First-in-Human AAV-CRISPR Therapy for Duchenne Muscular Dystrophy Shows Editing in Muscle but a Fatal Immune Reaction at the Higher Dose

Preclinical studies and first-in-human trial · CellOctober 31, 2026 · 1 min read · Dr. Abdelmuhsen Abusneina

Schematic: a single AAV9 vector delivers hfCas12Max and a guide RNA to muscle fibers to edit the DMD exon 51 splice donor site, with partial dystrophin restoration reported in biopsies and complement activation and cytokine response reported at the higher dose — The therapy design as described in the abstract and the trial registry (illustration prepared for this brief, not a figure from the paper).

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin, a protein that protects muscle fibers. A group in Shanghai now reports the first human data for a genome-editing therapy for DMD given as a single intravenous dose. Muscle biopsies showed editing and dystrophin, but at the higher dose level one participant had a fatal reaction, and the authors say the findings show a narrow therapeutic window.

Background

DMD is an X-linked disease that begins in early childhood and leads to progressive loss of muscle and function. According to the trial registry, treatment today relies on glucocorticoids, exon-skipping oligonucleotides that restore only small amounts of dystrophin, and an approved AAV gene-replacement therapy that delivers a shortened mini-dystrophin gene. Editing the patient's own DMD gene is a different strategy: the aim is a lasting change in the gene itself.

The therapy

The therapy, called HG302 in the registry, uses a single adeno-associated virus (AAV9) vector that carries the CRISPR system hfCas12Max, designed to edit the splice donor site of DMD exon 51. The first-in-human study (NCT06594094, called MUSCLE) is an open-label, dose-escalation trial at one center in Shanghai. The registry lists boys aged 4 to 8 years with deletions in specific exons, safety over 26 weeks as the primary outcome, and an enrollment of four.

What was found before and in the first trial

In humanized DMD mice, systemic administration produced targeted genome editing, partial dystrophin restoration and improved muscle function. In non-human primates, on-target editing was efficient and no dose-limiting toxicity was identified under the conditions tested. In the human trial, muscle biopsies after treatment gave early molecular evidence of hfCas12Max-mediated editing and detectable dystrophin expression in participants.

Schematic of the evidence reported: humanized DMD mice showed targeted editing, partial dystrophin restoration and improved muscle function; non-human primates showed efficient on-target editing with no dose-limiting toxicity under the conditions tested; the first-in-human trial showed editing and detectable dystrophin in biopsies and, at the higher dose, one treatment-related fatal event — The sequence of evidence as described in the abstract (illustration prepared for this brief, not a figure from the paper).

The safety finding

At the higher dose level, one participant had a treatment-related fatal serious adverse event, characterized by marked complement activation and a systemic cytokine response shortly after dosing. The authors conclude that the work gives initial human proof of concept for muscle genome editing, and that it shows the importance of immune risks and the narrow therapeutic window of systemic AAV-CRISPR therapies. They state that safer dosing and immunomodulation strategies are needed.

What it means

The result shows that editing of muscle after one intravenous dose is possible in people, and that the immune response to high doses of AAV vectors can be dangerous. The abstract names complement activation and a systemic cytokine response as the features of the fatal event.

Keep in mind

The abstract does not give the number of participants treated, the dose values, how much dystrophin was produced, or any change in muscle function, so no judgment about benefit can be made from it. The therapy is investigational and not approved. The authors include employees of HuidaGene Therapeutics, which the registry lists as the sponsor. The abstract does not describe what happened to the trial afterward.

Original paper

Paper: Li G, Han F, Wang C, et al. In vivo genome-editing therapy for Duchenne muscular dystrophy: preclinical studies and first-in-human trial. Cell. 2026. Published October 26, 2026. ClinicalTrials.gov NCT06594094.
Type: Preclinical studies and an open-label first-in-human dose-escalation trial
DOI: 10.1016/j.cell.2026.09.059
PubMed: PMID 42933389
Funding: Sponsor listed in ClinicalTrials.gov: HuidaGene Therapeutics Co., Ltd.; the abstract does not state the funding.

KeywordsCRISPR Gene therapy Clinical trials Duchenne muscular dystrophy AAV vectors

Abdelmuhsen Abusneina, PhDAssociate Professor
Research focus: Molecular Oncology and Cancer Metabolism
Department of Molecular Diagnostics, Faculty of Biomedical Sciences, University of Benghazi, Libya

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