# Characterization of a humanized mouse model of Duchenne muscular dystrophy to support the development of genetic medicines

## TL;DR

This study shows that the hDMDΔ52/mdx mouse model accurately reflects Duchenne muscular dystrophy and can be used to test human-targeted genetic treatments.

## Contribution

The study validates a humanized mouse model suitable for evaluating human-targeted genetic therapies for DMD.

## Key findings

- hDMDΔ52/mdx mice show increased fibrosis and muscle damage compared to controls.
- CRISPR/Cas9 gene editing restored dystrophin expression and improved muscle function in the model.

## Abstract

Duchenne muscular dystrophy (DMD) is a rare, progressive neuromuscular disease resulting from DMD variants, leading to loss of functional dystrophin. To evaluate human-targeted genetic medicines for functional dystrophin restoration, humanized genetic models containing the full human locus are required. This study characterized the hDMDΔ52/mdx mouse model previously reported by Pickar-Oliver and colleagues. Genomic characterization confirmed complete DMD duplication with identical exon 52 deletion junctions on both copies. Histological analysis showed increased diaphragm fibrosis and skeletal muscle central nuclei in hDMDΔ52/mdx mice versus hDMD/mdx controls. hDMDΔ52/mdx mice demonstrated reduced tibialis anterior specific force, decreased skeletal muscle fiber diameter, decreased resistance to eccentric contraction-induced damage and cardiac defects. Multiple serum biomarkers of disease were identified. Using a CRISPR/Cas9 gene-editing strategy to restore human functional dystrophin protein expression, detectable dystrophin expression in the heart and skeletal muscle and increased resistance to injury in the tibialis anterior muscle were observed. In summary, hDMDΔ52/mdx mice display multiple physiological and functional deficits associated with DMD pathology, which can be restored by human-targeted therapy, confirming the suitability of this model for developing human-targeted genetic medicines.

Summary: The humanized genetic model of Duchenne muscular dystrophy (DMD), the hDMDΔ52/mdx mouse, displays molecular and functional deficits of DMD, confirming its suitability for developing human genetic medicines for treatment of DMD.