{"doi":"10.1016/j.ymthe.2020.11.005","title":"Getting Back to Normal: Correcting SCN by Universal or Precision Strikes","abstract":"This has been a year full of surprises, but the awarding of the Nobel Prize in Chemistry to Jennifer Doudna and Emmanuelle Charpentier for their discovery of CRISPR/Cas9 editing was not one of them.1Ledford H. Callaway E. Pioneers of revolutionary CRISPR gene editing win chemistry Nobel.Nature. 2020; 586: 346-347Crossref PubMed Scopus (9) Google Scholar These genomic scissors are being widely applied in experimental, diagnostic, and therapeutic areas. Of more than 10,000 monogenic diseases, a subset of these affecting blood development and function proffers the most fertile ground for proof-of-concept in therapeutics. In this issue of Molecular Therapy, Tran et al.2Tran N.T. Graf R. Wulf-Goldenberg A. Stecklum M. Strauß G. Kühn R. Kocks C. Rajewsky K. Chu V.T. CRISPR-Cas9-Mediated ELANE Mutation Correction in Hematopoietic Stem and Progenitor Cells to Treat Severe Congenital Neutropenia.Mol Ther. 2020; 28 (this issue): 2621-2634Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar compellingly advance CRISPR-Cas9-mediated repair of a missense mutation in ELANE, the most commonly affected gene causing severe congenital neutropenia (SCN). SCN is a life-long deficiency of neutrophils, which serve as the primary defense against infections.3Skokowa J. Dale D.C. Touw I.P. Zeidler C. Welte K. Severe congenital neutropenias.Nat. Rev. Dis. Primers. 2017; 3: 17032Crossref PubMed Scopus (99) Google Scholar Children typically present within the first several months of life with life-threatening bacterial infections of the skin, gut, or lungs. There is a near absence of neutrophils (normal range is between 1,500 and 7,500 neutrophils/μL) owing to a maturation arrest at the promyelocyte stage of neutrophil production. Studying families with cyclic neutropenia 20 years ago, Horwitz et al.4Horwitz M.S. Corey S.J. Grimes H.L. Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology.Hematol. Oncol. Clin. North Am. 2013; 27: 19-41, viiAbstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar identified that the disease was associated with mutations in ELANE (ELA2), which encodes a neutrophil serine protease. These mutations, which number more than 100, behave in an autosomal dominant fashion. Twenty years later, we still do not understand how this protease causes such havoc. Apoptosis is among the proposed hypotheses due to unfolded protein response and/or mislocalization or impaired differentiation.5Garg B. Mehta H.M. Wang B. Kamel R. Horwitz M.S. Corey S.J. Inducible expression of a disease-associated ELANE mutation impairs granulocytic differentiation, without eliciting an unfolded protein response.J. Biol. Chem. 2020; 295: 7492-7500Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The pharmacologic use of granulocyte colony-stimulating factor (G-CSF) increases neutrophil counts to protective levels in the majority of SCN patients. However, the growth factor may promote transformation to acute myeloid leukemia, facilitated by somatic mutation of the receptor for G-CSF.6Touw I.P. Game of clones: the genomic evolution of severe congenital neutropenia.Hematology (Am. Soc. Hematol. Educ. Program). 2015; 2015: 1-7Crossref PubMed Scopus (28) Google Scholar The association between factor use, receptor mutation, and leukemia prompts clinicians to develop better interventions. As a potential treatment for SCN, Tran et al.2Tran N.T. Graf R. Wulf-Goldenberg A. Stecklum M. Strauß G. Kühn R. Kocks C. Rajewsky K. Chu V.T. CRISPR-Cas9-Mediated ELANE Mutation Correction in Hematopoietic Stem and Progenitor Cells to Treat Severe Congenital Neutropenia.Mol Ther. 2020; 28 (this issue): 2621-2634Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar provide proof-of-principle for the use of CRISPR/Cas9-mediated gene editing to correct mutations in ELANE. The authors selected a mutation in exon 4 of ELANE (L172P), which fortuitously creates a protospacer adjacent motif (PA","journal":"Molecular Therapy","year":2020,"id":131615,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":386074,"name":"Seth J. Corey","orcid":"0000-0002-3575-6401","position":1,"is_corresponding":false},{"id":386073,"name":"Hrishikesh Mehta","orcid":"0000-0001-9140-9765","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:16:03.875886Z","pmid":"33176167","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":[]}