmed genetic diagnosis.
“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.”
Larson said the results point to a possible way LRRK2-targeted therapies might act on the disease process itself rather than only treating symptoms.
Clinical benefits remain unproven
Larson emphasized, however, that the trial was not intended to test whether BIIB094 improved symptoms, cognition, movement, or disease progression. Larger studies that follow patients for longer will be needed to learn whether lowering LRRK2 levels leads to meaningful benefits.
“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.”
Precision therapies move closer
Larson said the findings represent an important move toward targeted treatments that address the underlying biology of Parkinson’s disease, and they highlight the promise of BIIB094 and other precision medicine approaches.
“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.”
Reference: “LRRK2-targeting antisense oligonucleotide in Parkinson’s disease: a phase 1 randomized controlled trial” by Omar S. Mabrouk, Ben Tichler, H. Moore Arnold, Eva C. Thoma, Sara M. Alexanian, Jingxian Chen, Tzu-Ying Liu, Beth Hirschhorn, Roy Llorens Arenas, John W. Annand, Unnati Kapadnis, Alan A. Shomo, Kelly E. Glajch, Kyle Ferber, Yuka Moroishi, Julie Czerkowicz, Jennifer Inra, Ronald B. Postuma, Tanya Gurevich, Pablo Mir, Huw R. Morris, Jason Aldred, Matthew A. Brodsky, Aaron Ellenbogen, Danielle Larson, Christopher M. Tolleson, Andrew Siderowf, Charalampos Tzoulis, Ernest Balaguer, Maria J. Marti, Hien T. Zhao, Holly B. Kordasiewicz, Roger Lane, Warren D. Hirst, Stephanie Fradette and Danielle L. Graham, 24 March 2026, Nature Medicine.
DOI: 10.1038/s41591-026-04262-4
The study was funded by Biogen.
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