School of Basic Medical Science and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Laboratory of Aging Neuroscience and Neuropharmacology, China Pharmaceutical University, Nanjing, 210009, China.
Genome Biol. 2024 Jul 7;25(1):179. doi: 10.1186/s13059-024-03326-3.
Pathogenic allele silencing is a promising treatment for genetic hereditary diseases. Here, we develop an RNA-cleaving tool, TaqTth-hpRNA, consisting of a small, chimeric TaqTth, and a hairpin RNA guiding probe. With a minimal flanking sequence-motif requirement, in vitro and in vivo studies show TaqTth-hpRNA cleaves RNA efficiently and specifically. In an Alzheimer's disease model, we demonstrate silencing of mutant APP mRNA without altering the wild-type APP mRNA. Notably, due to the compact size of TaqTth, we are able to combine with APOE2 overexpression in a single AAV vector, which results in stronger inhibition of pathologies.
致病等位基因沉默是一种有前途的治疗遗传性疾病的方法。在这里，我们开发了一种 RNA 切割工具 TaqTth-hpRNA，它由一个小的嵌合 TaqTth 和一个发夹 RNA 引导探针组成。体外和体内研究表明，TaqTth-hpRNA 在具有最小侧翼序列基序要求的情况下，能够高效且特异性地切割 RNA。在阿尔茨海默病模型中，我们证明了突变 APP mRNA 的沉默而不改变野生型 APP mRNA。值得注意的是，由于 TaqTth 的紧凑尺寸，我们能够将其与 APOE2 过表达在单个 AAV 载体中结合，从而更有效地抑制病变。
