Duchenne muscular dystrophy (DMD) is a progressive and severe genetic muscle disease that occurs due to the inability to functionally produce the dystrophin protein because of mutations in the DMD gene. Dystrophin deficiency causes damage to muscle fibers, leading to a decrease in muscle strength and mobility over time. Although current treatments aim to slow disease progression or alleviate symptoms, they do not directly correct the genetic defect. For this reason, CRISPR-based genome editing approaches are of importance for research targeting the molecular cause of the disease.
In the study by Li et al. published in the journal Cell, an in vivo genome editing approach administered via a single adeno-associated virus (AAV9) vector for DMD was investigated. The researchers used the compact and high-accuracy hfCas12Max nuclease to ensure the system could be delivered within a single vector. Designed together with a guide RNA targeting exon 51, this system aimed to restore the reading frame of the DMD transcript in muscle cells and partially regain dystrophin production.
Within the scope of the research, preclinical experiments were primarily conducted in cell models and humanized DMD mice. Following systemic administration in mice, targeted genome editing, partial dystrophin restoration, and improvement in muscle functions were observed. Genome editing at the target site was also detected in non-human primates, and dose-limiting toxicity was not determined under the tested conditions. Following these results, the therapeutic approach named HG302 was evaluated in a first-in-human, open-label, dose-escalation clinical trial involving four male participants
In the human study, genome editing at a rate of 1.02–4.31% at the DNA level and a quantity of dystrophin protein corresponding to 2.29–3.83% of the normal dystrophin level were detected in muscle biopsies post-treatment. In RNA analyses, editing associated with the restoration of the reading frame was observed in 14.60–18.70% of the transcripts. While reading frame restoration stood out in the majority of edited sequences, no detectable exon skipping events were observed in the study. However, a treatment-related fatal serious adverse event developed in one participant in the high-dose group (1.0 × 10¹⁴ vg/kg), and the participant lost their life. This event was associated with marked complement activation and a systemic cytokine response. The findings highlighted the importance of immune-mediated safety risks in systemic AAV applications.
The study provides early evidence regarding the feasibility of in vivo CRISPR genome editing performed with a single AAV vector at the molecular level in human muscle tissue. However, due to the limited number of participants, the heterogeneity of clinical functional outcomes, and the severe safety issue occurring at the high dose, these findings are insufficient to prove the clinical efficacy of the treatment. While the research represents an important step in the development of genome editing approaches for DMD, it demonstrates that the safe dose range needs to be determined and immune responses must be controlled.
Translated by: Elinsu Ak
Editor:Hazel Birgül
Reference: Li, G., Han, F., Wang, C., Jin, M., Lin, J., Zhang, H., Yan, X., Wang, X., Sun, X., Yuan, Y., Zhang, S., Zhang, S., Zhu, J., Xu, Y., Wang, Y., Deng, Y., Li, F., Shi, L., Luk, A., … Wang, J. (2026). In vivo genome-editing therapy for Duchenne muscular dystrophy: Preclinical studies and first-in-human trial. Cell. https://doi.org/10.1016/j.cell.2026.09.059
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