Optimizing lentiviral genomic integrations to cure beta-thalassemia: The least required for success?

Gene addition by ex vivo lentiviral transduction of a curative beta-globin gene into hematopoietic stem cells of patients suffering from blood transfusion-dependent beta-thalassemia (TDT) has successfully treated several patients.1Locatelli F. Thompson A.A. Kwiatkowski J.L. Porter J.B. Thrasher A.J. Hongeng S. Sauer M.G. Thuret I. Lal A. Algeri M. et al.Betibeglogene Autotemcel Gene Therapy for Non-beta(0)/beta(0) Genotype beta-Thalassemia.N. Engl. J. Med. 2022; 386: 415-427https://doi.org/10.1056/NEJMoa2113206Google Scholar,2Marktel S. Scaramuzza S. Cicalese M.P. Giglio F. Galimberti S. Lidonnici M.R. Calbi V. Assanelli A. Bernardo M.E. Rossi C. et al.Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ss-thalassemia.Nat. Med. 2019; 25: 234-241https://doi.org/10.1038/s41591-018-0301-6Google Scholar,3Thompson A.A. Walters M.C. Kwiatkowski J. Rasko J.E.J. Ribeil J.A. Hongeng S. Magrin E. Schiller G.J. Payen E. Semeraro M. et al.Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia.N. Engl. J. Med. 2018; 378: 1479-1493https://doi.org/10.1056/NEJMoa1705342Google Scholar In particular, the vector BB305 was used in phase 3 clinical trials (HGB-207 and HGB-212) to transduce hematopoietic stem cells of patients with TDT.4Pawliuk R. Westerman K.A. Fabry M.E. Payen E. Tighe R. Bouhassira E.E. Acharya S.A. Ellis J. London I.M. Eaves C.J. et al.Correction of sickle cell disease in transgenic mouse models by gene therapy.Science. 2001; 294: 2368-2371https://doi.org/10.1126/science.1065806Google Scholar The drug product (betibeglogene autotemcel or beti-cel; also known as Zynteglo) was then infused to treat 41 patients.1Locatelli F. Thompson A.A. Kwiatkowski J.L. Porter J.B. Thrasher A.J. Hongeng S. Sauer M.G. Thuret I. Lal A. Algeri M. et al.Betibeglogene Autotemcel Gene Therapy for Non-beta(0)/beta(0) Genotype beta-Thalassemia.N. Engl. J. Med. 2022; 386: 415-427https://doi.org/10.1056/NEJMoa2113206Google Scholar,3Thompson A.A. Walters M.C. Kwiatkowski J. Rasko J.E.J. Ribeil J.A. Hongeng S. Magrin E. Schiller G.J. Payen E. Semeraro M. et al.Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia.N. Engl. J. Med. 2018; 378: 1479-1493https://doi.org/10.1056/NEJMoa1705342Google Scholar Of these, 37 patients (90%) attained transfusion independence (as defined as an average hemoglobin level of ≥9 g/dL).5Whitney D. Ilya S. Maeva F. Marc d'A. Kelly K. Marisa G. Francis J.P. Richard A.C. Drug Product Attributes Predict Clinical Efficacy in betibeglogene autotemcel Gene Therapy for β-thalassemia.Molecular Therapy - Methods 31101155https://doi.org/10.1016/j.omtm.2023.101155Google Scholar Based on these results, in 2022, the FDA approved Zynteglo as the first cell-based gene therapy to treat adult and pediatric patients with TDT. The report by Dr. Whitney and colleagues investigated several manufacturing parameters for their potential to predict clinical efficacy, indicated as blood transfusion independence.5Whitney D. Ilya S. Maeva F. Marc d'A. Kelly K. Marisa G. Francis J.P. Richard A.C. Drug Product Attributes Predict Clinical Efficacy in betibeglogene autotemcel Gene Therapy for β-thalassemia.Molecular Therapy - Methods 31101155https://doi.org/10.1016/j.omtm.2023.101155Google Scholar They observed a significant correlation between peripheral blood vector copy number (VCN) and gene-therapy-derived therapeutic protein expression. The main finding is that patients showing peripheral VCN of ∼0.75 copies per diploid genome (c/dg) achieved blood transfusion independence. In contrast, patients with peripheral blood VCN 6 months post-infusion)a Summary of the best surrogate biomarkers and transfusion independence described in this manuscript.b Desirable additional correlation for present and future trials. Open table in a new tab This work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases Institute of the National Institutes of Health (R01 DK133475 and R01 DK095112), the Institute for Translational Medicine and Therapeutics (ITMAT), the Irish Health Research Board-Health Research Charities Ireland (HRCI-HRB), the Acceleration-Seed program/CHOP and The Sickle Cell and Red Cell Disorders Curative Therapy Center (CuRED) and the Molecular Therapies for Inborn Errors of Metabolism-Frontier Program, and the Institute of Regenerative Medicine (IRM)-University of Pennsylvania. S.R. is a scientific advisory board member of Ionis Pharmaceuticals, Meira GTx, Vifor, and Disc Medicine. Present–last 5 years: S.R. has been or is a consultant for GSK, BMS, Incyte, Cambridge Healthcare Res, Celgene Corporation, Catenion, First Manhattan Co., FORMA Therapeutics, Ghost Tree Capital, Keros Therapeutics, Noble Insight, Protagonist Therapeutics, Sanofi Aventis US, Slingshot Insight, Spexis AG, Techspert.io, BVF Partners L.P., Rallybio, LLC, venBio Select LLC, ExpertConnect LLC, and LifeSci Capital.