The list of successful gene therapy trials using adeno-associated virus (AAV)-based vectors continues to grow and includes a wide range of monogenic diseases. Replication incompetent AAV genomes typically remain episomal and expression dilutes as cells divide and die. Consequently, long-term transgene expression from AAV is best suited for quiescent cell types, such as retinal cells, myocytes, or neurons. For genetic diseases that involve cells with steady turnover, AAV-conferred correction may require routine readministration, where every dose carries the risk of developing an adaptive immune response that renders treatment ineffective. Here, we discuss innovative approaches to permanently modify the host genome using AAV-based platforms, thus potentially requiring only a single dose. Such approaches include using AAV delivery of DNA transposons, homologous recombination templates into safe harbors, and nucleases for targeting integration. In tissues with continual cell turnover, genetic modification of progenitor cell populations will help ensure persistent therapeutic outcomes. Combining the safety profile of AAV-based gene therapy vectors with the ability to integrate a therapeutic transgene creates novel solutions to the challenge of lifelong curative treatments for human genetic diseases.

中文翻译：

---

基于腺相关病毒的基因治疗，用于终身纠正遗传病。


使用腺相关病毒 (AAV) 载体进行的成功基因治疗试验不断增加，其中包括多种单基因疾病。复制不充分的 AAV 基因组通常保持游离状态，并且随着细胞分裂和死亡，表达会减弱。因此，AAV 的长期转基因表达最适合静止细胞类型，例如视网膜细胞、肌细胞或神经元。对于涉及细胞稳定更新的遗传疾病，AAV 赋予的纠正可能需要常规重新给药，其中每次剂量都有产生适应性免疫反应的风险，从而导致治疗无效。在这里，我们讨论使用基于 AAV 的平台永久修改宿主基因组的创新方法，因此可能只需要单剂量。这些方法包括使用 AAV 传递 DNA 转座子、将同源重组模板引入安全港以及使用核酸酶进行靶向整合。在细胞不断更新的组织中，祖细胞群的基因修饰将有助于确保持久的治疗结果。将基于 AAV 的基因治疗载体的安全性与整合治疗性转基因的能力相结合，为人类遗传疾病终身治疗的挑战创造了新的解决方案。