The bmx mouse models Becker muscular dystrophy via dual CRISPR-induced deletions


Pre-Clinical Research

Poster Number: 149


Alyson Fiorillo, PhD, Children's National Hospital, Nikki McCormack, PhD, Children's National Hospital, Christopher Tully, MS, Children's National Hospital, Nhu Nguyen, PhD, Children's National Hospital, James Novak, PhD, Children's National Hospital; The George Washington University, Christopher Heier, PhD, Children's National Hospital; The George Washington University

Background: Significant therapeutic advancements have been made in Duchenne Muscular Dystrophy. Becker Muscular Dystrophy (BMD), however, is understudied and underserved. This discordance is explained in part, by the absence of a BMD mouse model: generation of such a model which would enable a greater understanding of disease pathophysiology and de-risk potential therapeutics before first-in-human trials.
Objectives: To fill this void, we used CRISPR-Cas9 to create genomic deletion of dystrophin exons 45-47, the most common BMD mutation, to generate bmx (Becker muscular dystrophy, X-linked) mice.
Results: Bmx mice show impaired motor function, including reduced grip strength and in vivo isometric torque. Histologically, Bmx muscles show increased myofiber size variability, centrally localized nuclei, inflammatory/necrotic foci, and collagen staining. Immunofluorescence and capillary western immunoassay (Wes) show reduced dystrophin protein levels in bmx skeletal and cardiac muscles; interestingly, dystrophin mRNA levels remain unchanged. Related to this, bmx muscles show elevated expression of NF-kB-regulated dystrophin-targeting miRNAs. Higher levels of NF-kB regulated inflammatory genes and inflammatory miRNAs, as well as genes indicative of fibrosis are also observed.
Conclusions: Collectively, our data demonstrate that bmx mice recapitulate the BMD disease phenotype and can serve as a useful tool to the muscular dystrophy research community. Moving forward, this model can be utilized for in-depth characterization of BMD disease progression, to identify biomarkers and therapeutic targets, and to perform preclinical drug studies aimed at identifying a first treatment for BMD patients.