Creation of de novo cryptic splicing for ALS and FTD precision medicine
Authors:
- Oscar G. WilkinsOWOscar G. Wilkins
- Max Z. Y. J. ChienMCMax Z. Y. J. Chien
- Josette J. WlaschinJWJosette J. Wlaschin
- Simone BarattucciSBSimone Barattucci
- Peter HarleyPHPeter Harley
- Francesca MattediFMFrancesca Mattedi
- Puja R. MehtaPMPuja R. Mehta
- Maria PisliakovaMPMaria Pisliakova
- Matthew J. KeussMKMatthew J. Keuss
- David ThompsonDTDavid Thompson
- Holly DigbyHDHolly Digby
Open Access
- 4 October 2024
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 386 (6717) , 61-69
Abstract
Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders.Keywords
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