In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model.
In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model.
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DOI：
10.1016/j.ymthe.2017.04.003
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发表时间：
2017-08-02
期刊：
影响因子：
--
通讯作者：
Chan JKY
中科院分区：
文献类型：
--
作者：
Mattar CNZ;Gil-Farina I;Rosales C;Johana N;Tan YYW;McIntosh J;Kaeppel C;Waddington SN;Biswas A;Choolani M;Schmidt M;Nathwani AC;Chan JKY
在器官损伤发生之前，在子宫内安全纠正遗传性出血性疾病是非常可取的。在这里，我们报告了长期的转基因表达超过6年，没有毒性后，一个单一的子宫内基因转移（IUGT）在0.9G使用重组腺相关载体（AAV）-人因子IX（hFIX）在非人灵长类动物模型，我们以前描述。监测约74个月的6只给药动物中有4只表达治疗水平的hFIX（3.9%-120.0%）。与AAV 5相比，AAV 8在雄性中的长期表达高6倍，在该阶段几乎完全由随机的全基因组肝前病毒整合介导，没有热点的证据。在表现出慢性低转基因表达的两只动物中评价了无免疫抑制的出生后AAV攻击。引起的短暂中和免疫反应没有不良反应，尽管在给药剂量下表达没有改善，但没有观察到临床毒性。因此，这种长期监测证实了妊娠晚期AAV-hFIX转移的安全性，并表明出生后再给药可以在没有免疫抑制的情况下进行，尽管它需要剂量优化以实现所需的表达。然而，最终的载体遗传毒性和生殖系传播的可能性将需要终身监测和进一步评价治疗动物的生殖功能。Mattar等人提供了来自子宫内AAV-hFIX基因转移的猕猴模型的长期数据，证明了来自通常整合的载体的持续治疗性hFIX表达、在雄性和雌性中的差异功效以及对出生后AAV施用的免疫耐受性，并通过不存在肝毒性和肿瘤发生来确立这种干预的安全性。
The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%–120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots. Post-natal AAV challenge without immunosuppression was evaluated in two animals exhibiting chronic low transgene expression. The brief neutralizing immune reaction elicited had no adverse effect and, although expression was not improved at the dose administered, no clinical toxicity was observed. This long-term surveillance thus confirms the safety of late-gestation AAV-hFIX transfer and demonstrates that postnatal re-administration can be performed without immunosuppression, although it requires dose optimization for the desired expression. Nevertheless, eventual vector genotoxicity and the possibility of germline transmission will require lifelong monitoring and further evaluation of the reproductive function of treated animals. Mattar et al. present long-term data from a macaque model of intrauterine AAV-hFIX gene transfer demonstrating sustained therapeutic hFIX expression from a generally integrated vector, differential efficacy in males and females, and immune tolerance to postnatal AAV administration, and establish the safety of this intervention through an absence of hepatotoxicity and tumorigenesis.
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