{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T18:30:46Z","timestamp":1755801046040,"version":"3.44.0"},"reference-count":20,"publisher":"Danish Medical Association","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Ugeskr L\u00e6ger"],"abstract":"<jats:p>Primary immunodeficiencies are rare monogenic inborn errors of immunity and can involve any combination of infection, autoimmunity, inflammation, and malignancy. While increased use of whole genome sequencing has vastly improved diagnosis, curative treatment options beyond haematopoietic stem cell transplantation are still lacking behind. In this review, we present and discuss the promising avenues of CRISPR\/Cas gene editing of patient stem cells for curing these diseases through homology-directed repair, base- or prime editing and delivery by nanoparticles or viral derivatives. However, technological, regulatory, and economic challenges exist on the road to safe and broad implementation of this technology for personalized medicine in the clinic.<\/jats:p>","DOI":"10.61409\/v02250083","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T06:16:15Z","timestamp":1749536175000},"page":"1-7","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR\/Cas gene editing of haematopoietic stem cells for curing primary immunodeficiency"],"prefix":"10.61409","author":[{"given":"Rasmus O","family":"Bak","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mette","family":"Holm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bjarne","family":"M\u00f8ller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob Giehm","family":"Mikkelsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trine H.","family":"Mogensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"40208","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-1507. https:\/\/doi.org\/10.1007\/s10875-022-01289-3","DOI":"10.1007\/s10875-022-01289-3"},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Thalhammer J, Kindle G, Nieters A, et al. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. 2021;148(5):1332-1341.e5. https:\/\/doi.org\/10.1016\/j.jaci.2021.04.015","DOI":"10.1016\/j.jaci.2021.04.015"},{"key":"ref2","unstructured":"Ifversen MS, Masmas TN, Kornblit B, et al. Behandling af monogene sygdomme ved viral transduktion af h\u00e6matopoietiske stamceller. Ugeskr L\u00e6ger. 2020;182:V06200458. https:\/\/ugeskriftet.dk\/videnskab\/behandling-af-monogene-sygdomme-ved-viral-transduktion-af-haematopoietiske-stamceller"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Wolff JH, Mikkelsen JG. Delivering genes with human immunodeficiency virus-derived vehicles: still state-of-the-art after 25 years. J Biomed Sci. 2022;29(1):79. https:\/\/doi.org\/10.1186\/s12929-022-00865-4","DOI":"10.1186\/s12929-022-00865-4"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Candotti F, Shaw KL, Muul L, et al. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012;120(18):3635-3646. https:\/\/doi.org\/10.1182\/blood-2012-02-400937","DOI":"10.1182\/blood-2012-02-400937"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Gaspar HB, Parsley KL, Howe S, et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004;364(9452):2181-2187. https:\/\/doi.org\/10.1016\/S0140-6736(04)17590-9","DOI":"10.1016\/S0140-6736(04)17590-9"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Kohn DB, Booth C, Shaw KL, et al. Autologous ex vivo lentiviral gene therapy for adenosine deaminase deficiency. N Engl J Med. 2021;384(21):2002-2013. https:\/\/doi.org\/10.1056\/NEJMoa2027675","DOI":"10.1056\/NEJMoa2027675"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Eichler F, Duncan C, Musolino PL, et al. Lentiviral gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2024;391(15):1302-1312. https:\/\/doi.org\/10.1056\/NEJMoa2400442","DOI":"10.1056\/NEJMoa2400442"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Calabria A, Spinozzi G, Cesana D, et al. Long-term lineage commitment in haematopoietic stem cell gene therapy. 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Gene regulation in inborn errors of immunity: implications for gene therapy design and efficacy. Immunol Rev. 2024;322:157-177 https:\/\/doi.org\/10.1111\/imr.13305","DOI":"10.1111\/imr.13305"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Fontana M, Solomon SD, Kachadourian J, et al. CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy. N Engl J Med. 2024;391(23):2231-2241. https:\/\/doi.org\/10.1056\/NEJMoa2412309","DOI":"10.1056\/NEJMoa2412309"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Janns JH, Mikkelsen JG. Gene editing by ferrying of CRISPR\/Cas ribonucleoprotein complexes in enveloped virus-derived particles. Hum Gene Ther. 2024;35:604-616 https:\/\/doi.org\/10.1089\/hum.2024.105","DOI":"10.1089\/hum.2024.105"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Laustsen A, Bak RO. Electroporation-based CRISPR\/Cas9 gene editing using Cas9 protein and chemically modified sgRNAs. 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