737. Long Term Correction of Canine X-Linked Severe Combined Immunodeficiency by In Vivo Gene Therapy Using Retroviral or Lentiviral Vectors

Abstract Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA–severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children's growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 and #NCT00599781.

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Long-Term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-Linked Severe Combined Immunodeficiency

Science Translational Medicine ◽

10.1126/scitranslmed.3002715 ◽

2011 ◽

Vol 3 (97) ◽

pp. 97ra79-97ra79 ◽

Cited By ~ 129

Author(s):

H. B. Gaspar ◽

S. Cooray ◽

K. C. Gilmour ◽

K. L. Parsley ◽

S. Adams ◽

...

Keyword(s):

Gene Therapy ◽

T Cell ◽

Severe Combined Immunodeficiency ◽

T Cell Repertoire ◽

Combined Immunodeficiency ◽

Cell Repertoire

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Severe Combined Immunodeficiency Mice Engrafted With Human T Cells, B Cells, and Myeloid Cells After Transplantation With Human Fetal Bone Marrow or Liver Cells and Implanted With Human Fetal Thymus: A Model for Studying Human Gene Therapy

Blood ◽

10.1182/blood.v89.5.1800.1800_1800_1810 ◽

1997 ◽

Vol 89 (5) ◽

pp. 1800-1810 ◽

Cited By ~ 5

Author(s):

Sergey Yurasov ◽

Tobias R. Kollmann ◽

Ana Kim ◽

Christina A. Raker ◽

Moshe Hachamovitch ◽

...

Keyword(s):

Gene Therapy ◽

Bone Marrow ◽

T Cells ◽

Peripheral Blood ◽

Severe Combined Immunodeficiency ◽

Precursor Cells ◽

Scid Mice ◽

Combined Immunodeficiency ◽

Human T Cells

To develop an in vivo model wherein human hematopoiesis occurs, we transplanted severe combined immunodeficiency (SCID) mice with either human fetal bone marrow (HFBM) or human fetal liver (HFL). After transplantation of SCID mice with cultured HFBM (BM-SCID-hu mice) or HFL cells (Liv-SCID-hu mice), significant engraftment of the mouse bone marrow (BM) and population of the peripheral blood with human leukocytes was detected. Human colony-forming unit–granulocyte macrophage and burst forming unit-erythroid were detected in the BM of the BM-SCID-hu and Liv-SCID-hu mice up to 8 months after transplantation. When the HFBM or HFL cells were transduced with a retroviral vector before transplantation, integrated retroviral sequences were detected in human precursor cells present in the SCID mouse BM and in leukocytes circulating in the peripheral blood (PB) up to 7 months after transplantation. The PB of the BM-SCID-hu mice also became populated with human T cells after implantation with human thymic tissue, which provided a human microenvironment wherein human pre-T cells from the BM could mature. When the HFBM was retrovirally transduced before transplantation, integrated retrovirus was detected in sorted CD4+CD8+ double positive and CD4+ single positive cells from the thymic implant and CD4+ cells from the PB. Taken together, these data indicated that the BM of our BM-SCID-hu and Liv-SCID-hu mice became engrafted with retrovirally transduced human hematopoietic precursors that undergo the normal human hematopoietic program and populate the mouse PB with human cells containing integrated retroviral sequences. In addition to being a model for studying in vivo human hematopoiesis, these mice should also prove to be a useful model for investigating in vivo gene therapy using human stem/precursor cells.

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441. Direct Comparison of EF1α and PGK Promoters Reveals Superior Performance of the PGK Promoter for Expression of the Common Gamma Chain in a Canine Model of In Vivo Foamy Virus Gene Therapy for Severe Combined Immunodeficiency

Molecular Therapy ◽

10.1016/s1525-0016(16)34050-3 ◽

2015 ◽

Vol 23 ◽

pp. S174-S175

Author(s):

Christopher R. Burtner ◽

Humbert Olivier ◽

Patricia O'Donnell ◽

Nicholas Hubbard ◽

Daniel Humphrys ◽

...

Keyword(s):

Gene Therapy ◽

Foamy Virus ◽

Severe Combined Immunodeficiency ◽

Canine Model ◽

Superior Performance ◽

Combined Immunodeficiency ◽

Gamma Chain ◽

Virus Gene ◽

The Common

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Gene therapy in PIDs, hemoglobin, ocular, neurodegenerative, and hemophilia B disorders

Open Life Sciences ◽

10.1515/biol-2021-0033 ◽

2021 ◽

Vol 16 (1) ◽

pp. 431-441

Author(s):

Arome Solomon Odiba ◽

Nkwachukwu Oziamara Okoro ◽

Olanrewaju Ayodeji Durojaye ◽

Yanjun Wu

Keyword(s):

