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Background <p>Duchenne muscular dystrophy (DMD) is a&#xa0;severe monogenic hereditary disease with early manifestation and a&#xa0;progressive course. Treatment options have so far been limited. Gene therapy opens up new options for DMD patients.</p> Objectives <p>Against the background of further deaths following DMD gene therapy, the side effects and risks of the gene therapeutics already approved or undergoing clinical trials will be evaluated and alternative gene therapeutics will be described. Based thereon, the future of DMD gene therapy will be discussed.</p> Current data <p>For the first time, in June 2023, delandistrogene moxeparvovec (SRP-9001), a&#xa0;gene replacement therapy based on an adeno-associated virus (AAV) vector, was approved in the USA for children aged 4–5&#xa0;years with DMD. Other promising gene therapies are in preclinical development or clinical trials, including CRISPR/Cas9-mediated strategies to restore dystrophin expression. At least two of a&#xa0;total of five deaths following DMD gene therapy with high-dose AAV vectors in &gt; 1000 patients were attributed to AAV-mediated immune responses. The pre-existing disease underlying the therapy is most likely involved in the fatal toxicity.</p> Conclusions <p>Although gene therapy applications of AAV vectors are generally considered safe, the systemic administration of high vector doses can lead to severe side effects with a&#xa0;potentially fatal outcome in individual patients, especially after activation of the immune system. In the future, new methods for immunosuppression, reduction of AAV dose and alternative vectors will therefore increasingly come to the fore.</p>

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„Wie sicher ist die Gentherapie der Duchenne-Muskeldystrophie? Weitere Todesfälle in klinischen Studien nach Duchenne-Therapie“

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月29日

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  • Stefan Horn,
  • Boris Fehse

摘要

Background

Duchenne muscular dystrophy (DMD) is a severe monogenic hereditary disease with early manifestation and a progressive course. Treatment options have so far been limited. Gene therapy opens up new options for DMD patients.

Objectives

Against the background of further deaths following DMD gene therapy, the side effects and risks of the gene therapeutics already approved or undergoing clinical trials will be evaluated and alternative gene therapeutics will be described. Based thereon, the future of DMD gene therapy will be discussed.

Current data

For the first time, in June 2023, delandistrogene moxeparvovec (SRP-9001), a gene replacement therapy based on an adeno-associated virus (AAV) vector, was approved in the USA for children aged 4–5 years with DMD. Other promising gene therapies are in preclinical development or clinical trials, including CRISPR/Cas9-mediated strategies to restore dystrophin expression. At least two of a total of five deaths following DMD gene therapy with high-dose AAV vectors in > 1000 patients were attributed to AAV-mediated immune responses. The pre-existing disease underlying the therapy is most likely involved in the fatal toxicity.

Conclusions

Although gene therapy applications of AAV vectors are generally considered safe, the systemic administration of high vector doses can lead to severe side effects with a potentially fatal outcome in individual patients, especially after activation of the immune system. In the future, new methods for immunosuppression, reduction of AAV dose and alternative vectors will therefore increasingly come to the fore.