小干扰RNA
基因沉默
全身给药
体内
马查多-约瑟夫病
RNA干扰
突变体
生物
药理学
核酸
病毒学
核糖核酸
医学
细胞生物学
基因
生物化学
脊髓小脑共济失调
遗传学
作者
Mariana Conceição,Liliana Mendonça,Clévio Nóbrega,Célia Gomes,Pedro M. Costa,Hirokazu Hirai,João Nuno Moreira,Maria C. Pedroso de Lima,N. Manjunath,Luís Pereira de Almeida
出处
期刊:Biomaterials
[Elsevier]
日期:2016-03-01
卷期号:82: 124-137
被引量:85
标识
DOI:10.1016/j.biomaterials.2015.12.021
摘要
Others and we showed that RNA interference holds great promise for the treatment of dominantly inherited neurodegenerative disorders such as Machado-Joseph disease (MJD), for which there is no available treatment. However, successful experiments involved intracranial administration of viral vectors and there is a need for a safer and less invasive procedure. In this work, we successfully generated stable nucleic acid lipid particles (SNALPs), incorporating a short peptide derived from rabies virus glycoprotein (RVG-9r) and encapsulating small interfering RNAs (siRNAs), which can target mutant ataxin-3. The developed formulation exhibited important features that make it adequate for systemic administration: high encapsulation efficiency of siRNAs, ability to protect the encapsulated siRNAs, appropriate and homogeneous particle size distribution. Following optimization of the formulation and in vitro validation of its efficacy to silence the MJD-causing protein - mutant ataxin-3 - in neuronal cells, in vivo experiments showed that intravenous administration of RVG-9r-targeted SNALPs efficiently silenced mutant ataxin-3 reducing neuropathology and motor behavior deficits in two mouse models of MJD. To our knowledge, this is the first report showing beneficial impact of a non-viral gene silencing strategy in MJD and the first time that a non-invasive systemic administration proved to be beneficial on a polyglutamine disorder. Our study opens new avenues towards MJD therapy that can also be applied to other neurodegenerative diseases linked to the production of pathogenic proteins.
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