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Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

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 (?c) of several interleukin receptors. Gamma-retroviral (?RV) 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 ?c 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.

SUBMITTER: De Ravin SS

PROVIDER: S-EPMC5557273 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

De Ravin Suk See SS Wu Xiaolin X Moir Susan S Anaya-O'Brien Sandra S Kwatemaa Nana N Littel Patricia P Theobald Narda N Choi Uimook U Su Ling L Marquesen Martha M Hilligoss Dianne D Lee Janet J Buckner Clarissa M CM Zarember Kol A KA O'Connor Geraldine G McVicar Daniel D Kuhns Douglas D Throm Robert E RE Zhou Sheng S Notarangelo Luigi D LD Hanson I Celine IC Cowan Mort J MJ Kang Elizabeth E Hadigan Coleen C Meagher Michael M Gray John T JT Sorrentino Brian P BP Malech Harry L HL Kardava Lela

Science translational medicine 20160401 335

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 immun ...[more]

PMID: 27099176

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Project description:IntroductionEx vivo gene therapy for treatment of Inborn errors of Immunity (IEIs) have demonstrated significant clinical benefit in multiple Phase I/II clinical trials. Current approaches rely on engineered retroviral vectors to randomly integrate copy(s) of gene-of-interest in autologous hematopoietic stem/progenitor cells (HSPCs) genome permanently to provide gene function in transduced HSPCs and their progenies. To circumvent concerns related to potential genotoxicities due to the random vector integrations in HSPCs, targeted correction with CRISPR-Cas9-based genome editing offers improved precision for functional correction of multiple IEIs.MethodsWe compare the two approaches for integration of IL2RG transgene for functional correction of HSPCs from patients with X-linked Severe Combined Immunodeficiency (SCID-X1 or XSCID); delivery via current clinical lentivector (LV)-IL2RG versus targeted insertion (TI) of IL2RG via homology-directed repair (HDR) when using an adeno-associated virus (AAV)-IL2RG donor following double-strand DNA break at the endogenous IL2RG locus.Results and discussionIn vitro differentiation of LV- or TI-treated XSCID HSPCs similarly overcome differentiation block into Pre-T-I and Pre-T-II lymphocytes but we observed significantly superior development of NK cells when corrected by TI (40.7% versus 4.1%, p = 0.0099). Transplants into immunodeficient mice demonstrated robust engraftment (8.1% and 23.3% in bone marrow) for LV- and TI-IL2RG HSPCs with efficient T cell development following TI-IL2RG in all four patients' HSPCs. Extensive specificity analysis of CRISPR-Cas9 editing with rhAmpSeq covering 82 predicted off-target sites found no evidence of indels in edited cells before (in vitro) or following transplant, in stark contrast to LV's non-targeted vector integration sites. Together, the improved efficiency and safety of IL2RG correction via CRISPR-Cas9-based TI approach provides a strong rationale for a clinical trial for treatment of XSCID patients.

Dataset Information

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

Publications

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

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