RNAi mechanisms in Huntington's disease therapy: siRNA versus shRNA.
RNAi mechanisms in Huntington's disease therapy: siRNA versus shRNA.
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DOI：
10.1186/s40035-017-0101-9
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发表时间：
2017
影响因子：
12.6
通讯作者：
Cortese FAB
中科院分区：
文献类型：
--
作者：
Aguiar S;van der Gaag B;Cortese FAB
亨廷顿病（HD）是由亨廷顿（HTT）基因内的CAG重复超过正常范围（> 36个CAG）引起的遗传显性三核苷酸重复病症。这种疾病的症状表现在中年，包括舞蹈病，肌张力障碍和认知能力下降。从诊断到死亡的典型潜伏期为20年。目前尚无可用于HD患者的疾病缓解疗法。RNAi是一种潜在的治疗HD的方法。一种流行的研究路线采用siRNA或反义寡核苷酸（阿索）来敲低突变亨廷顿蛋白mRNA（mHTT）。不幸的是，这种方式需要重复给药，通常表现出脱靶效应（OTE），并产生肾脏和肝脏毒性。相比之下，单个AAV介导的短发夹RNA（shRNA）剂量可以持续数年，毒性低。此外，我们强调的研究表明，当进行头对头测试时，shRNA比siRNA产生更少的OTE。尽管有这样的前景，但shRNA治疗由于难以控制表达（RNA构建体的毒性水平使细胞过饱和）而受到阻碍。在这篇综述中，我们比较了RNAi方式的HD，并提出了新的方法，优化shRNA的表达和靶保真度。
Huntington’s Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within the Huntingtin (HTT) gene exceeding a normal range (> 36 CAGs). Symptoms of the disease manifest in middle age and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA (mHTT). Unfortunately, this modality requires repeated dosing, commonly exhibit off target effects (OTEs), and exert renal and hepatic toxicity. In contrast, a single AAV-mediated short-hairpin RNA (shRNA) dose can last years with low toxicity. In addition, we highlight research indicating that shRNA elicits fewer OTEs than siRNA when tested head-to-head. Despite this promise, shRNA therapy has been held back by difficulties controlling expression (oversaturating cells with toxic levels of RNA construct). In this review, we compare RNAi modalities for HD and propose novel methods of optimizing shRNA expression and on-target fidelity.
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影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
3.7
作者：
Klinghoffer RA;Frazier J;Annis J;Berndt JD;Roberts BS;Arthur WT;Lacson R;Zhang XD;Ferrer M;Moon RT;Cleary MA
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Cleary MA
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16.2
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通讯作者：
Cleveland DW
影响因子：
4.8
作者：
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通讯作者：
Dehay B
影响因子：
4.5
作者：
Klinghoffer, Richard A.;Magnus, Jill;Cleary, Michele A.
通讯作者：
Cleary, Michele A.