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

Award Number: R21NS149463
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $225,474 )
2026	2026	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/20/2026	NEW	$225,474
														Subtotal = $225,474

Grand Total All Awards = $225,474

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

Award Number: R21NS149463

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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