Targeted Gene Repair Therapy for Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) Caused by ACTA2 R179H Mutation

Pathogenic missense variants in the ACTA2 gene at arginine 179 (most commonly replacement by histidine) cause a severe Ultra-Rare syndrome termed Multisystem smooth muscle dysfunction syndrome (MSMDS) characterized by systemic smooth muscle cell (SMC) dysfunction causing hypotension, aortic aneurysms and devastating cerebrovascular disease that leads to neurodegeneration and death in the first 3 decades of life. The recurrent nature of the mutation and the severity of the disorder make MSMDS a candidate for genomic editing approaches. In this proposal we present proof of concept data in animal models of a novel gene therapeutic approach to treat MSMDS involving a novel CRISPR/Cas9-directed Adenine Base Editor (ABE) to correct the most common mutation (ACTA2 c.536G>A, p.R179H). The ABE is delivered to the vasculature by a novel AAV vascular-targeting capsid named AAV-PR. We noted complete rescue of multiple clinical phenotypes in a mouse model of MSMDS accompanied by efficient levels of correction of the mutation. In this proposal we propose IND-enabling studies including: GLP and GMP drug product (DP) production, completion of POC studies, murine and NHP toxicity studies, as well as clinical and regulatory development activities. We provide a comprehensive plan to enable an IND application for a novel genomic editing gene therapeutic by the end of the proposal period. Project Number: 1U01NS142895-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Patricia Musolino (+1 co-PI) | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $2,541,084 | Activity Code: U01 | Study Section: Advancing Therapeutics - B Study Section[ATB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11348523