U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis

Puja R. Mehta; Tomas Solomon; Sarah R. Pickles; Peter Harley; Michela Barioglio; Christoph Schweingruber; Alessandro Marrero‐Gagliardi; Yujing Gao; Francesca Mattedi; Simone Barattucci; Lilian Tsai‐Wei Lin; Eugeni M. Ryadnov; Matteo Zanovello; Alexander J. Cammack; Adrian M. Isaacs; Juan Burrone; Christopher E. Shaw; Matthew J. Keuss; Leonard Petrucelli; Pietro Fratta; Marc‐David Ruepp

doi:10.1101/2025.11.26.690143

NeurosciencebioRxivNov 26, 2025

Preprint

U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis

Puja R. Mehta iD, Tomas Solomon iD, Sarah R. Pickles iD, Peter Harley iD, Michela Barioglio iD, Christoph Schweingruber iD, Alessandro Marrero‐Gagliardi iD, Yujing Gao iD, Francesca Mattedi iD, Simone Barattucci iD, Lilian Tsai‐Wei Lin iD, Eugeni M. Ryadnov iD, Matteo Zanovello iD, Alexander J. Cammack iD, Adrian M. Isaacs iD, Juan Burrone iD, Christopher E. Shaw iD, Matthew J. Keuss iD, Leonard Petrucelli iD, Pietro Fratta iD, Marc‐David Ruepp iD

Abstract

TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including UNC13A and STMN2, disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement in vivo, positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.

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