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

  1. Puja R. Mehta
  2. Tomas Solomon
  3. Sarah Pickles
  4. Peter Harley
  5. Michela Barioglio
  6. Christoph Schweingruber
  7. Alessandro Marrero-Gagliardi
  8. Yujing Gao
  9. Francesca Mattedi
  10. Simone Barattucci
  11. Lilian Tsai-Wei Lin
  12. Eugeni Ryadnov
  13. Matteo Zanovello
  14. Alexander J. Cammack
  15. Adrian M. Isaacs
  16. Juan Burrone
  17. Christopher E. Shaw
  18. Matthew J. Keuss
  19. Leonard Petrucelli
  20. Pietro Fratta
  21. Marc-David Ruepp
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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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