Novel therapeutic approaches using the delivery of specific miRNAs for polyglutamine diseases

脊髓延髓肌萎缩症（SBMA）是一种遗传性神经退行性疾病，由雄激素受体的多聚谷氨酰胺（polyQ）通道扩张引起。最近的功能研究表明，特异性miRNA在体外和体内都具有作为疾病调节剂的有效活性。因此，靶向miRNA加工途径的潜在治疗方法最近引起了关注。我们证明了一种新的治疗方法，使用腺相关病毒（AAV）载体介导的SBMA的特异性miRNA的交付。我们发现miR-196 a通过沉默CUGBP，Elav-like家族成员2（CELF 2）增强AR mRNA的衰减。CELF 2可直接作用于AR mRNA，增强AR mRNA的稳定性。此外，我们发现通过AAV载体递送的miR-196 a的早期干预改善了小鼠模型中的SBMA表型。我们的研究结果确立了疾病特异性miRNA递送在神经退行性疾病中可能有用的原则证据。

Spinal and bulbar muscular atrophy (SBMA) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine (polyQ) tract of the androgen receptor. Recent functional studies have shown the potent activity of specific miRNAs as disease modifiers both in vitro and in vivo. Thus, potential therapeutic approaches that target the miRNA processing pathway have recently attracted attention. We demonstrated a novel therapeutic approach using the adeno-associated virus (AAV) vector;mediated delivery of a specific miRNA for SBMA. We found that miR-196a enhanced the decay of the AR mRNA by silencing CUGBP, Elav-like family member 2 (CELF2). CELF2 directly acted on AR mRNA and enhanced the stability of AR mRNA. Furthermore, we found that the early intervention of miR-196a delivered by an AAV vector ameliorated the SBMA phenotypes in a mouse model. Our results establish the proof of principle that disease-specific miRNA delivery could be useful in neurodegenerative diseases.