In Vivo Genome Engineering for the Treatment of Muscular Dystrophies

Purpose of Review Muscular dystrophies (MDs) are a heterogeneous collection of inherited disorders which cause progressive muscle loss and weakness/hypotonia. Owing to the genetic root of MDs, CRISPR/Cas9 genome editing has been investigated as a possible therapy, with significant advancements having been made. This review aims to provide an overview of recent progress on the in vivo utilization of CRISPR/Cas9 in MD animal models. Recent Findings Three primary methods for correcting MD with CRISPR/Cas9 exist: restoration of the full-length protein, restoration of a truncated but partially functional protein, and modulation of gene expression. All these approaches have been (DMD) models with varying degrees of success. In congenital muscular dystrophy type 1A (MDC1A) mice, full-length protein restoration and disease modifier upregulation strategies significantly improved the phenotype. Lastly, efficient elimination of pathogenic CTG repeats via CRISPR/Cas9 was achieved in myotonic dystrophy type 1 (DM1) mice. Delivery of CRISPR machinery into MD animals was frequently accomplished with adeno-associated viruses (AAVs), which currently significantly outperform nanoparticle-based delivery. The targeting of satellite cells in vivo by AAVs has been evaluated by several groups in DMD mice, yielding conflicting results which require clarification. Summary Partial or nearly complete phenotypic rescue has been achieved in DMD, MDC1A, and DM1 animals with numerous CRISPR/Cas9 strategies. While considerable work will be necessary to advance CRISPR/Cas9 genome editing past preclinical stages, its therapeutic potential for MD is extremely promising and warrants the investment.