Hum Mol Genet. 2013 Oct 15;22(20):4127-35. doi: 10.1093/hmg/ddt261. Epub 2013 Jun 4.
microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1)(G93A) rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1(G93A) mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS.
微小 RNA（miRNAs）在多种疾病状态下失调，表明这一新兴的基因表达抑制剂家族可能成为可行的治疗靶点。在 ALS 模型超氧化物歧化酶 1（SOD1）（G93A）啮齿动物的 miRNA 变化微阵列中，有 12 个 miRNA 被确定为显著变化。在人类 ALS 组织中测试的 6 个 miRNA 被证实增加。具体来说，miR-155 在小鼠中增加了 5 倍，在人类脊髓中增加了 2 倍。为了测试 miRNA 抑制在中枢神经系统（CNS）中作为一种潜在的新型治疗方法的效果，我们开发了基于寡核苷酸的 miRNA 抑制剂（anti-miRs），可以抑制 CNS 及外周的 miRNA。Anti-miR-155 导致腹膜巨噬细胞中的靶基因全面去抑制，并且在脑室给药后，在大脑和脊髓中显示出广泛的功能分布。在用 anti-miR-155 治疗 SOD1（G93A）小鼠后，我们将其生存时间显著延长了 10 天，疾病持续时间延长了 15 天（38%），而对照 anti-miR 并没有显著提高生存时间或疾病持续时间。因此，反义寡核苷酸可用于成功抑制大脑和脊髓中的 miRNA，miR-155 是人类 ALS 的一个有前途的新治疗靶点。
