Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum.
Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum.
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DOI：
10.1093/brain/awr333
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Kaemmerer WF
中科院分区：
文献类型：
--
作者：
Grondin R;Kaytor MD;Ai Y;Nelson PT;Thakker DR;Heisel J;Weatherspoon MR;Blum JL;Burright EN;Zhang Z;Kaemmerer WF
亨廷顿病是由一种突变形式的亨廷顿蛋白表达引起的，该蛋白含有一个扩展的多谷氨酰胺重复序列。亨廷顿病的一种可能的治疗方法可能是通过RNA干扰减少突变的亨廷顿蛋白在大脑中的表达。除非治疗分子被设计成等位基因特异性的，否则野生型和突变蛋白都将被RNA干扰治疗抑制。一个关键的问题是，在目标大脑区域抑制野生型和突变型Huntingtin是否可以容忍，并为亨廷顿病患者带来净收益。亨廷顿是否在成人大脑中发挥必要的功能尚不清楚。在这里，我们测试了一种假设，即成年灵长类动物的大脑可以在较长一段时间内耐受适度降低的野生型Huntingtin蛋白水平。将编码针对恒河猴亨廷顿蛋白信使RNA的短发夹状RNA的2型腺相关病毒载体(活性载体)注射到4只成年恒河猴的双侧纹状体内。另外四只动物获得了编码扰乱的对照短发夹状RNA(对照载体)的可比载体。观察6个月的一般健康状况和运动行为。终止实验后，对脑组织进行盲法检测：(I)Huntingtin信使RNA基因敲除；(Ii)Huntingtin蛋白表达；(Iii)神经病理改变。注射6个月后，主动载体接受者的纹状体内野生型亨廷顿蛋白信使核糖核酸水平平均下降了∼30%。免疫组织化学也观察到这些动物体内亨廷顿蛋白水平的普遍降低，通过免疫印迹分析，主动载体受体的壳核中的∼蛋白平均比对照减少了45%。与对照载体受体一样，在行为上没有观察到不良反应，在主动载体受体的组织学检查中也没有发现神经变性。我们的结果表明，长期部分抑制野生型Huntingtin可能是安全的，因此，如果对突变Huntingtin的抑制水平相同是有益的，那么部分抑制野生型和突变Huntingtin可能会导致杂合型亨廷顿病患者的净收益。
Huntington's disease is caused by expression of a mutant form of Huntingtin protein containing an expanded polyglutamine repeat. One possible treatment for Huntington's disease may be to reduce expression of mutant Huntingtin in the brain via RNA interference. Unless the therapeutic molecule is designed to be allele-specific, both wild-type and mutant protein will be suppressed by an RNA interference treatment. A key question is whether suppression of wild-type as well as mutant Huntingtin in targeted brain regions can be tolerated and result in a net benefit to patients with Huntington's disease. Whether Huntingtin performs essential functions in the adult brain is unclear. Here, we tested the hypothesis that the adult primate brain can tolerate moderately reduced levels of wild-type Huntingtin protein for an extended period of time. A serotype 2 adeno-associated viral vector encoding for a short hairpin RNA targeting rhesus huntingtin messenger RNA (active vector) was bilaterally injected into the striatum of four adult rhesus monkeys. Four additional animals received a comparable vector encoding a scrambled control short hairpin RNA (control vector). General health and motor behaviour were monitored for 6 months. Upon termination, brain tissues were sampled and assessed blindly for (i) huntingtin messenger RNA knockdown; (ii) Huntingtin protein expression; and (iii) neuropathological changes. Reduction in wild-type huntingtin messenger RNA levels averaging ∼30% was measured in the striatum of active vector recipients 6 months post-injection. A widespread reduction in Huntingtin protein levels was also observed by immunohistochemistry in these animals, with an average protein reduction of ∼45% relative to controls measured by western blot analysis in the putamen of active vector recipients. As with control vector recipients, no adverse effects were observed behaviourally, and no neurodegeneration was found on histological examination of active vector recipients. Our results suggest that long-term partial suppression of wild-type Huntingtin may be safe, and thus if a comparable level of suppression of mutant Huntingtin is beneficial, then partial suppression of both wild-type and mutant Huntingtin may result in a net benefit in patients with heterozygous Huntington's disease.
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影响因子：
4.2
作者：
Walton, Ashley;Scheib, Jami L.;Grondin, Richard
通讯作者：
Grondin, Richard
影响因子：
3.5
作者：
Tenenbaum, L;Chtarto, A;Levivier, M
通讯作者：
Levivier, M
影响因子：
2.9
作者：
Andersen, AH;Zhang, ZM;Avison, MJ
通讯作者：
Avison, MJ
影响因子：
5.1
作者：
McCarty, DM;Fu, H;Samulski, RJ
通讯作者：
Samulski, RJ
影响因子：
5.3
作者：
Lombardi, Maria Stella;Jaspers, Leonie;Kaemmerer, William F.
通讯作者：
Kaemmerer, William F.