Gene Therapy ◽

Gene Transfer ◽

Globin Gene ◽

Severe Combined Immunodeficiency ◽

Retinal Disease ◽

Cell Types ◽

Biologically Active ◽

Hemophilia B ◽

Combined Immunodeficiency

Abstract A new approach is adopted to treat primary immunodeficiency disorders, such as the severe combined immunodeficiency (SCID; e.g., adenosine deaminase SCID [ADA-SCID] and IL-2 receptor X-linked severe combined immunodeficiency [SCID-X1]). The success, along with the feasibility of gene therapy, is undeniable when considering the benefits recorded for patients with different classes of diseases or disorders needing treatment, including SCID-X1 and ADA-SCID, within the last two decades. β-Thalassemia and sickle cell anemia are two prominent monogenic blood hemoglobin disorders for which a solution has been sought using gene therapy. For instance, transduced autologous CD34+ HSCs via a self-inactivating (SIN)-Lentivirus (LV) coding for a functional copy of the β-globin gene has become a feasible procedure. adeno-associated virus (AAV) vectors have found application in ocular gene transfer in retinal disease gene therapy (e.g., Leber’s congenital amaurosis type 2), where no prior treatment existed. In neurodegenerative disorders, successes are now reported for cases involving metachromatic leukodystrophy causing severe cognitive and motor damage. Gene therapy for hemophilia also remains a viable option because of the amount of cell types that are capable of synthesizing biologically active FVIII and FIX following gene transfer using AAV vectors in vivo to correct hemophilia B (FIX deficiency), and it is considered an ideal target, as proven in preclinical studies. Recently, the clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 gene-editing tool has taken a center stage in gene therapy research and is reported to be efficient and highly precise. The application of gene therapy to these areas has pushed forward the therapeutic clinical application.

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Restoration of Lymphoid Populations in a Murine Model of X-Linked Severe Combined Immunodeficiency by a Gene-Therapy Approach

Blood ◽

10.1182/blood.v94.9.3027.421k11_3027_3036 ◽

1999 ◽

Vol 94 (9) ◽

pp. 3027-3036 ◽

Cited By ~ 1

Author(s):

Mindy Lo ◽

Michael L. Bloom ◽

Kazunori Imada ◽

Maria Berg ◽

Julie M. Bollenbacher ◽

...

Keyword(s):

Gene Therapy ◽

Murine Model ◽

Severe Combined Immunodeficiency ◽

Interleukin 2 ◽

Intraepithelial Lymphocytes ◽

Cytokine Receptor ◽

Combined Immunodeficiency ◽

Hematopoietic Stem ◽

Deficient Mice

X-linked severe combined immunodeficiency (XSCID) is a life-threatening syndrome in which both cellular and humoral immunity are profoundly compromised. This disease results from mutations in theIL2RG gene, which encodes the common cytokine receptor γ chain, γc. Previously, we generated γc-deficient mice as a murine model of XSCID. We have now used lethally irradiated γc-deficient mice to evaluate a gene therapeutic approach for treatment of this disease. Transfer of the human γc gene to repopulating hematopoietic stem cells using an ecotropic retrovirus resulted in an increase in T cells, B cells, natural killer (NK) cells, and intestinal intraepithelial lymphocytes, as well as normalization of the CD4:CD8 T-cell ratio and of serum Ig levels. In addition, the restored cells could proliferate in response to interleukin-2 (IL-2). Thus, our results provide added support that gene therapy is a feasible therapeutic strategy for XSCID. Moreover, because we used a vector directing expression of human γc to correct a defect in γc-deficient mice, these data also indicate that human γc can cooperate with the distinctive cytokine receptor chains such as IL-2Rβ and IL-7R to mediate responses to murine cytokines in vivo.

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Restoration of Lymphoid Populations in a Murine Model of X-Linked Severe Combined Immunodeficiency by a Gene-Therapy Approach

Blood ◽

10.1182/blood.v94.9.3027 ◽

1999 ◽

Vol 94 (9) ◽

pp. 3027-3036 ◽

Cited By ~ 60

Author(s):

Mindy Lo ◽

Michael L. Bloom ◽

Kazunori Imada ◽

Maria Berg ◽

Julie M. Bollenbacher ◽

...

Keyword(s):

Gene Therapy ◽

Murine Model ◽

Severe Combined Immunodeficiency ◽

Interleukin 2 ◽

Intraepithelial Lymphocytes ◽

Cytokine Receptor ◽

Combined Immunodeficiency ◽

Hematopoietic Stem ◽

Deficient Mice

Abstract X-linked severe combined immunodeficiency (XSCID) is a life-threatening syndrome in which both cellular and humoral immunity are profoundly compromised. This disease results from mutations in theIL2RG gene, which encodes the common cytokine receptor γ chain, γc. Previously, we generated γc-deficient mice as a murine model of XSCID. We have now used lethally irradiated γc-deficient mice to evaluate a gene therapeutic approach for treatment of this disease. Transfer of the human γc gene to repopulating hematopoietic stem cells using an ecotropic retrovirus resulted in an increase in T cells, B cells, natural killer (NK) cells, and intestinal intraepithelial lymphocytes, as well as normalization of the CD4:CD8 T-cell ratio and of serum Ig levels. In addition, the restored cells could proliferate in response to interleukin-2 (IL-2). Thus, our results provide added support that gene therapy is a feasible therapeutic strategy for XSCID. Moreover, because we used a vector directing expression of human γc to correct a defect in γc-deficient mice, these data also indicate that human γc can cooperate with the distinctive cytokine receptor chains such as IL-2Rβ and IL-7R to mediate responses to murine cytokines in vivo.

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