Gene therapy has emerged as a possible treatment for progressive, debilitating Mendelian cardiomyopathies with limited therapeutic options. This paper arises from discussions at the 2023 Cardiovascular Clinical Trialists Forum and highlights several challenges relevant to gene therapy clinical trials, including low prevalence and high phenotypic heterogeneity of Mendelian cardiomyopathies, outcome selection complexities and resulting regulatory uncertainty, and immune responses to the adeno-associated viral vectors that are being used in ongoing studies. Avenues to address these challenges such as natural history studies, external controls, novel regulatory pathways, and immunosuppression are discussed. Relevant cases of recent therapy approvals are highlighted. Ultimately, this work aims to broadly frame discussions on and provide potential future avenues for clinical trial design for rare cardiomyopathy gene therapies.

中文翻译：

---

心肌病基因治疗临床试验设计中的挑战。


基因疗法已成为治疗进行性、使人衰弱的孟德尔心肌病的一种可能治疗方法，但治疗选择有限。本文源于 2023 年心血管临床试验者论坛的讨论，强调了与基因治疗临床试验相关的几个挑战，包括孟德尔心肌病的低患病率和高表型异质性、结果选择复杂性和由此产生的监管不确定性，以及对正在进行的研究中使用的腺相关病毒载体的免疫反应。讨论了应对这些挑战的途径，例如自然史研究、外部控制、新的调节途径和免疫抑制。突出显示了最近治疗批准的相关案例。最终，这项工作旨在广泛构建罕见心肌病基因疗法临床试验设计的讨论，并为未来可能的临床试验设计提供可能的途径。