Successes and challenges in clinical gene therapy

Cavazzana M, Bushman FD, Miccio A, André-Schmutz I, Six E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat Rev Drug Discov. 2019;18:447–62.

Article  CAS  PubMed  Google Scholar 

Ferrari G, Thrasher AJ, Aiuti A. Gene therapy using haematopoietic stem and progenitor cells. Nat Rev Genet. 2021;22:216–34.

Article  CAS  PubMed  Google Scholar 

Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968;2:1366–9.

Article  CAS  PubMed  Google Scholar 

Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014;371:434–46.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cuvelier GDE, Logan BR, Prockop SE, Buckley RH, Kuo CY, Griffith LM, et al. Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC. Blood. 2022;140:685–705.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288:669–72.

Article  CAS  PubMed  Google Scholar 

Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002;296:2410–3.

Article  CAS  PubMed  Google Scholar 

Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9.

Article  CAS  PubMed  Google Scholar 

Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Investig. 2008;118:3143–50.

Article  CAS  PubMed  PubMed Central  Google Scholar 

De Ravin SS, Wu X, Moir S, Anaya-O’Brien S, Kwatemaa N, Littel P, et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016;8:335ra57.

Article  PubMed  PubMed Central  Google Scholar 

Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, et al. Lentiviral gene therapy combined with low-dose busulfan in infants with SCID-X1. N Engl J Med. 2019;380:1525–34.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, et al. Autologous ex vivo lentiviral gene therapy for adenosine deaminase deficiency. N Engl J Med. 2021;384:2002–13.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cowan MJ, Yu J, Facchino J, Fraser-Browne C, Sanford U, Kawahara M. et al. Lentiviral gene therapy for artemis-deficient SCID. N Engl J Med. 2022;387:2344–55.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341:1233151.

Article  PubMed  PubMed Central  Google Scholar 

Magnani A, Semeraro M, Adam F, Booth C, Dupré L, Morris EC, et al. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome. Nat Med. 2022;28:71–80.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kohn DB, Booth C, Kang EM, Pai SY, Shaw KL, Santilli G, et al. Lentiviral gene therapy for X-linked chronic granulomatous disease. Nat Med. 2020;26:200–6.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kohn DB, Sevilla J, Rao G, Chitty-Lopez M, Almarza D, Terrazas D. et al. Interim results from an ongoing phase 1/2 study of lentiviral-mediated ex-vivo gene therapy for pediatric patients with severe leukocyte adhesion deficiency-I (LAD-1). Mol Ther. 2022;30:550

Google Scholar 

Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818–23.

Article  CAS  PubMed  Google Scholar 

Gentner B, Tucci F, Galimberti S, Fumagalli F, De Pellegrin M, Silvani P, et al. Hematopoietic stem- and progenitor-cell gene therapy for hurler syndrome. N Engl J Med. 2021;385:1929–40.

Article  CAS  PubMed  Google Scholar 

Fumagalli F, Calbi V, Natali Sora MG, Sessa M, Baldoli C, Rancoita PMV, et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet. 2022;399:372–83.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018;378:1479–93.

Article  CAS  PubMed  Google Scholar 

Locatelli F, Thompson AA, Kwiatkowski JL, Porter JB, Thrasher AJ, Hongeng SS. et al. Betibeglogene autotemcel gene therapy for non-β. N Engl J Med. 2022;386:415–27. Epub 20211211.

Article  CAS  PubMed  Google Scholar 

Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330:1639–44.

Article  CAS  PubMed  Google Scholar 

White SL, Hart K, Kohn DB. Diverse approaches to gene therapy of sickle cell disease. Annu Rev Med. 2023;74:473–87.

Article  PubMed  Google Scholar 

Magrin E, Semeraro M, Hebert N, Joseph L, Magnani A, Chalumeau A, et al. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial. Nat Med. 2022;28:81–8.

Article  CAS  PubMed  Google Scholar 

Kanter J, Walters MC, Krishnamurti L, Mapara MY, Kwiatkowski JL, Rifkin-Zenenberg S, et al. Biologic and clinical efficacy of lentiglobin for sickle cell disease. N Engl J Med. 2022;386:617–28.

Article  CAS  PubMed  Google Scholar 

Esrick EB, Lehmann LE, Biffi A, Achebe M, Brendel C, Ciuculescu MF, et al. Post-transcriptional genetic silencing of. N Engl J Med. 2021;384:205–15.

Article  CAS  PubMed  Google Scholar 

Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384:252–60.

Article  CAS  PubMed  Google Scholar 

Lattanzi A, Camarena J, Lahiri P, Segal H, Srifa W, Vakulskas CA, et al. Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. Sci Transl Med. 2021;13:eabf2444.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Magis W, DeWitt MA, Wyman SK, Vu JT, Heo SJ, Shao SJ, et al. High-level correction of the sickle mutation is amplified. iScience. 2022;25:104374.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zeng J, Wu Y, Ren C, Bonanno J, Shen AH, Shea D, et al. Therapeutic base editing of human hematopoietic stem cells. Nat Med. 2020;26:535–41.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Newby GA, Yen JS, Woodard KJ, Mayuranathan T, Lazzarotto CR, Li Y, et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature. 2021;595:295–302.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cornetta K, Koop S, Nance E, House K, Duffy L. Replication-competent lentivirus analysis of vector-transduced T cell products used in cancer immunotherapy clinical trials. Methods Mol Biol. 2020;2086:181–94.

Article  CAS  PubMed  Google Scholar 

FDA Advisory Committee Unanimously Endorses eli-cel Gene Therapy for Cerebral Adrenoleukodystrophy 2022. https://investor.bluebirdbio.com/news-releases/news-release-details/fda-advisory-committee-unanimously-endorses-eli-cel-gene-therapy.

De Ravin SS, Liu S, Sweeney CL, Brault J, Whiting-Theobald N, Ma M, et al. Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked severe combined immunodeficiency. Nat Commun. 2022;13:3710.

Article  PubMed  PubMed Central  Google Scholar 

Comments (0)

No login
gif