Wilkins, Oscar G;
Chien, Max ZYJ;
Wlaschin, Josette J;
Barattucci, Simone;
Harley, Peter;
Mattedi, Francesca;
Mehta, Puja R;
... Fratta, Pietro; + view all
(2024)
Creation of de novo cryptic splicing for ALS and FTD precision medicine.
Science
, 386
(6717)
pp. 61-69.
10.1126/science.adk2539.
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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.
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