Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1(G93A) Mice and Nonhuman Primates.
Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1(G93A) Mice and Nonhuman Primates.
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DOI：
10.1089/hum.2015.122
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发表时间：
2016-01
影响因子：
4.2
通讯作者：
Mueller C
中科院分区：
文献类型：
--
作者：
Borel F;Gernoux G;Cardozo B;Metterville JP;Toro Cabrera GC;Song L;Su Q;Gao GP;Elmallah MK;Brown RH Jr;Mueller C
肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病；ALS的存活期通常为3-5年。任何治疗都不能延长患者的生存时间超过三个月。大约20%的家族性肌萎缩侧索硬化症和1-3%的散发性肌萎缩侧索硬化症患者携带编码超氧化物歧化酶1的基因突变。在表达突变的SOD1G93A蛋白的转基因ALS小鼠模型中，沉默SOD1基因可以延长存活时间。一项研究报告了在系统治疗的成年ALS小鼠中沉默SOD1基因的治疗效果；这是通过短发夹状RNA(一种引起多种安全问题的沉默分子)和重组腺相关病毒(RAAV)9实现的。在这里，我们报告了一种基于人工微RNA的沉默方法，称为miR-SOD1，用腺相关病毒rAAVRh10系统地传递，这种血清型在中枢神经系统临床试验中被证明是安全的。在成年SOD1G93A转基因小鼠中，沉默SOD1G93A显著推迟了SOD1G93A转基因小鼠的发病和死亡，并显著保留了肌肉力量以及运动和呼吸功能。我们还证明，鞘内注射相同的rAAVR10-miR-SOD1在非人类灵长类动物中显著且安全地沉默下运动神经元中的SOD1。这项研究支持rAAVrh10-miR-SOD1值得进一步开发用于治疗SOD1连锁的人类ALS的观点。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3–5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1–3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1G93A protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1G93A transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1G93A mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans.