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

Mehta, P. R.; Solomon, T.; Pickles, S.; Harley, P.; Barioglio, M.; Schweingruber, C.; Marrero-Gagliardi, A.; Gao, Y.; Mattedi, F.; Barattucci, S.; Lin, L. T.-W.; Ryadnov, E.; Zanovello, M.; Cammack, A. J.; Isaacs, A.; Burrone, J.; Shaw, C. E.; Keuss, M. J.; Petrucelli, L.; Fratta, P.; Ruepp, M.-D.

doi:10.1101/2025.11.26.690143

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bioRxiv · 10.1101/2025.11.26.690143

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

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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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Mehta, P. R., Solomon, T., Pickles, S., Harley, P., Barioglio, M., Schweingruber, C., Marrero-Gagliardi, A., Gao, Y., Mattedi, F., Barattucci, S., Lin, L. T.-W., Ryadnov, E., Zanovello, M., Cammack, A. J., Isaacs, A., Burrone, J., Shaw, C. E., Keuss, M. J., Petrucelli, L., Fratta, P., Ruepp, M.-D.. 2025-11-30. U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis. https://doi.org/10.1101/2025.11.26.690143

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