Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype
Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype
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DOI：
10.1016/j.biomaterials.2015.12.021
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发表时间：
2016-03-01
期刊：
影响因子：
14
通讯作者：
de Almeida, Luis Pereira
中科院分区：
文献类型：
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作者：
Conceicao, Mariana;Mendonca, Liliana;de Almeida, Luis Pereira
其他人和我们表明，RNA干扰对治疗显性遗传性神经退行性疾病如马查多约瑟夫病（MJD）有很大的希望，对此没有可用的治疗方法。然而，成功的实验涉及颅内施用病毒载体，并且需要更安全和侵入性更小的程序。在这项工作中，我们成功地产生了稳定的核酸脂质颗粒（SNALPs），将来自狂犬病病毒糖蛋白（RVG-9 r）的短肽和封装小干扰RNA（siRNA），它可以靶向突变型共济失调蛋白-3。所开发的制剂表现出使其适合全身给药的重要特征：siRNA的高包封效率、保护包封的siRNA的能力、适当且均匀的粒度分布。在优化制剂并体外验证其在神经元细胞中沉默引起MJD的蛋白质突变型共济失调蛋白-3的功效之后，体内实验显示，静脉内施用RVG-9 r靶向的SNALP有效地沉默了突变型共济失调蛋白-3，减少了两种MJD小鼠模型中的神经病理学和运动行为缺陷。据我们所知，这是第一份显示非病毒基因沉默策略对MJD的有益影响的报告，也是第一次证明非侵入性全身给药对多聚谷氨酰胺疾病有益。我们的研究为MJD治疗开辟了新的途径，也可以应用于与致病蛋白质产生相关的其他神经退行性疾病。(C)2015爱思唯尔有限公司版权所有。
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. (C) 2015 Elsevier Ltd. All rights reserved.