Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI.
Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI.
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DOI：
10.1016/j.omtm.2017.07.004
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Auricchio A
中科院分区：
文献类型：
--
作者：
Ferla R;Alliegro M;Marteau JB;Dell'Anno M;Nusco E;Pouillot S;Galimberti S;Valsecchi MG;Zuliani V;Auricchio A
用腺相关病毒（AAV）载体进行体内基因治疗是安全有效的。我们最近证明，aav8介导的肝脏基因转移在粘多糖病VI型（MPS VI）动物模型中是有效的，粘多糖病是一种罕见的溶酶体积存病，由芳香基磺化酶B （ARSB）缺乏引起。在准备首次人体试验时，我们进行了非临床研究，以评估静脉给药AAV2/8.TBG的安全性。在良好的生产规范条件下生产。在aav处理的小鼠中，除了雌性丙氨酸转氨酶短暂增加和甲状腺上皮肥大外，未观察到毒性。AAV2/8.TBG。hARSB的生物分布和表达证实肝脏是感染和转导的主要部位。脱落和繁殖研究表明，水平传播和种系传播的风险很小。在MPS VI小鼠中进行了AAV剂量反应研究，以确定临床研究中使用的剂量范围。总的来说，这些数据支持AAV2/8.TBG的非临床安全性和有效性。为基于血管内输注AAV8治疗MPS VI患者的I/II期临床试验铺平道路。
In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.TBG.hARSB produced under good manufacturing practice-like conditions. No toxicity was observed in AAV-treated mice, except for a transient increase in alanine aminotransferase in females and thyroid epithelial hypertrophy. AAV2/8.TBG.hARSB biodistribution and expression confirmed the liver as the main site of both infection and transduction. Shedding and breeding studies suggest that the risk of both horizontal and germline transmission is minimal. An AAV dose-response study in MPS VI mice was performed to define the range of doses to be used in the clinical study. Overall, these data support the non-clinical safety and efficacy of AAV2/8.TBG.hARSB and pave the way for a phase I/II clinical trial based on intravascular infusions of AAV8 in patients with MPS VI.
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