<i>In vivo</i> Treatment of a Severe Vascular Disease via a Bespoke CRISPR-Cas9 Base Editor.

ABSTRACT: Genetic vascular disorders are prevalent diseases that have diverse etiologies and few treatment options. Pathogenic missense mutations in the alpha actin isotype 2 gene (ACTA2) primarily affect smooth muscle cell (SMC) function and cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection, and death in childhood. Here, we explored genome editing to correct the most common MSMDS-causative mutation ACTA2 R179H. In a first-in-kind approach, we performed mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the R179H sequence. To directly correct the R179H mutation, we screened dozens of configurations of base editors (comprised of Cas9

SUBMITTER: Alves CRR 

PROVIDER: S-EPMC11601241 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature