For the first time, an RNA editing therapy has entered clinical trials for Duchenne muscular dystrophy, and early data suggest it works.
The therapy, called LEAPER 2.0 and delivered as a drug candidate named LE051, uses circular RNAs to recruit the body’s own RNA editing enzymes and skip over disease-causing mutations in the dystrophin gene. In a study published July 9 in Cell (DOI: 10.1016/j.cell.2026.05.030), researchers from Peking University, Kunming University of Science and Technology, and Shanghai Children’s Medical Center report data from both nonhuman primates and a first-in-human trial involving three boys with Duchenne.
The results show dose-dependent exon skipping, detectable dystrophin restoration, and functional improvements that exceeded what the modest protein levels alone would predict.
From Linear to Circular
The LEAPER platform, short for Leveraging Endogenous ADAR for Programmable Editing of RNA, was first described in 2019. The original version used linear RNAs to recruit ADAR enzymes, which convert adenosine to inosine in target messenger RNA. The ribosome reads inosine as guanosine, effectively altering splice signals and inducing exon skipping.
The 2.0 version introduces a critical structural change: the recruiting RNA is circularized. Circular RNAs resist exonuclease degradation, giving them far greater stability inside cells. The result is approximately three times higher editing efficiency than the linear predecessor, with lower off-target editing. Moreover, the circular RNAs appear to work through a dual mechanism, both ADAR-dependent editing of splice regulatory elements and ADAR-independent physical blocking of spliceosome assembly.
“We found that the circular structure not only lasts longer but also engages the spliceosome in a different way,” said corresponding author Professor Wensheng Wei of Peking University’s Biomedical Pioneering Innovation Center. “This dual mechanism may explain why even modest editing levels produce disproportionate functional benefit.”
Nonhuman Primate Data: Single Dose, 18 Months of Benefit
The researchers first tested LE051, targeting exon 51 of the dystrophin gene, applicable to roughly 13% of Duchenne patients, in a nonhuman primate model carrying a 7-base-pair deletion in exon 50. A single intravenous dose delivered via MyoAAV 4E, a muscle-tropic AAV capsid variant, produced exon-skipping rates of 31% in quadriceps and 62% in triceps at eight weeks.
Dystrophin protein reached approximately 3-7% of wild-type levels in muscle tissue, below the 15-20% threshold typically considered necessary for meaningful clinical benefit, yet motor improvements persisted for at least 18 months. Walking distance increased, gait improved, and the animals rose from prone and supine positions more quickly. No anti-dystrophin immune response was detected, a key advantage over AAV microdystrophin gene therapies, which have triggered immune reactions in some patients.
First-in-Human Data: Three Boys, Early Functional Gains
The first-in-human trial (NCT06900049), an investigator-initiated study at Shanghai Children’s Medical Center, enrolled three boys aged 4 to 8 with Duchenne and mutations amenable to exon 51 skipping. Two received a low dose of 2 x 10^13 vector genomes per kilogram; the third received a higher dose of 5 x 10^13 vg/kg.
At eight weeks, muscle biopsy from the high-dose patient showed more than 2% dystrophin restoration by mass spectrometry. Both low-dose patients showed exon skipping at lower levels. No dose-limiting toxicities occurred. All adverse events were Grade 1 and transient, headache, abdominal pain, nausea, vomiting, with no clinically significant liver enzyme elevations.
Functionally, the results were striking. All three patients showed an 8-point improvement on the North Star Ambulatory Assessment (NSAA) at six months, with two reaching the maximum score. Gains were maintained through 6 to 12 months of follow-up. The six-minute walk test improved by a mean of 96 meters. In the high-dose patient, creatine kinase levels, a marker of muscle damage, dropped by 60%. Early improvements in cardiopulmonary function (forced vital capacity, peak VO2) were also noted.
“The functional improvement is disproportionate to the level of dystrophin restoration we detected in bulk tissue,” said Dr. Jiwen Wang of Shanghai Children’s Medical Center, the trial’s principal investigator. “This may reflect heterogeneous expression, small clusters of muscle fibers with higher dystrophin levels driving functional rescue.”
A Competitive Landscape
LEAPER 2.0 enters a crowded Duchenne therapeutic field. Antisense oligonucleotides such as eteplirsen and casimersen require weekly intravenous infusions and produce modest benefit at best. AAV-based microdystrophin gene therapies deliver a truncated dystrophin gene but have been complicated by anti-dystrophin immune responses and a cap on the size of the expressed protein. CRISPR-based approaches carry concerns about off-target DNA edits and immunogenicity from bacterial nucleases.
LEAPER 2.0 avoids several of these pitfalls. Because it relies on endogenous ADAR enzymes, no foreign protein is delivered, reducing immunogenicity. The circular RNA cargo is smaller than the full dystrophin coding sequence, allowing efficient AAV packaging. And because the therapy edits RNA rather than DNA, any unintended effects are transient.
Path Forward
The ongoing phase 1 trial is enrolling up to 12 patients total, with expected completion in December 2026. The Cell paper explicitly discusses expansion to other exons and the development of combination arRNAs that could skip multiple exons simultaneously, suggesting a pipeline of follow-on candidates.
But the small sample size, three patients, and the modest dystrophin restoration levels mean these early functional gains will need to be replicated in larger, controlled trials. The durability beyond 12 months in humans also remains unknown, though the NHP data out to 18 months is encouraging. Approximately 87% of Duchenne patients have mutations not amenable to exon 51 skipping, requiring the development of additional LEAPER candidates targeting other exons.
Leaper Bio Inc., the Beijing-based spinout commercializing the platform, has not yet disclosed formal phase 2 or phase 3 development plans, but the authors note that exon-skipping efficiency correlated nearly perfectly with vector copy number, reaching nearly 100% at high levels without toxicity, suggesting room for further gains with optimized dosing or improved AAV capsids.
Source: Guo, W., Tang, H., Yi, Z. et al. “Long-term reversal of Duchenne muscular dystrophy via circular arRNA-guided exon skipping in monkeys and humans.” Cell 189(14), 4377-4395.e20 (2026). DOI: 10.1016/j.cell.2026.05.030
Clinical trial: NCT06900049, “Evaluation of the Safety, Tolerability, and Efficacy of LE051 in Patients with Duchenne Muscular Dystrophy”