? PROJECT 3 The overall goal of this project is to determine if lentiviral gene therapy combined with subablative busulfan conditioning can be used to treat a broad spectrum of patients with severe combined immunodeficiency (XSCID). This catastrophic disease of childhood is caused by mutations in the IL2RG gene that lead to profound defects in T cell, NK cell, and B-cell mediated immunity. Allogeneic transplant is the standard therapy, but results in suboptimal outcomes in patients that lack matched sibling donors. While prior gene therapy trials with gamma- retroviral vectors showed clinical benefit, incomplete immune reconstitution and vector-related leukemia was seen in a significant number of cases. We propose a new approach using a safety-modified lentiviral vector and reduced intensity conditioning in order establish long-term correction via bone marrow engraftment of transduced hematopoietic stem cells. During the past funding period, we opened the first clinical lentiviral trials with subablative busulfan for XSCID and have obtained remarkable success in 12 cases treated thus far. The LVXSCID-OC trial at the NIH Clinical Center has enrolled eight XSCID patients who had waning immunity despite having undergone a prior allogeneic transplant. These cases have shown high levels of myeloid marking that are unprecedented in prior XSCID gene therapy trials and complete immune reconstitution in some cases. In particular, B cell function was restored in the first two cases leading to independence from gamma-globulin replacement therapy, which has not been obtained in prior gene therapy trials. We have also opened a newly diagnosed protocol (LVXSCID-ND) at St. Jude, UCSF, and Seattle and have treated four infants with transduced bone marrow cells following targeted subablative conditioning over the past seven months. Gene marking in blood and bone marrow myeloid cells has been very high and has been associated with rapid reconstitution of T and NK cell numbers and function. B cell marking levels have averaged 0.8 copies/cell and have been noted with preliminary evidence of endogenous gamma-globulin production in one case. Based on these results, we now seek support to complete both of these Phase I studies by validating more GMP-grade vector batches, completing enrollment on both protocols, and performing detailed, long term analyses of immune reconstitution, vector marking/clonality studies, and clinical safety in these cases. We anticipate that these studies will provide a new therapy for XSCID and leading to commercialization of this gene therapy approach so that this treatment can be made widely available.

Public Health Relevance

? PROJECT 3 The overall objective of this project is to test the use of safety modified, lentiviral vector and subablative busulfan conditioning for gene therapy in two independent phase I studies. The long-term goal is to develop a new, curative form of gene therapy for XSCID.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL053749-23
Application #
9983811
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Qasba, Pankaj
Project Start
Project End
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
23
Fiscal Year
2020
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Abraham, Allistair; Kim, Yoon-Sang; Zhao, Huifen et al. (2016) Increased Engraftment of Human Short Term Repopulating Hematopoietic Cells in NOD/SCID/IL2r?null Mice by Lentiviral Expression of NUP98-HOXA10HD. PLoS One 11:e0147059
Wielgosz, Matthew M; Kim, Yoon-Sang; Carney, Gael G et al. (2015) Generation of a lentiviral vector producer cell clone for human Wiskott-Aldrich syndrome gene therapy. Mol Ther Methods Clin Dev 2:14063
Pestina, Tamara I; Hargrove, Phillip W; Zhao, Huifen et al. (2015) Amelioration of murine sickle cell disease by nonablative conditioning and ?-globin gene-corrected bone marrow cells. Mol Ther Methods Clin Dev 2:15045
Zhou, Sheng; Bonner, Melissa A; Wang, Yong-Dong et al. (2015) Quantitative shearing linear amplification polymerase chain reaction: an improved method for quantifying lentiviral vector insertion sites in transplanted hematopoietic cell systems. Hum Gene Ther Methods 26:4-12
Urbinati, Fabrizia; Hargrove, Phillip W; Geiger, Sabine et al. (2015) Potentially therapeutic levels of anti-sickling globin gene expression following lentivirus-mediated gene transfer in sickle cell disease bone marrow CD34+ cells. Exp Hematol 43:346-351
Treanor, Louise M; Zhou, Sheng; Janke, Laura et al. (2014) Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential. J Exp Med 211:701-13
Griffith, Linda M; Cowan, Morton J; Notarangelo, Luigi D et al. (2014) Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol 133:335-47
De Ravin, Suk See; Gray, John T; Throm, Robert E et al. (2014) False-positive HIV PCR test following ex vivo lentiviral gene transfer treatment of X-linked severe combined immunodeficiency vector. Mol Ther 22:244-245

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