CRISPR/AAV-Mediated Gene Therapy for Cardiovascular and Neuromuscular Disorders: From Bench to Bedside

Cardiovascular and neuromuscular disorders represent some of the most burdensome genetic diseases worldwide, with limited curative options and significant unmet clinical need. The combination of CRISPR/Cas-based gene editing and adeno-associated virus (AAV) delivery has emerged as one of the most promising therapeutic platforms for these conditions, offering the potential for durable, tissue-specific correction of pathogenic mutations. Beyond correcting pathogenic mutations, these platforms are increasingly relevant to spinal cord injury, neural regeneration, neuromuscular repair, and translational regenerative medicine, where restoring tissue function is as important as fixing the underlying genetic defect. However, the path from proof-of-concept editing in cell and animal models to safe, scalable clinical application remains complex and incompletely understood.Key challenges include achieving efficient in vivo homology-directed repair (HDR) in post-mitotic cells such as cardiomyocytes and skeletal muscle fibres, engineering AAV capsids with selective tropism for cardiac, neural, and neuromuscular tissue, and controlling transgene expression with sufficient precision to avoid toxicity or immune activation. Advances in promoter engineering, including enhancer-controlled and microRNA-mediated detargeting strategies, are beginning to address the tissue-specificity problem, while optimized HDR templates and delivery regimens are improving editing outcomes in vivo. Parallel progress in base editing and prime editing now offers alternatives to classical HDR for correcting point mutations associated with cardiomyopathies and muscular dystrophies.Despite these advances, critical translational gaps remain. The immunogenicity of AAV capsids and CRISPR components, the durability of editing in dividing and non-dividing tissues, the scalability of manufacturing, and the safety profile of off-target edits all require rigorous investigation before broad clinical deployment. Bridging the distance between experimental models and first-in-human trials demands integrated efforts across molecular engineering, preclinical disease modelling, regenerative medicine, and clinical translation.This Research Topic invites original research, reviews, methods articles, and perspectives addressing the application of CRISPR/Cas and AAV systems to cardiovascular and neuromuscular genetic disease, including regenerative and repair-focused approaches. We welcome contributions covering, but not limited to, the following themes:- In vivo CRISPR editing in cardiac and skeletal muscle: Strategies to enhance HDR, base editing, and prime editing efficiency in post-mitotic cells, including cardiomyocytes and muscle fibres.- AAV vector engineering for tissue-specific delivery: Design of novel capsids, synthetic promoters, enhancer-controlled expression systems, and microRNA-mediated detargeting approaches for cardiac, neural, and neuromuscular tropism.- Gene therapy for cardiomyopathies and heart failure: Preclinical and translational studies targeting genetic drivers of dilated, hypertrophic, or arrhythmogenic cardiomyopathy and heart failure with reduced ejection fraction.- CRISPR/AAV approaches for muscular dystrophies: Correction of Duchenne and Becker muscular dystrophy mutations via exon skipping, HDR-mediated integration, or regulatory element targeting.- Spinal cord injury and neural regeneration: CRISPR/Cas and AAV strategies to promote axonal regeneration and restore neural circuitry after injury.- Neuromuscular repair and translational regenerative medicine: Gene editing and delivery approaches supporting neuromuscular reconnection and tissue-level functional recovery, including preclinical-to-clinical translation.- Immunogenicity and safety: Host immune responses to AAV serotypes and CRISPR components, off-target editing assessment, and strategies to improve the safety profile of in vivo therapies.- Scalability and manufacturing: Advances in AAV production, purification, and formulation relevant to clinical-grade gene therapy programmes.- First-in-human and early-phase clinical studies: Outcomes, lessons, and design considerations from clinical trials of CRISPR or AAV-based therapies in cardiac and neuromuscular indications. Topic editors: Yanjiang Zheng, Hao Zhong Source: https://www.frontiersin.org/research-topics/83691/crispraav-mediated-gene-therapy-for-cardiovascular-and-neuromuscular-disorders-from-bench-to-bedside