Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B
Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B
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DOI：
10.1016/j.ymthe.2020.06.001
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发表时间：
2020-09-02
影响因子：
12.4
通讯作者：
High, Katherine A.
中科院分区：
文献类型：
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作者：
George, Lindsey A.;Ragni, Margaret, V;High, Katherine A.
腺相关病毒（AAV）载体是用于单基因和复杂获得性疾病的基于基因的疗法的领先平台。AAV基因转移的成功强调了需要回答安全性、耐久性和人类对AAV载体的免疫应答的性质等突出的临床问题。在这里，我们提出了纵向随访数据的受试者谁参加了第一次试验的系统交付的AAV载体。患有重度血友病B的成年男性（n = 7）接受剂量范围为8 × 10（10）至2 × 10（12）vg/kg的AAV 2载体，以靶向凝血因子IX的肝细胞特异性表达;在载体施用后对亚组（n = 4）进行12-15年的随访。未观察到重大安全性问题。通过肝转氨酶值、血清甲胎蛋白和肝脏超声评估，没有证据表明存在持续肝毒性或肝细胞癌。在随访期间，受试者对输注的AAV血清型2（AAV 2）以及所有其他测试的AAV血清型（AAV 5和AAV 8）表现出持续增加的AAV中和抗体（NAb）。这些数据代表接受血管内AAV的受试者的最长可用纵向随访数据，并支持在成人中以测试剂量进行血管内AAV施用的初步安全性。数据首次证明了AAV载体给药后高滴度、多血清型交叉反应性AAV NAb的持续性长达15年。我们的观察结果广泛适用于AAV介导的基因治疗的发展。
Adeno-associated virus (AAV) vectors are a leading platform for gene-based therapies for both monogenic and complex acquired disorders. The success of AAV gene transfer highlights the need to answer outstanding clinical questions of safety, durability, and the nature of the human immune response to AAV vectors. Here, we present longitudinal follow-up data of subjects who participated in the first trial of a systemically delivered AAV vector. Adult males (n = 7) with severe hemophilia B received an AAV2 vector at doses ranging from 8 x 10(10) to 2 x 10(12) vg/kg to target hepatocyte-specific expression of coagulation factor IX; a subset (n = 4) was followed for 12-15 years post-vector administration. No major safety concerns were observed. There was no evidence of sustained hepatic toxicity or development of hepatocellular carcinoma as assessed by liver transaminase values, serum alpha-fetoprotein, and liver ultrasound. Subjects demonstrated persistent, increased AAV neutralizing antibodies (NAbs) to the infused AAV serotype 2 (AAV2) as well as all other AAV serotypes tested (AAV5 and AAV8) for the duration of follow-up. These data represent the longest available longitudinal follow-up data of subjects who received intravascular AAV and support the preliminary safety of intravascular AAV administration at the doses tested in adults. Data demonstrate, for the first time, the persistence of high-titer, multi-serotype cross-reactive AAV NAbs for up to 15 years postAAV vector administration. Our observations are broadly applicable to the development of AAV-mediated gene therapy.