Template-independent genome editing and restoration for correcting frameshift disorders

作者: Shiwei Qiu, Lian Liu, Bin Xiang, Ziqin Jin, Yahong Li, Dong Li, Hanqing Hou, Kuan Li, Gege Wei, Jiangping Xie, Shang Li, Shuang Liu, Chunlai Chen, Xin Liang, Qianwen Sun & Wei Xiong
杂志: Nature Biomedical Engineering
Doi: https://www.doi.org/10.1038/s41551-026-01635-5
出版日期: 2026/3/23

论文中使用的产品/服务

摘要

Frameshift mutations, responsible for >20% of Mendelian inherited diseases, pose substantial therapeutic challenges. Here we developed Template-Independent Genome Editing for Restoration (TIGER), a platform for the efficient and precise correction of frameshift mutations across various models. By identifying reproducible nucleotide-level factors that influence therapeutic efficacy across cells and tissues, we developed a scoring system for guide RNA (gRNA)–Cas9 outcomes. Approximately 75% of deletion and 50% of insertion mutations produced ≥30% in-frame products, sufficient for phenotypic restoration, with 38% and 65% achieving wild-type correction, respectively. To expand the applicability of TIGER across species and genome wide, we retrained the inDelphi algorithm to predict therapeutic gRNAs for single-nucleotide frameshifts. In a mouse model of deafness, delivery of SpCas9 and optimal gRNA via dual adeno-associated virus restored hearing thresholds to wild-type levels, with ~90% of in-frame edits being wild type. TIGER provides a robust and broadly applicable strategy for in vivo correction of inherited frameshift diseases.

文章链接

关于派真

作为一家专注于AAV 技术十余年，深耕基因治疗领域的CRO&CDMO，派真生物可提供从载体设计、构建到 AAV、慢病毒和 mRNA 服务的一站式解决方案。凭借深厚的技术实力、卓越的运营管理和高标准的服务交付，我们为全球客户提供一站式CMC解决方案，包括从早期概念验证、成药性评估到IIT、IND及BLA的各个阶段。

凭借我们独立知识产权的π-alpha^TM 293 细胞AAV高产技术平台，我们能将AAV产量提高多至10倍，每批次产量可达1×10¹⁷vg，以满足多样化的商业化和临床项目需求。此外，我们定制化的mRNA和脂质纳米颗粒（LNP）产品及服务覆盖药物和疫苗开发的各个阶段，从研发到符合GMP的生产，提供端到端的一站式解决方案。