Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice.
Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice.
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DOI：
10.1097/nen.0b013e3181f530ec
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发表时间：
2010-10
影响因子：
3.2
通讯作者：
Messer A
中科院分区：
文献类型：
--
作者：
Snyder-Keller A;McLear JA;Hathorn T;Messer A
亨廷顿病（HD）是由突变亨廷顿蛋白（mhtt）中多聚谷氨酰胺序列的扩增引起的进行性神经变性疾病，其产生异常折叠和聚集，导致核和细胞质神经元包涵体的形成。尽管mhtt聚集体在发病机制中的确切作用尚不清楚，但减少mhtt蛋白积累的尝试已改善了多种细胞和体内HD模型中的表型。在这里，我们提供了关键的结果，颅内输送单链抗体，C4，其目标的前17个氨基酸的htt蛋白，一个区域的httExon 1，越来越多地被认为是关键。为了评估长期疗效和安全性问题，我们使用腺相关病毒载体（AAV 2/1）将胞内抗体基因递送至近交系B6.HDR6/1小鼠的纹状体。在疾病的各个阶段开始治疗表明，早期治疗保留了最大数量的细胞，没有核聚集体，聚集物质的积累可以延迟几个月。即使直到临床疾病阶段才开始胞内抗体治疗，也观察到了显著的（尽管较小）效应。这些数据表明，针对关键N-末端表位的神经元胞内抗体可以使用AAV 2/1安全有效地递送，以在该HD模型中在持续的时间段内延迟聚集表型，即使在疾病发作后开始递送。
Huntington disease (HD) is a progressive neurodegenerative disease caused by an expansion of a polyglutamine sequence in mutant huntingtin (mhtt) that produces abnormal folding and aggregation that results in the formation of nuclear and cytoplasmic neuronal inclusion bodies. Although the precise role of mhtt aggregates in the pathogenesis is unclear, attempts to reduce accumulated mhtt protein have ameliorated the phenotype in multiple cellular and in vivo HD models. Here, we provide critical results on intracranial delivery of a single-chain Fv intrabody, C4, which targets the first 17 amino acids of the htt protein, a region of httExon1 that is increasingly being recognized as pivotal. To assess long-term efficacy and safety issues, we used adeno-associated viral vectors (AAV2/1) to deliver intrabody genes to striatum of inbred B6.HDR6/1 mice. Treatment initiation at various stages of the disease showed that early treatment preserved the largest number of cells without nuclear aggregates and that the accumulation of aggregated material could be delayed by several months. Even when intrabody treatment was not initiated until the clinical disease stage, significant, albeit smaller, effects were seen. These data indicate that neuronal intrabodies against critical N-terminal epitopes can be safely and effectively delivered using AAV2/1 to delay the aggregation phenotype over a sustained period of time in this HD model, even when delivery is initiated after disease onset.