{"doi":"10.1016/j.drudis.2024.104201","title":"Therapeutic development approaches to treat haploinsufficiency diseases: restoring protein levels","abstract":"• Haploinsufficiency is caused a heterozygous loss-of-function gene mutation. • Because of the presence of a normal allele, haploinsufficiency is a unique group of rare genetic diseases in need of therapeutic development. • Therapeutic approaches to treat haploinsufficiency involve increasing normal gene allele expression, protein synthesis and protein function as well as decreasing protein degradation. • Drug repurposing screens and drug combination therapy should be considered. Rare diseases affect one in ten people but only a small fraction of these diseases have an FDA-approved treatment. Haploinsufficiency, caused by a dominant loss-of-function mutation, is a unique rare disease group because patients have one normal allele of the affected gene. This makes rare haploinsufficiency diseases promising candidates for drug development by increasing expression of the normal gene allele, decreasing the target protein degradation and enhancing the target protein function. This review summarizes recent progresses and approaches used in the translational research of therapeutics to treat haploinsufficiency diseases including gene therapy, nucleotide-based therapeutics and small-molecule drug development. We hope that these drug development strategies will accelerate therapeutic development to treat haploinsufficiency diseases.","journal":"Drug Discovery Today","year":2024,"id":443416,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"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":277918,"name":"Zeenat A. Shyr","orcid":"0000-0001-8710-9938","position":1,"is_corresponding":false},{"id":240475,"name":"Bryan J. Traynor","orcid":"0000-0003-0527-2446","position":2,"is_corresponding":false},{"id":227992,"name":"Wei Zheng","orcid":"0000-0003-1034-0757","position":3,"is_corresponding":false},{"id":1258035,"name":"Elena F Evans","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T02:01:24.471942Z","pmid":"39384033","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":[]}