Targeted gene repair therapy for multisystemic smooth muscle dysfunction syndrome (msmds) caused by ACTA2 R179H mutation

The National Institute of Neurological Disorders and Stroke awarded Massachusetts General Hospital a $2.541 million cooperative agreement on May 1, 2026, to develop targeted gene repair therapy for multisystem smooth muscle dysfunction syndrome caused by ACTA2 R179H mutation, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The award funds IND-enabling studies for a novel CRISPR/Cas9-directed adenine base editor delivered via AAV-PR vascular-targeting capsid to correct the ACTA2 C.536G>A (p.R179H) mutation. Deliverables include GLP and GMP drug product production, proof-of-concept completion, murine and nonhuman primate toxicity studies, and clinical and regulatory development activities to support an IND application by the conclusion of the performance period.

Work is performed in Boston, Massachusetts, through April 30, 2029. University of Massachusetts Medical School serves as sub-grantee, with the Keeler Lab responsible for immunological characterization including ELISPOT assays to evaluate antigen-specific T-cell responses to AAV redosing and neutralizing antibody assays to evaluate B-cell responses. The Keeler Lab will provide T-cell and B-cell response results and data interpretation to the primary investigator teams.

Abstract

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.