Cardiovascular disease remains the foremost cause of morbidity and mortality globally, affecting millions of individuals. Recent discoveries illuminate the substantial role of genetics in cardiovascular disease pathogenesis, encompassing both monogenic and polygenic mechanisms and identifying tangible targets for gene therapies. Innovative strategies have emerged to rectify pathogenic variants that cause monogenic disorders such as hypertrophic, dilated, and arrhythmogenic cardiomyopathies and hypercholesterolemia. These include delivery of exogenous genes to supplement insufficient protein levels caused by pathogenic variants or genome editing to correct, delete, or modify mutant sequences to restore protein function. However, effective delivery of gene therapy to specified cells presents formidable challenges. Viral vectors, notably adeno-associated viruses and nonviral vectors such as lipid and engineered nanoparticles, offer distinct advantages and limitations. Additional risks and obstacles remain, including treatment durability, tissue-specific targeting, vector-associated adverse events, and off-target effects. Addressing these challenges is an ongoing imperative; several clinical gene therapy trials are underway, and many more first-in-human studies are anticipated. This science advisory reviews core concepts of gene therapy, key obstacles, patient risks, and ongoing research endeavors to enable clinicians to understand the complex landscape of this emerging therapy and its remarkable therapeutic potential to benefit cardiovascular disease.

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心血管疾病的基因治疗：科学的最新进展和未来方向：来自美国心脏协会的科学咨询。


心血管疾病仍然是全球发病率和死亡率的首要原因，影响着数百万人。最近的发现阐明了遗传学在心血管疾病发病机制中的重要作用，包括单基因和多基因机制，并确定了基因治疗的有形靶点。已经出现了创新策略来纠正导致单基因疾病的致病性变异，例如肥厚、扩张和致心律失常性心肌病和高胆固醇血症。这些包括递送外源基因以补充由致病性变异引起的蛋白质水平不足，或进行基因组编辑以纠正、删除或修改突变序列以恢复蛋白质功能。然而，将基因疗法有效地递送到特定细胞带来了艰巨的挑战。病毒载体，特别是腺相关病毒和非病毒载体，如脂质和工程纳米颗粒，具有明显的优势和局限性。其他风险和障碍仍然存在，包括治疗持久性、组织特异性靶向、媒介相关不良事件和脱靶效应。应对这些挑战是一项持续的当务之急;几项临床基因治疗试验正在进行中，预计还会有更多首次人体研究。该科学咨询回顾了基因治疗的核心概念、主要障碍、患者风险和正在进行的研究工作，使临床医生能够了解这种新兴疗法的复杂情况及其造福心血管疾病的非凡治疗潜力。