Musolino and colleagues provide a comprehensive review of how gene therapy is being developed for cardiovascular applications, with a special focus on strategies targeting the heart and vasculature. They discuss myocardial gene transfer in the context of heart failure, noting the example of SERCA2a delivery in the CUPID trials, which ultimately failed to show significant benefit on primary or secondary outcomes. Although major safety concerns were not observed, side effects appeared to affect compliance, underscoring the difficulty of translating promising biology into durable clinical impact.

Inherited cardiomyopathies emerge as strong candidates for both traditional gene augmentation or inhibition strategies and for gene editing aimed at correcting causal mutations. The review points to a number of early clinical studies in whichsafety is the main concern, such as those targeting LAMP2B, PKP2, MYBPC3, and RBM20. Together, these examples highlight both the potential of gene-based precision therapies for inherited cardiomyopathies and the need to carefully weigh benefits against risks as the field moves forward.
The potential of gene therapy to stimulate cardiac regeneration is also discussed. Strategies include manipulation of key signaling pathways such as YAP, as well as stymulating cardiomyocyte proliferation through combinational delivery of CDK1, CDK4, cyclin B1, and cyclin D1. Several microRNAs have likewise been tested to promote regenerative responses. However, the activity of these pro-proliferative factors needs careful regulation, since prolonged expression delivered by AAV vectors may trigger hyperproliferation and harmful effects, as demonstrated with AAV6-miR-199a in pig models. Additionally, VEGF-based gene delivery continues to be investigated for its ability to enhance angiogenesis and improve perfusion in ischemic myocardium. The review extends beyond the myocardium to ex vivo vascular gene therapy, mentioning the approach in coronary bypass surgery, where harvested saphenous vein grafts can be genetically modified outside the body with adenovirus carrying TIMP-3to improve graft function before transplantation. Advances in gene editing technologies are presented as another major step forward, with CRISPR-based knockdown of PCSK9 showing durable lipid-lowering effects in preclinical models, and in vivo editing strategies being tested for correcting single-gene vascular disorders.

A prominent, recurring theme of the review is the importance of regulating the expression of therapeutic genes. The authors highlight progress in using tissue-specific promoters to restrict specificity to the heart, as well as inducible systems that enable therapy to be switched on or off according to clinical needs. These strategies are crucial to balancing efficacy with safety in cardiovascular gene therapy.

While questions remain about safety, delivery efficiency, immune responses, and large-scale production, the perspective of the first approved gene therapy medicine for the cardiovascular system seems promising.