CRISPR Gene Editing Could Cure Duchenne Muscular Dystrophy but Fatal AAV Immune Responses Remain Unresolved

Abstract

Duchenne muscular dystrophy (DMD) remains, despite decades of careful clinical management, a relentless disease - and for a long time, medicine could only slow it down, not stop it. That may be changing. CRISPR-Cas genome editing now offers something earlier therapies could not: a route to permanent, DNA-level correction of the mutations that silence dystrophin. This review draws together the molecular, delivery, and safety literature on CRISPR strategies for DMD, tracing how single-cut and double-cut non-homologous end joining, homology-independent targeted integration, base and prime editing, and CRISPR activation of utrophin each attempt to restore or compensate for lost dystrophin, depending on where and how a patient's mutation falls. It then turns to the harder, less glamorous problem: getting these tools into more than forty percent of the human body safely. Recombinant adeno-associated viruses remain the dominant in vivo vector, prized for their muscle tropism, yet constrained by a packaging ceiling near 4.7 kilobases and by immune responses that have, in several trials, proven fatal at the doses required for systemic correction. High-capacity adenoviral vectors and non-viral platforms - lipid nanoparticles, extracellular vesicles, and gold nanoparticles - are examined as partial answers, each trading some efficiency for a better safety margin. Evidence from mouse, canine, porcine, and human iPSC-derived models is synthesized to show where preclinical promise has, and has not, translated toward the clinic. Taken together, the literature suggests that vector engineering, transient non-viral delivery, and precision DSB-free editors, paired with realistic manufacturing and immunosuppression strategies, will likely determine whether CRISPR therapeutics for DMD become a durable clinical reality rather than a preclinical curiosity.