2012年11月7日 訊 /生物谷BIOON/ --亨廷頓氏病是一種遺傳性神經(jīng)退行性疾病，能導(dǎo)致不協(xié)調(diào)的肢體動作和認(rèn)知能力下降,。在最近發(fā)表在PNAS雜志上的一項研究中,，西班牙研究人員成功地減少了亨廷頓氏病突變基因的染色體表達(dá)，抑制了亨廷頓氏病的發(fā)展,。
研究人員表示成年人特別需要亨廷頓蛋白,，亨廷頓蛋白位于人體不同組織，能確保神經(jīng)元的發(fā)育和生存,。突變基因?qū)е潞嗤㈩D蛋白以異常形式存在,。
當(dāng)發(fā)生這種情況時，身體出現(xiàn)不自主的動作,、老年癡呆癥等一些癥狀,。目前，沒有人能夠找到治療亨廷頓氏病的有效方式,。目前的治療手段以減輕患者的疼痛和不適,，但大多數(shù)患者在第一次癥狀出現(xiàn)后的約15年后會死亡,。科學(xué)家們已經(jīng)知道,，一個基因是誘發(fā)亨廷頓氏病的主要原因,，這一基因不是其他神經(jīng)系統(tǒng)疾病如帕金森或老年癡呆癥的主要致病基因。
因此,，研究人員希望制定出一個抑制突變的亨廷頓基因的治療方式來治療亨廷頓氏病,。目前該研究集中在修改鋅指蛋白（ZFP）上，這一蛋白有能力識別并結(jié)合特定DNA序列,。應(yīng)用這種治療方法時,，攜帶亨廷頓基因突變的轉(zhuǎn)基因小鼠模型，遲發(fā)性癥狀被延遲,。 該研究的作者之一Agustín Pavón說：下一步是進(jìn)行優(yōu)化設(shè)計,，希望能有效和持久的治療患者。（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.
