《生命科学》 2026, 38(8): 1463-1482
罕见病基因治疗研究进展：从技术突破到临床转化
摘 要：
罕见病（rare diseases）单一病种患病率虽低，但全球累计患者规模庞大，其中约80%由单基因遗传缺陷所
致，使其成为基因治疗技术最具可行性和示范意义的优先应用场景，也是医学创新的重要前沿。长期以来，罕见病患者普遍面临诊断延迟、治疗选择匮乏甚至“无药可医”的临床困境。近年来，随着腺相关病毒载体和非病毒递送系统的工程化迭代和成熟，以及治疗策略从基因替代向基因编辑乃至基因组层级重塑的跨越式演进，罕见病治疗范式正由终身对症管理逐步迈向潜在的“一次性治愈”干预。基于当前不断积累的罕见病临床前与临床研究证据，本文系统综述了基因治疗的关键技术图谱；重点分析了治疗策略、递送载体、安全性风险、规模化制造瓶颈以及高昂定价所引发的多维挑战；探讨了基因治疗从“通用型平台化策略”向个体化定制方案并行发展的双轨路径；并阐明了罕见病研究如何通过显著的“科学溢出效应”推动相关技术向常见病治疗领域拓展。总体而言，罕见病基因治疗不仅正在重塑罕见病研究与临床实践本身，也将持续引领医学向精准化和根本性疾病干预的长期目标迈进。
通讯作者：袁慧军 , Email:yuanhj301@wchscu.cn
Abstract:
Rare diseases, though individually infrequent, collectively affect a substantial global population, with approximately 80% of these conditions arising from monogenic defects. This unique genetic architecture makes rare diseases the most viable and paradigmatic application areas for gene therapy, positioning the field at the forefront of modern biomedical innovation. For decades, the rare disease community has faced the daunting reality of delayed diagnosis and a profound lack of disease-modifying treatments, often leaving many patients without effective treatment options. This review aims to systematically delineate the rapid technological evolution in the field and discuss the critical transition from laboratory breakthroughs to successful clinical translation. The manuscript provides a comprehensive mapping of the key technological landscapes, beginning with a detailed categorization of the rapid progression in therapeutic strategies. It discusses thetransition from traditional gene replacement—providing functional copies of defective genes—to precise gene editing using CRISPR-based tools, and even genome-level reprogramming. These advancements are driving a fundamental shift in the treatment paradigm from lifelong symptom management toward potential ″one-time curative″ interventions. Following this, the review evaluates the current state of delivery systems, focusing on the engineering iterations of adeno-associated virus (AAV) vectors optimized for enhanced tissue specificity and reduced immunogenicity, as well as the rising prominence of non-viral platforms such as lipid nanoparticles. Building on these technical foundations, the article systematically summarizes the latest clinical landscape, including approved therapies and promising clinical trial progress across various organ systems, such as hematological, neurological, and neuromuscular disorders, highlighting the real-world impact of these technologies. Beyond technical milestones, the article delves into the multi-dimensional challenges hindering widespread adoption, including complex safety risks like immunogenicity and insertional mutagenesis, the bottlenecks in large-scale GMP manufacturing, and the socio-economic pressures exerted by exorbitant pricing. Based on current clinical evidence, we propose a ″dual-track″ developmental roadmap that advocates for the parallel advancement of ″universal platform-based″ strategies and ″individualized, customized″ solutions for ultra-rare conditions. We also emphasize the ″scientific spillover effect,″ where technological maturity in rare disease research serves as a catalyst for expanding gene therapy into more prevalent chronic conditions. Ultimately, gene therapy is not only reshaping the framework of rare disease research but is also spearheading the global transition toward an era of definitive, precision-based medicine.
Communication Author：YUAN Hui-Jun , Email:yuanhj301@wchscu.cn
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