bioRxivNeurosciencePreprint
U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis
Puja R. MehtaiD, Tomas SolomoniD, Sarah R. PicklesiD, Peter HarleyiD, Michela BarioglioiD, Christoph SchweingruberiD, Alessandro Marrero‐GagliardiiD, Yujing GaoiD, Francesca MattediiD, Simone BarattucciiD, Lilian Tsai‐Wei LiniD, Eugeni M. RyadnoviD, Matteo ZanovelloiD, Alexander J. CammackiD, Adrian M. IsaacsiD, Juan BurroneiD, Christopher E. ShawiD, Matthew J. KeussiD, Leonard PetrucelliiD, Pietro FrattaiD, Marc‐David RueppiD
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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