LB: A Novel Personalized Becker Muscular Dystrophy (BMD) Mouse Model Simulating Patient’s Muscular Dystrophy Phenotype


Translational Research

Poster Number: V444


Sankalp Sharma, B.S., University of California, San Francisco, Yusef Samimi, University of California, Berkeley, Isha Pema, B.A., University of California, San Francisco, Gabriel Franchet - Schaer, University of California, Irvine, Aboubacar Wague, B.A., University of California, San Francisco, Sanvi Sharma, Amador Valley High School, Brian Feeley, MD, University of California, San Francisco, Hubert Kim, MD, PhD, University of California, San Francisco, Xuhui Liu, MD, University of California, San Francisco

A male patient with a mutation in the Intron7-Exon8 region of the dystrophin gene developed symptoms of Becker muscular dystrophy (BMD), with sequencing revealing a deletion of several amino acids encoded by Exon 8 in the dystrophin gene. To develop personalized therapy for the patient, a mouse dystrophy model was generated by swapping a 39-base pair region for a 12-base pair region in Exon 8 of the mouse dystrophin gene using CRISPR/Cas9 on DBA2/J mice. Founder mice with the correct mutation survived and were further mated with DBA2/J mice. The carriers (41331BMD) (n = 25) consistently exhibited significantly lower body weight (P < 0.01) compared to their littermate non-carrier DBA controls. Moreover, these dystrophic mice displayed proportionately diminished forelimb grip force (P < 0.01) compared to DBA controls. Three groups of male mice at 12 months of age— 41331BMD, DBA, and D2/DMX (n = 6 in each) — were sacrificed and tibialis anterior (TA) muscles were collected and immunohistochemically analyzed. Centrally located nuclei regenerating fibers are significantly higher in 41331BMD (20.06 ± 2.16%) compared to DBA (0 %), but lower than that of D2MDX (m = 28.21 ± 2.09%, P < 0.0001). Furthermore, dystrophin immunostaining across the three groups showed that the 41331BMD exhibited significantly lower dystrophin levels than DBA. Masson’s Trichrome staining also showed a significant increase in the percentage of collagen area/muscle area, indicative of fibrosis, in 41331BMD (5.6 ± 4.07%) compared to DBA (0.295 ± 0.25%, P < 0.05). These data suggest that we successfully generated a novel personalized Becker Muscular Dystrophy (BMD) mouse model with dystrophic muscle phenotype observed in the patient. The cardiac function and phenotype of this mouse model are currently under investigation.