Development of a Base Editing Gene Therapy to Treat Parkinson's Disease by Modulating LRRK2

Summary Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive motor and cognitive decline. Despite extensive research efforts, current treatment protocols are limited to symptomatic management, and, therefore, there is a high need to develop new therapies that can address the underlying pathogenic mechanisms. Since mutations in the LRRK2 gene are major contributors to both familial and sporadic PD, several therapeutic approaches aim to reduce LRRK2 activity using small-molecule inhibitors or antisense oligonucleotides. However, these strategies face substantial obstacles, including safety concerns, suboptimal biodistribution, and a lack of durable effects. One strategy that can overcome some of those problems is genome editing. Base editors are a class of genome editing tools capable of introducing specific nucleotide substitutions without generating double-strand DNA breaks. Given the precision and ability to induce permanent modifications following a single administration, this project proposes to develop a base editing gene therapy that either silences LRRK2 expression or precisely modulates its activity using genome editing. Using an intein-split base editor delivered by adeno-associated viruses (AAVs), we will test two therapeutic strategies in disease-relevant cellular and animal models of PD. In Aim 1, we will evaluate the feasibility and impact of knocking out LRRK2 using base editors to introduce premature stop codons. In Aim 2, we will assess whether base editing can create LRRK2 variants with reduced LRRK2 activity and attenuate PD-related cellular phenotypes in genetic and sporadic PD models. These studies will clarify whether tuning or eliminating LRRK2 activity offers therapeutic benefit and will address key safety and efficacy questions related to base editing in the central nervous system. Project Number: 1R21NS149463-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Pablo Perez-Pinera | Institution: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN, CHAMPAIGN, IL | Award Amount: $225,474 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 NV-F (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11363344