Although recombinant adeno-associated virus serotype 8 (AAV8) and serotype 5 (AAV5) vectors have shown efficacy in Phase 1 clinical trials for gene therapy of hemophilia B, it has become increasingly clear that these serotypes are not optimal for transducing primary human hepatocytes. We have previously reported that among the 10 most commonly used AAV serotypes, AAV serotype 3 (AAV3) vectors are the most efficient in transducing primary human hepatocytes in vitro as well as in “humanized” mice in vivo, and suggested that AAV3 vectors expressing human coagulation factor IX (hFIX) may be a more efficient alternative for clinical gene therapy of hemophilia B. In the present study, we extended these findings to develop an AAV3 vector incorporating a compact yet powerful liver-directed promoter as well as optimized hFIX cDNA sequence inserted between two AAV3 inverted terminal repeats. When packaged into an AAV3 capsid, this vector yields therapeutic levels of hFIX in hemophilia B and in “humanized” mice in vivo. Together, these studies have resulted in an AAV3 vector predicted to achieve clinical efficacy at reduced vector doses, without the need for immune-suppression, for clinical gene therapy of hemophilia B.

中文翻译：

---

用于血友病 B 基因治疗的临床候选 AAV3 载体的开发。

尽管重组腺相关病毒血清型 8 (AAV8) 和血清型 5 (AAV5) 载体已在血友病 B 基因治疗的 1 期临床试验中显示出疗效，但越来越清楚的是，这些血清型对于转导原代人肝细胞并不是最佳选择。我们之前曾报道过，在 10 种最常用的 AAV 血清型中，AAV 血清型 3 (AAV3) 载体在体外和体内“人源化”小鼠中最有效地转导原代人肝细胞，并表明表达人凝血因子 IX (hFIX) 的 AAV3 载体可能是血友病 B 临床基因治疗的更有效替代方案。启动子以及插入两个 AAV3 反向末端重复序列之间的优化 hFIX cDNA 序列。当包装到 AAV3 衣壳中时，该载体在血友病 B 和体内“人源化”小鼠中产生治疗水平的 hFIX 。总之，这些研究产生了一种 AAV3 载体，预计它可以在减少载体剂量的情况下实现临床疗效，而无需免疫抑制，用于血友病 B 的临床基因治疗。