Lentiviral Hematopoietic Stem Cell Gene Therapy for X-linked Severe Combined Immunodeficiency

Overview

Journal Sci Transl Med

Specialties General Medicine
Science

Date 2016 Apr 22

PMID 27099176

Citations 134

Authors

Suk See de Ravin

Xiaolin Wu

Susan Moir

Sandra Anaya-OBrien

Nana Kwatemaa

Patricia Littel

Narda Theobald

Uimook Choi

Ling Su

Martha Marquesen

Dianne Hilligoss

Janet Lee

Clarissa M Buckner

Kol A Zarember

Geraldine OConnor

Daniel McVicar

Douglas Kuhns

Robert E Throm

Sheng Zhou

Luigi D Notarangelo

I Celine Hanson

Mort J Cowan

Elizabeth Kang

Coleen Hadigan

Michael Meagher

John T Gray

Brian P Sorrentino

Harry L Malech

Lela Kardava

Affiliations

Soon will be listed here.

Abstract

X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1.

Citing Articles

Viral-based gene therapy clinical trials for immune deficiencies and blood disorders from 2013 until 2023 - an overview.

Eshghi S, Mousakhan Bakhtiari M, Behfar M, Izadi E, Naji P, Jafari L Regen Ther. 2025; 28():262-279.

PMID: 39844821 PMC: 11751425. DOI: 10.1016/j.reth.2024.12.007.

Cardiomyopathy: pathogenesis and therapeutic interventions.

Huang S, Li J, Li Q, Wang Q, Zhou X, Chen J MedComm (2020). 2024; 5(11):e772.

PMID: 39465141 PMC: 11502724. DOI: 10.1002/mco2.772.

High-fidelity PAMless base editing of hematopoietic stem cells to treat chronic granulomatous disease.

Bzhilyanskaya V, Ma L, Liu S, Fox L, Whittaker M, Meis R Sci Transl Med. 2024; 16(769):eadj6779.

PMID: 39413163 PMC: 11753194. DOI: 10.1126/scitranslmed.adj6779.

Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency.

Zakas P, Cunningham S, Doherty A, van Dijk E, Ibraheim R, Yu S Mol Ther. 2024; 32(10):3356-3371.

PMID: 38981468 PMC: 11489535. DOI: 10.1016/j.ymthe.2024.06.021.

International Society for Cell & Gene Therapy Stem Cell Engineering Committee report on the current state of hematopoietic stem and progenitor cell-based genomic therapies and the challenges faced.

Gupta A, Azul M, Bhoopalan S, Abraham A, Bertaina A, Bidgoli A Cytotherapy. 2024; 26(11):1411-1420.

PMID: 38970612 PMC: 11471386. DOI: 10.1016/j.jcyt.2024.06.002.

References

Chinen J, Davis J, de Ravin S, Hay B, Hsu A, Linton G . Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency. Blood. 2007; 110(1):67-73. PMC: 1896128. DOI: 10.1182/blood-2006-11-058933. View

Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F . Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010; 467(7313):318-22. PMC: 3355472. DOI: 10.1038/nature09328. View

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

Dell Railey M, Lokhnygina Y, Buckley R . Long-term clinical outcome of patients with severe combined immunodeficiency who received related donor bone marrow transplants without pretransplant chemotherapy or post-transplant GVHD prophylaxis. J Pediatr. 2009; 155(6):834-840.e1. PMC: 2784223. DOI: 10.1016/j.jpeds.2009.07.049. View

Wu X, Li Y, Crise B, Burgess S . Transcription start regions in the human genome are favored targets for MLV integration. Science. 2003; 300(5626):1749-51. DOI: 10.1126/science.1083413. View

Greene M, Lockey T, Mehta P, Kim Y, Eldridge P, Gray J . Transduction of human CD34+ repopulating cells with a self-inactivating lentiviral vector for SCID-X1 produced at clinical scale by a stable cell line. Hum Gene Ther Methods. 2012; 23(5):297-308. PMC: 3732136. DOI: 10.1089/hgtb.2012.150. View

Suryani S, Fulcher D, Santner-Nanan B, Nanan R, Wong M, Shaw P . Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood. 2009; 115(3):519-29. DOI: 10.1182/blood-2009-07-234799. View

Deichmann A, Hacein-Bey-Abina S, Schmidt M, Garrigue A, Brugman M, Hu J . Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy. J Clin Invest. 2007; 117(8):2225-32. PMC: 1934585. DOI: 10.1172/JCI31659. View

Thrasher A, Hacein-Bey-Abina S, Gaspar H, Blanche S, Davies E, Parsley K . Failure of SCID-X1 gene therapy in older patients. Blood. 2005; 105(11):4255-7. DOI: 10.1182/blood-2004-12-4837. View

10.

Throm R, Ouma A, Zhou S, Chandrasekaran A, Lockey T, Greene M . Efficient construction of producer cell lines for a SIN lentiviral vector for SCID-X1 gene therapy by concatemeric array transfection. Blood. 2009; 113(21):5104-10. PMC: 2686181. DOI: 10.1182/blood-2008-11-191049. View

11.

Kamili Q, Seeborg F, Saxena K, Nicholas S, Banerjee P, Angelo L . Severe cutaneous human papillomavirus infection associated with natural killer cell deficiency following stem cell transplantation for severe combined immunodeficiency. J Allergy Clin Immunol. 2014; 134(6):1451-1453.e1. PMC: 5182041. DOI: 10.1016/j.jaci.2014.07.009. View

12.

Pai S, Logan B, Griffith L, Buckley R, Parrott R, Dvorak C . Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014; 371(5):434-46. PMC: 4183064. DOI: 10.1056/NEJMoa1401177. View

13.

Huang D, Sherman B, Lempicki R . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2008; 37(1):1-13. PMC: 2615629. DOI: 10.1093/nar/gkn923. View

14.

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

15.

Zhou S, Mody D, DeRavin S, Hauer J, Lu T, Ma Z . A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. Blood. 2010; 116(6):900-8. PMC: 2924228. DOI: 10.1182/blood-2009-10-250209. View

16.

Hacein-Bey-Abina S, Pai S, Gaspar H, Armant M, Berry C, Blanche S . A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med. 2014; 371(15):1407-17. PMC: 4274995. DOI: 10.1056/NEJMoa1404588. View

17.

Neven B, Leroy S, Decaluwe H, Le Deist F, Picard C, Moshous D . Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood. 2009; 113(17):4114-24. DOI: 10.1182/blood-2008-09-177923. View

18.

Gillet N, Malani N, Melamed A, Gormley N, Carter R, Bentley D . The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones. Blood. 2011; 117(11):3113-22. PMC: 3062313. DOI: 10.1182/blood-2010-10-312926. View

19.

Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T . Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013; 341(6148):1233158. DOI: 10.1126/science.1233158. View

20.

Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E . A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003; 348(3):255-6. DOI: 10.1056/NEJM200301163480314. View