Background: Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder caused by mutations in the dystrophin gene. LEAPER 2.0 is an RNA editing platform that uses circular ADAR-recruiting RNA (circ-arRNA) to induce exon skipping and restore dystrophin expression. LE051 is an adeno-associated virus (AAV)–delivered circ-arRNA therapy targeting exon 51, potentially applicable to ~13% of patients.
Objectives: To evaluate the safety, pharmacology, and preliminary efficacy of LE051 in preclinical models and in an investigator-initiated trial (IIT).
Results: In a DMD mouse model with exon 50 deletion, a single systemic administration of a surrogate construct (LE051m) induced robust exon skipping, dystrophin restoration, and functional improvement. In wild-type non-human primates, LE051 achieved dose-dependent exon 51 skipping across multiple muscle groups, with no observed toxicity at doses up to 5E13 vg/kg. Across mouse and non-human primate studies, exon-skipping efficiency correlated strongly with vector copy number, reaching nearly 100% at high levels without detectable toxicity, supporting the potential for further efficacy gains with improved delivery.
In the IIT, three boys with DMD received single intravenous doses of 2E13 or 5E13 vg/kg. No dose-limiting toxicities occurred in the first month. All adverse events were Grade 1 and transient, including headache, abdominal pain, nausea, and vomiting. In light of recent concerns about AAV-related liver toxicity, these relatively low doses (2E13–5E13 vg/kg) provide a favorable safety margin. All three patients showed an 8-point increase in North Star Ambulatory Assessment scores at 6 months, which was maintained through the latest follow-up (6–12 months), accompanied by a mean 96-meter gain in the 6-Minute Walk Test. Patients treated at 5E13 vg/kg demonstrated >2% dystrophin protein restoration in muscle biopsies at 8 weeks.
Conclusions: LE051, based on the LEAPER 2.0 RNA editing platform, has shown a favorable safety profile at clinically relevant AAV doses, together with encouraging functional and molecular benefits in boys with DMD. The strong vector copy number–dependent relationship between exposure and exon skipping, combined with a wide preclinical safety window, supports continued dose exploration and optimization of delivery strategies to maximize long-term benefit for patients amenable to exon 51 skipping.