Bridging Duchenne muscular dystrophy therapy from rhesus monkeys to patients

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Duchenne muscular dystrophy (DMD) remains a fatal, progressive neuromuscular disease despite major advances in multidisciplinary care and genetic therapies.Its therapeutic landscape is complicated by thousands of pathogenic DMD variants and by differences in age, disease stage, muscle involvement, fibrosis, and immunity, all of which may influence treatment response.Successful translation therefore requires more than the production of detectable dystrophin.It requires matching therapies to the appropriate patients and disease stages, restoring biologically meaningful dystrophin across skeletal, respiratory, and cardiac muscles, maintaining efficacy for years, and achieving an acceptable safety profile.To address these interconnected challenges, we began by using CRISPR/Cas9 to disrupt the DMD gene in rhesus monkeys in 2015.1,2 Although the initial founders were mosaic, they established the feasibility of modelling dystrophin deficiency in primates.Subsequently, we spent nearly a decade obtaining hemizygous DMD monkeys that developed progressive muscle degeneration, markedly elevated serum creatine kinase, fibrosis, and motor impairment resembling early human DMD. 3 More recently, we shortened the generation of patientrelevant DMD monkeys from approximately 6-7 years to less than 1 year by directly introducing exon 50 mutations within the major exon 45-55 mutational hotspot.4 These models are not intended for high-throughput screening; their value lies in mechanistic studies and evaluating systemic delivery, tissue distribution, motor function, immunogenicity, and durability under clinically relevant conditions.Mechanism dissection revealed early immune activation, abnormal fibro-adipogenic progenitor differentiation, TGF-β-independent fibrosis, and intrinsic muscle stem-cell dysfunction, which imply important therapeutic implications.3 Our recent work with circular ADARrecruiting RNAs (circ-arRNAs) represents a translational

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