Genome Biology (Jul 2024)

TaqTth-hpRNA: a novel compact RNA-targeting tool for specific silencing of pathogenic mRNA

  • Chong Xu,
  • Jiyanuo Cao,
  • Huanran Qiang,
  • Yu Liu,
  • Jialin Wu,
  • Qiudan Luo,
  • Meng Wan,
  • Yujie Wang,
  • Peiliang Wang,
  • Qian Cheng,
  • Guohua Zhou,
  • Jian Sima,
  • Yongjian Guo,
  • Shu Xu

DOI
https://doi.org/10.1186/s13059-024-03326-3
Journal volume & issue
Vol. 25, no. 1
pp. 1 – 25

Abstract

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Abstract 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 swe 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.

Keywords