Gene of the Month - June: DMD
Targeted exon skipping of the DMD gene as a novel RNA-based therapeutic approach for Duchenne muscular dystrophy is the focus of a recent study published in Cell. In this work, the authors employ the RNA editing platform LEAPER 2.0, using endogenous adenosine deaminase acting on RNA (ADAR) enzymes together with highly stable circular ADAR‑recruiting RNAs (circ‑arRNAs) to guide the splicing machinery to defined sites within the DMD mRNA.
Duchenne muscular dystrophy is a severe neuromuscular disorder characterized by progressive muscle wasting, loss of mobility and premature death and is caused by variants in the DMD gene that typically disrupt the open reading frame and prevent the production of full‑length, functional dystrophin. Restoring the reading frame through deliberate skipping of a mutation-carrying exon can enable synthesis of a shorter, yet partially functional dystrophin protein, resembling the milder Becker muscular dystrophy phenotype.
According to Guo et al., a single administration of AAV‑delivered circ‑arRNAs in specific DMD models of nonhuman primates carrying DMD hotspot mutations achieved sustained restoration of dystrophin expression and improved motor performance for at least 1.5 years, without triggering detectable immune responses. Complementary experiments in patient‑derived cardiomyocytes demonstrated robust circ‑arRNA‑mediated exon skipping and dystrophin rescue in human cells. In an initial first‑in‑human study, a single dose of an AAV vector encoding circ‑arRNAs induced safe, dose‑dependent exon skipping in three individuals with DMD and was associated with measurable gains in motor function and cardiopulmonary performance.
Guo X, Zhang Y, Li J, … Wei W. Long-term reversal of Duchenne muscular dystrophy via circular arRNA-guided exon skipping in monkeys and humans. Cell. 2026 Jun 10:S0092-8674(26)00589-1. doi: 10.1016/j.cell.2026.05.030.