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：

---

用于终生纠正遗传疾病的腺相关病毒基因治疗。

使用基于腺相关病毒 (AAV) 的载体的成功基因治疗试验的名单不断增加，包括广泛的单基因疾病。无法复制的 AAV 基因组通常保持游离状态，并且随着细胞分裂和死亡，表达会稀释。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。对于涉及具有稳定更新的细胞的遗传疾病，AAV 赋予的校正可能需要常规再给药，其中每剂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，我们讨论了使用基于 AAV 的平台永久修改宿主基因组的创新方法，因此可能只需要一次剂量。这些方法包括使用 AAV 递送 DNA 转座子，同源重组模板进入安全港，以及用于靶向整合的核酸酶。在细胞持续更新的组织中，祖细胞群的遗传修饰将有助于确保持久的治疗效果。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，为人类遗传疾病终生治愈性治疗的挑战创造了新的解决方案。