{"doi":"10.1126/science.adk2539","title":"Creation of de novo cryptic splicing for ALS and FTD precision medicine","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.","journal":"Science","year":2024,"id":420516,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1211927,"name":"Max Z. Y. J. Chien","orcid":"0009-0001-7731-605X","position":1,"is_corresponding":false},{"id":906803,"name":"Josette J Wlaschin","orcid":"0000-0003-1532-3905","position":2,"is_corresponding":false},{"id":1211928,"name":"Simone Barattucci","orcid":"0009-0006-8380-2931","position":3,"is_corresponding":false},{"id":1211929,"name":"Peter Harley","orcid":"0000-0001-6689-0227","position":4,"is_corresponding":false},{"id":559559,"name":"Francesca Mattedi","orcid":"0000-0002-0306-5796","position":5,"is_corresponding":false},{"id":677199,"name":"Puja R. Mehta","orcid":"0000-0002-0255-407X","position":6,"is_corresponding":false},{"id":1211930,"name":"Maria Pisliakova","orcid":"0009-0007-5157-5639","position":7,"is_corresponding":false},{"id":1211931,"name":"Eugeni Ryadnov","orcid":"0009-0003-9921-1755","position":8,"is_corresponding":false},{"id":805614,"name":"Matthew J. Keuss","orcid":"0000-0002-2628-4115","position":9,"is_corresponding":false},{"id":1211932,"name":"David Thompson","orcid":"0000-0002-2444-9844","position":10,"is_corresponding":false},{"id":1211933,"name":"Holly Digby","orcid":"0000-0003-1360-9686","position":11,"is_corresponding":false},{"id":1211934,"name":"Lea Knez","orcid":"0000-0002-7743-2827","position":12,"is_corresponding":false},{"id":1046429,"name":"Rebecca L. Simkin","orcid":"0000-0001-8093-2139","position":13,"is_corresponding":false},{"id":1211935,"name":"Juan Antinao Díaz","orcid":"0000-0001-7295-2738","position":14,"is_corresponding":false},{"id":805615,"name":"Matteo Zanovello","orcid":"0000-0003-3343-1547","position":15,"is_corresponding":false},{"id":238158,"name":"Anna‐Leigh Brown","orcid":"0000-0003-1493-208X","position":16,"is_corresponding":false},{"id":1211936,"name":"Annalucia Darbey","orcid":"0000-0001-8541-5472","position":17,"is_corresponding":false},{"id":1211937,"name":"Rajvinder Karda","orcid":"0000-0001-9821-483X","position":18,"is_corresponding":false},{"id":238175,"name":"Elizabeth Fisher","orcid":"0000-0003-2850-9936","position":19,"is_corresponding":false},{"id":1211938,"name":"Thomas J. Cunningham","orcid":"0000-0002-4751-3140","position":20,"is_corresponding":false},{"id":566864,"name":"Claire E. Le Pichon","orcid":"0000-0002-9274-3615","position":21,"is_corresponding":false},{"id":617895,"name":"Jernej Ule","orcid":"0000-0002-2452-4277","position":22,"is_corresponding":false},{"id":238180,"name":"Pietro Fratta","orcid":"0000-0002-8762-8188","position":23,"is_corresponding":false},{"id":805613,"name":"Oscar G. Wilkins","orcid":"0000-0002-3334-0568","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T01:57:31.041511Z","pmid":"39361759","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}