An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models.
An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models.
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DOI：
10.1038/mtm.2014.44
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发表时间：
2014
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--
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中科院分区：
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Friedreich 共济失调 (FRDA) 是一种遗传性疾病，由 frataxin 基因内含子 1 中的 GAA 三核苷酸重复增加所致。该突变导致 frataxin 表达减少。我们生产了一种编码人 frataxin (AAV9-hFXN) 的腺相关病毒 (AAV)9。这种 AAV 通过腹膜内 (IP) 注射到年轻的条件性基因敲除小鼠体内，这些小鼠在胚胎发生过程中某些组织中的 frataxin 基因已被敲除，方法是将其与在肌肉肌酸激酶 (MCK) 或神经元特异性烯醇化酶 (NSE) 启动子下表达 Cre 重组酶基因的小鼠进行繁殖。在研究的第一部分中，从 6 × 1011 v.p. 开始测试不同剂量的病毒。至 6 × 109 v.p.在 NSE-cre 小鼠中，所有这些都导致小鼠寿命的延长。较高和较低剂量也在 MCK-cre 小鼠中进行了测试。以 6 × 1011 v.p 的单次施用 AAV9-hFXN。这些小鼠的寿命延长了一倍多。事实上，用 AAV9-hFXN 治疗的 MCK-cre 小鼠在 29 周龄时被处死以进行进一步的分子研究，没有明显症状。心脏功能的回波描记分析清楚地表明，接受 6 × 1011 v.p. 的小鼠的心脏收缩功能得到了更好的保存。 AAV9-hFXN。在两种小鼠模型中，使用较高剂量的病毒，通过 ELISA 在心脏、大脑、肌肉、肾脏和肝脏中检测到人 frataxin 蛋白。因此，使用 AAV9-hFXN 进行基因治疗是 FRDA 的潜在治疗方法。
Friedreich ataxia (FRDA) is a genetic disease due to increased repeats of the GAA trinucleotide in intron 1 of the frataxin gene. This mutation leads to a reduced expression of frataxin. We have produced an adeno-associated virus (AAV)9 coding for human frataxin (AAV9-hFXN). This AAV was delivered by intraperitoneal (IP) injection to young conditionally knockout mice in which the frataxin gene had been knocked-out in some tissues during embryogenesis by breeding them with mice expressing the Cre recombinase gene under the muscle creatine kinase (MCK) or the neuron-specific enolase (NSE) promoter. In the first part of the study, different doses of virus were tested from 6 × 1011 v.p. to 6 × 109 v.p. in NSE-cre mice and all leading to an increase in life spent of the mice. The higher and the lower dose were also tested in MCK-cre mice. A single administration of the AAV9-hFXN at 6 × 1011 v.p. more than doubled the life of these mice. In fact the MCK-cre mice treated with the AAV9-hFXN were sacrificed for further molecular investigations at the age of 29 weeks without apparent symptoms. Echography analysis of the heart function clearly indicated that the cardiac systolic function was better preserved in the mice that received 6 × 1011 v.p. of AAV9-hFXN. The human frataxin protein was detected by ELISA in the heart, brain, muscles, kidney, and liver with the higher dose of virus in both mouse models. Thus, gene therapy with an AAV9-hFXN is a potential treatment of FRDA.
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