| First Author | Wilkins OG | Year | 2024 |
| Journal | Science | Volume | 386 |
| Issue | 6717 | Pages | 61-69 |
| PubMed ID | 39361759 | Mgi Jnum | J:393307 |
| Mgi Id | MGI:8166550 | Doi | 10.1126/science.adk2539 |
| Citation | Wilkins OG, et al. (2024) Creation of de novo cryptic splicing for ALS and FTD precision medicine. Science 386(6717):61-69 |
| abstractText | 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. |
