Rescue of the endogenous FVIII expression in hemophilia A mice using CRISPR-Cas9 mRNA LNPs.

ABSTRACT: Gene editing provides a promising alternative approach that may achieve long-term FVIII expression for hemophilia A (HemA) treatment. In this study, we investigated in vivo correction of a mutant factor VIII (FVIII) gene in HemA mice. We first developed MC3-based LNPs for efficient mRNA delivery into liver sinusoidal endothelial cells (LSECs), the major site of FVIII biosynthesis. To target a five base pair deletion in FVIII exon 1 in a specific HemA mouse strain, we injected LNPs encapsulating Cas9 mRNA and specifically designed sgRNAs intravenously for in vivo gene editing of the mutant FVIII. Indel variants generated at the mutant site contained mostly a single base-pair deletion, resulting in frameshift correction of FVIII gene. Sustained endogenous FVIII activity up to 6

SUBMITTER: Chen CY 

PROVIDER: S-EPMC11617921 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature