Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS.
Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS.
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DOI：
10.1016/j.omtn.2021.02.007
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发表时间：
2021-06-04
期刊：
影响因子：
--
通讯作者：
Katsuno M
中科院分区：
文献类型：
--
作者：
Hirunagi T;Sahashi K;Tachikawa K;Leu AI;Nguyen M;Mukthavaram R;Karmali PP;Chivukula P;Tohnai G;Iida M;Onodera K;Ohyama M;Okada Y;Okano H;Katsuno M
多聚谷氨酰胺（polyQ）疾病是由致病基因中的胞嘧啶-腺嘌呤-鸟嘌呤（CAG）-三核苷酸重复序列扩展引起的遗传性神经退行性疾病。这些疾病包括脊髓延髓肌萎缩症（SBMA）、亨廷顿病、齿状核红核-苍白球路易氏体萎缩症和脊髓小脑共济失调。靶向扩增的CAG重复序列是polyQ疾病的常见治疗方法，但伴随的具有正常CAG重复序列的基因沉默可能导致毒性。先前的研究表明，CAG重复靶向小干扰RNA双链体（CAG-siRNA）具有在polyQ疾病的体外细胞模型中选择性抑制突变蛋白的潜力。然而，这些siRNA的体内应用尚未被研究。在这项研究中，我们证明了解锁核酸（UNA）修饰的CAG-siRNA在体外细胞模型中显示出对polyQ扩增的雄激素受体（AR）抑制的高选择性，并且脂质纳米颗粒（LNP）介导的CAG-siRNA递送选择性地抑制SBMA小鼠模型中枢神经系统中的突变型AR。此外，皮下注射LNP递送的CAG-siRNA有效地抑制SBMA小鼠模型骨骼肌中的突变体AR。这些结果支持LNP递送的UNA修饰的CAG-siRNA用于选择性抑制SBMA和其他polyQ疾病中的突变蛋白的治疗潜力。通过CAG重复序列靶向寡核苷酸选择性抑制多聚谷氨酰胺等位基因是治疗多聚谷氨酰胺疾病的一种有前途的方法。Hirunagi等人在SBMA小鼠模型的小鼠CNS中，通过脂质纳米颗粒介导的靶向CAG扩增的siRNA的递送，证明了对聚谷氨酰胺扩增的雄激素受体的选择性抑制。
Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused by expansion of cytosine-adenine-guanine (CAG)-trinucleotide repeats in causative genes. These diseases include spinal and bulbar muscular atrophy (SBMA), Huntington’s disease, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxias. Targeting expanded CAG repeats is a common therapeutic approach to polyQ diseases, but concomitant silencing of genes with normal CAG repeats may lead to toxicity. Previous studies have shown that CAG repeat-targeting small interfering RNA duplexes (CAG-siRNAs) have the potential to selectively suppress mutant proteins in in vitro cell models of polyQ diseases. However, in vivo application of these siRNAs has not yet been investigated. In this study, we demonstrate that an unlocked nucleic acid (UNA)-modified CAG-siRNA shows high selectivity for polyQ-expanded androgen receptor (AR) inhibition in in vitro cell models and that lipid nanoparticle (LNP)-mediated delivery of the CAG-siRNA selectively suppresses mutant AR in the central nervous system of an SBMA mouse model. In addition, a subcutaneous injection of the LNP-delivered CAG-siRNA efficiently suppresses mutant AR in the skeletal muscle of the SBMA mouse model. These results support the therapeutic potential of LNP-delivered UNA-modified CAG-siRNAs for selective suppression of mutant proteins in SBMA and other polyQ diseases. Mutant-allele selective suppression by CAG repeat-targeting oligonucleotides is a promising therapeutic approach to polyglutamine diseases. Hirunagi et al. demonstrate selective suppression of polyglutamine-expanded androgen receptor by lipid nanoparticle-mediated delivery of siRNA targeting CAG expansions in the mouse CNS of an SBMA mouse model.
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