2012年11月7日 讯 /生物谷BIOON/ --亨廷顿氏病是一种遗传性神经退行性疾病,能导致不协调的肢体动作和认知能力下降。在最近发表在PNAS杂志上的一项研究中,西班牙研究人员成功地减少了亨廷顿氏病突变基因的染色体表达,抑制了亨廷顿氏病的发展。
研究人员表示成年人特别需要亨廷顿蛋白,亨廷顿蛋白位于人体不同组织,能确保神经元的发育和生存。突变基因导致亨廷顿蛋白以异常形式存在。
当发生这种情况时,身体出现不自主的动作、老年痴呆症等一些症状。目前,没有人能够找到治疗亨廷顿氏病的有效方式。目前的治疗手段以减轻患者的疼痛和不适,但大多数患者在第一次症状出现后的约15年后会死亡。科学家们已经知道,一个基因是诱发亨廷顿氏病的主要原因,这一基因不是其他神经系统疾病如帕金森或老年痴呆症的主要致病基因。
因此,研究人员希望制定出一个抑制突变的亨廷顿基因的治疗方式来治疗亨廷顿氏病。目前该研究集中在修改锌指蛋白(ZFP)上,这一蛋白有能力识别并结合特定DNA序列。应用这种治疗方法时,携带亨廷顿基因突变的转基因小鼠模型,迟发性症状被延迟。 该研究的作者之一Agustín Pavón说:下一步是进行优化设计,希望能有效和持久的治疗患者。(生物谷:Bioon.com)
doi:10.1073/pnas.1206506109
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'Synthetic zinc finger repressors reduce mutant Huntingtin expression in the brain of R6/2 mice'
Garriga-Canut, M., et al.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (HTT) gene. Although several palliative treatments are available, there is currently no cure and patients generally die 10–15 y after diagnosis. Several promising approaches for HD therapy are currently in development, including RNAi and antisense analogs. We developed a complementary strategy to test repression of mutant HTT with zinc finger proteins (ZFPs) in an HD model. We tested a “molecular tape measure” approach, using long artificial ZFP chains, designed to bind longer CAG repeats more strongly than shorter repeats. After optimization, stable ZFP expression in a model HD cell line reduced chromosomal expression of the mutant gene at both the protein and mRNA levels (95% and 78% reduction, respectively). This was achieved chromosomally in the context of endogenous mouse HTT genes, with variable CAG-repeat lengths. Shorter wild-type alleles, other genomic CAG-repeat genes, and neighboring genes were unaffected. In vivo, striatal adeno-associated virus viral delivery in R6/2 mice was efficient and revealed dose-dependent repression of mutant HTT in the brain (up to 60%). Furthermore, zinc finger repression was tested at several levels, resulting in protein aggregate reduction, reduced decline in rotarod performance, and alleviation of clasping in R6/2 mice, establishing a proof-of-principle for synthetic transcription factor repressors in the brain.