Gene Therapy for Primary Immunodeficiency

Overview

Journal Hemasphere

Publisher Wiley

Specialty Hematology

Date 2021 Jan 6

PMID 33403354

Citations 8

Authors

Benjamin C Houghton

Claire Booth

Affiliations

Soon will be listed here.

Abstract

Over the past 3 decades, there has been significant progress in refining gene therapy technologies and procedures. Transduction of hematopoietic stem cells ex vivo using lentiviral vectors can now create a highly effective therapeutic product, capable of reconstituting many different immune system dysfunctions when reinfused into patients. Here, we review the key developments in the gene therapy landscape for primary immune deficiency, from an experimental therapy where clinical efficacy was marred by adverse events, to a commercialized product with enhanced safety and efficacy. We also discuss progress being made in preclinical studies for challenging disease targets and emerging gene editing technologies that are showing promising results, particularly for conditions where gene regulation is important for efficacy.

Citing Articles

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Novel gene therapy advances for treating primary immunodeficiency disorders - an update.

Amin R, Darwin R, Chakraborty S, Dey B, Dhama K, Emran T Ann Med Surg (Lond). 2023; 85(12):5859-5862.

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The PID Odyssey 2030: outlooks, unmet needs, hurdles, and opportunities - proceedings from the IPOPI global multi-stakeholders' summit (June 2022).

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Improved Outcome Following Busulfan-Based Conditioning in Children with Functional Neutrophil Disorders Undergoing Hematopoietic Stem Cell Transplant from HLA-Matched Donors.

Jacoby E, Adam E, Hutt D, Somech R, Malkiel S, Toren A J Clin Immunol. 2023; 43(7):1603-1610.

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References

Hale J, Youngblood B, Latner D, Mohammed A, Ye L, Akondy R . Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity. 2013; 38(4):805-17. PMC: 3741679. DOI: 10.1016/j.immuni.2013.02.020. View

Ferrua F, Galimberti S, Courteille V, Slatter M, Booth C, Moshous D . Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study. J Allergy Clin Immunol. 2019; 143(6):2238-2253. DOI: 10.1016/j.jaci.2018.12.1010. View

Cicalese M, Ferrua F, Castagnaro L, Rolfe K, De Boever E, Reinhardt R . Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety. Mol Ther. 2018; 26(3):917-931. PMC: 5910668. DOI: 10.1016/j.ymthe.2017.12.022. View

Bauler M, Roberts J, Wu C, Fan B, Ferrara F, Yip B . Production of Lentiviral Vectors Using Suspension Cells Grown in Serum-free Media. Mol Ther Methods Clin Dev. 2020; 17:58-68. PMC: 6931067. DOI: 10.1016/j.omtm.2019.11.011. View

Noguchi M, Yi H, Rosenblatt H, Filipovich A, Adelstein S, Modi W . Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993; 73(1):147-57. DOI: 10.1016/0092-8674(93)90167-o. View

Bauer Jr T, Hickstein D . Gene therapy for leukocyte adhesion deficiency. Curr Opin Mol Ther. 2001; 2(4):383-8. View

Tebas P, Stein D, Tang W, Frank I, Wang S, Lee G . Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014; 370(10):901-10. PMC: 4084652. DOI: 10.1056/NEJMoa1300662. View

Chiesa R, Wang J, Blok H, Hazelaar S, Neven B, Moshous D . Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood. 2020; 136(10):1201-1211. DOI: 10.1182/blood.2020005590. View

Labrosse R, Chu J, Armant M, Everett J, Pellin D, Kareddy N . Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Blood. 2023; 142(15):1281-1296. PMC: 10731922. DOI: 10.1182/blood.2022019117. View

10.

Petrillo C, Thorne L, Unali G, Schiroli G, Giordano A, Piras F . Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells. Cell Stem Cell. 2018; 23(6):820-832.e9. PMC: 6292841. DOI: 10.1016/j.stem.2018.10.008. View

11.

de Ravin S, Wu X, Moir S, Anaya-OBrien S, Kwatemaa N, Littel P . Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016; 8(335):335ra57. PMC: 5557273. DOI: 10.1126/scitranslmed.aad8856. View

12.

Schambach A, Bohne J, Chandra S, Will E, Margison G, Williams D . Equal potency of gammaretroviral and lentiviral SIN vectors for expression of O6-methylguanine-DNA methyltransferase in hematopoietic cells. Mol Ther. 2005; 13(2):391-400. DOI: 10.1016/j.ymthe.2005.08.012. View

13.

Hacein-Bey-Abina S, Garrigue A, Wang G, Soulier J, Lim A, Morillon E . Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008; 118(9):3132-42. PMC: 2496963. DOI: 10.1172/JCI35700. View

14.

de la Morena M, Leonard D, Torgerson T, Cabral-Marques O, Slatter M, Aghamohammadi A . Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2016; 139(4):1282-1292. PMC: 5374029. DOI: 10.1016/j.jaci.2016.07.039. View

15.

Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L . Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009; 360(5):447-58. DOI: 10.1056/NEJMoa0805817. View

16.

Hacein-Bey Abina S, Gaspar H, Blondeau J, Caccavelli L, Charrier S, Buckland K . Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015; 313(15):1550-63. PMC: 4942841. DOI: 10.1001/jama.2015.3253. View

17.

Fischer A . Platelets are the Achilles' heel of Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2019; 144(3):668-670. DOI: 10.1016/j.jaci.2019.06.039. View

18.

Sacco M, Ungari M, Cato E, Villa A, Strina D, Notarangelo L . Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome. Cancer Gene Ther. 2000; 7(10):1299-306. DOI: 10.1038/sj.cgt.7700232. View

19.

Ott M, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U . Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006; 12(4):401-9. DOI: 10.1038/nm1393. View

20.

Brown M, Topham D, Sangster M, Zhao J, Flynn K, Surman S . Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nat Med. 1998; 4(11):1253-60. DOI: 10.1038/3233. View