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. DMD is a prevalent and devastating genetic disorder, impacting approximately 1 in every 3,500-5,000 male births, resulting in a large patient population. DMD is regarded as one of the most challenging diseases in the field of gene therapy. In recent years, AAV-mediated gene therapy and ASO-mediated exon-skipping therapies have advanced and brought hope to some patients. Challenges of gene therapy for DMD are highly limited to delivery, primarily due to the large size of the dystrophin cDNA. In contrast, patients with Becker muscular dystrophy (BMD) have internally-deleted but partially functional dystrophin. As a result, therapeutic strategies focus on generating a dystrophin similar to that in BMD provide a promising avenue for treating DMD. However, ASO-mediated exon-skipping therapies generally require repeated long-term administration and shows limited delivery efficiency in cardiac muscle. For a systemic and progressive disease, achieving broad tissue coverage, long-term efficacy, and a favorable safety profile remains a major challenge.

To address this challenge, the research group led by Prof. Wensheng Wei at Peking University/Changping Laboratory noticed that targeted adenosine-to-inosine (A-to-I) editing at splice regulatory elements can induce exon skipping. Building on this principle, researchers previously developed LEAPER, an RNA editing platform that had been upgraded to LEAPER 2.0. This advanced version uses a circular RNA (circ-arRNA) to recruit endogenous ADAR for A-to-I editing, making it both more efficient and longer lasting. This system significantly improved editing efficiency, duration of action, and editing precision, laying an important foundation for disease treatment. Previous results showed that LEAPER 2.0 achieves durable and safe RNA editing in mice and nonhuman primates when delivered via adeno-associated virus (AAV).

On June 10, 2026, the research team led by Prof. Wensheng Wei at Peking University and Changping Laboratory, in collaboration with Kunming University of Science and Technology and Shanghai Children’s Medical Center (Shanghai Jiao Tong University School of Medicine), published a study in Cell titled “Long-Term Reversal of Duchenne Muscular Dystrophy via Circular arRNA-Guided Exon Skipping in Monkeys and Humans.” The study reports long-term efficacy and safety in DMD non-human primate disease models and patients by RNA exon-skipping therapy. In this study, circ-arRNA regulates splicing of DMD through both ADAR-dependent and ADAR-independent mechanisms, achieving exon 5 and exon 51 skipping—the latter potentially benefiting approximately 13% of DMD patients. Delivered via a muscle-tropic AAV vector in non-human primate models of DMD, circ-arRNA efficiently restored functional dystrophin expression, reversal disease phenotypes, and showed durable safety. In patients, the AAV-circ-arRNA therapy exhibited dose-dependent exon skipping and improved motor and cardiac function, highlighting its translational promise as a safe and long-lasting therapeutic strategy.

In this study, circ-arRNA mediated exon skipping arises from a coordinated interplay between ADAR recruitment, A-to-I editing of splice elements, and steric blockade of spliceosome assembly. This dual-mode mechanism, combining editing-dependent and editing-independent pathways, confers LEAPER 2.0 a unique advantage over conventional ASO-based exon-skipping approaches. This strategy does not directly modify DNA; instead, it re-regulates RNA processing as the cell reads genetic information, thus offering better controllability and the potential to further improve therapeutic safety. Notably, compared with RNA editing strategies that primarily target single-base mutations, exon skipping can cover a broader range of mutation types, including exon deletions, duplications, and other structural variants that disrupt the reading frame, thereby holding wider clinical applicability. In theory, exon skipping is suitable for approximately 80% of DMD patients.

Safety has always been a central concern in the field of gene therapy. Many existing gene-editing technologies require the delivery of exogenous editing proteins into cells, which may trigger immune responses, long-term expression toxicity, and potential off-target effects. By relying on an endogenous protein-based strategy, the LEAPER platform circumvents the introduction of exogenous editing enzymes at the source. The results showed that no treatment-related serious adverse events were observed in either the DMD non-human primate models or in the treated patients, and no immunotoxicity, organ damage, or other systemic safety signals were detected. These findings further support the safety and feasibility of endogenous RNA editing strategies for clinical application. As subsequent clinical studies continue to advance, endogenous RNA editing is poised to become an entirely new therapeutic platform offering both efficacy and safety, providing a new technological option for the treatment of genetic diseases.

The therapy in DMD is an important culmination of nearly a decade of continuous innovation and accumulation in LEAPER technology. In 2019, Wei Wensheng’s team originally developed the LEAPER technology and demonstrated for the first time that programmable RNA editing could be achieved using only the endogenous ADAR protein naturally present in human cells, without the need to introduce any exogenous editing proteins, thereby opening a new technical route distinct from CRISPR-based systems. In 2022, the team further upgraded the technology with a more stable circular RNA architecture and developed LEAPER 2.0. These achievements were successively published in Nature Biotechnology (2019, 2022). Following continuous upgrades since then, the platform has now updated into LEAPER 3.0, as reported concurrently in Cell. Building on this foundation, the team has continued to push technological translation. DMD is an important starting point for the clinical application of RNA editing. In the future, the technology is expected to be extended to the treatment of more genetic diseases, neurological disorders, and metabolic diseases and so on.

Professor Wensheng Wei of Peking University/Changping Laboratory, Professor Yongchang Chen and Professor Weizhi Ji of Kunming University of Science and Technology, and Chief Physician Jiwen Wang of Shanghai Children’s Medical Center (Shanghai Jiao Tong University School of Medicine) are the co-corresponding authors of the paper. Dr. Wenting Guo (Kunming University of Science and Technology), Dr. Huixian Tang (Peking University) and Dr. Zongyi Yi (Peking University, currently an assistant professor at Tsinghua University), PhD student Ting Zhang (Kunming University of Science and Technology), Dr. Pengfei Yuan (Leaper Biotechnology Co., Ltd.) and Attending Physician Cuijin Wang (Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine) are co-first authors. The research was funded by the National Natural Science Foundation of China, the National Key Research and Development Program, the National Science and Technology Major Project (Chronic Non-communicable Disease Prevention and Control Special Project), Changping Laboratory, and the Peking-Tsinghua Center for Life Sciences.

LEAPER-mediated exon skipping: mechanism and therapeutic application in DMD nonhuman primate models and patients

Paper link: https://doi.org/10.1016/j.cell.2026.05.030