Long-term reversal of Duchenne muscular dystrophy via circular arRNA-guided exon skipping in monkeys and humans.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration, loss of mobility, and premature death. Here, we applied leverage endogenous adenosine deaminase acting on RNA (ADAR) for programmable editing of RNA (LEAPER) 2.0, an RNA editing platform, to achieve exon skipping by harnessing endogenous ADAR through circular ADAR-recruiting RNAs (circ-arRNAs). By engaging key splicing elements, circ-arRNAs bypass out-of-frame DMD mutations and restore dystrophin expression through ADAR-dependent and ADAR-independent mechanisms. In DMD nonhuman primates (NHPs) carrying hotspot mutations, a single administration achieved durable dystrophin restoration and sustained motor improvement for at least 1.5 years without eliciting anti-dystrophin immune responses. In a first-in-human study, a single dose of adeno-associated virus (AAV)-delivered circ-arRNA produced safe, dose-dependent exon skipping in three patients, accompanied by measurable gains in motor and cardiopulmonary function. Together, consistent dystrophin restoration across DMD NHP models, patient-derived cardiomyocytes, and treated patients highlights the translational potential of circ-arRNA-mediated exon skipping as a therapeutic strategy for DMD.