Commentary on: ribozyme-activated RNA trans-ligation: an emerging strategy for large gene delivery in muscular dystrophies

Abstract

Gene therapies for muscular dystrophies are limited by the large size of disease-associated genes, which exceed the packaging capacity of standard adeno-associated virus vectors. In a recent Science article, Lindley et al. introduced “StitchR”, a ribozyme-activated RNA trans-ligation platform designed to reconstitute full-length transcripts inside cells, thereby enabling expression of large therapeutic proteins. This commentary evaluates the StitchR platform in the context of existing dual-vector strategies, particularly split-intein systems that have advanced to human clinical trials. We review the mechanistic distinctions, comparative efficiency, and translational readiness of RNA versus protein-level reconstitution, and highlight key unknowns related to immunogenicity, efficiency, and fidelity. While StitchR represents a conceptually elegant and potentially transformative approach, its therapeutic relevance will depend on further validation in additional preclinical studies, regulatory engagement, and head-to-head comparisons with clinically advanced platforms.

Keywords

RNA splicing / RNA trans-splicing / RNA repair / split inteins / adeno-associated virus / dual-AAV vectors / gene therapy / therapeutic RNA engineering

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