This project involves the conduct of a therapeutic clinical trial using autologous blood stem cell targeted gene therapy to treat X-linked severe combined immune deficiency. Retroviral gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (gc) of receptors for interleukins (IL)-2, -4, -7, -9, -15 and -21. We investigated the safety and efficacy of gene therapy as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant(s) from a parent. Subjects received retrovirus transduced autologous peripherally mobilized CD34+ hematopoietic cells. Initial multi-lineage retroviral marking and improvements in health occurred in all 3 children, and T cell function significantly improved in the youngest subject (age 10 years). Since year 2009, all patients are at long term follow up stage. Long term benefit continues only in the youngest patient. The first treated patient undertook a matched, unrelated transplant successfully three years ago, while the second patient also underwent a matched, unrelated transplant three months ago. Further follow-up of clinical, immunologic and molecular parameters in the third patient is critical for establishing the long-term safety of this approach to gene therapy for pre-adolescents with XSCID who have failed to achieve or maintain immune reconstitution after BMT. In collaboration with investigators at St. Jude Children's Research Hospital, led by Brian Sorrentino at that institution, we are actively developing the vectors and procedures to embark on a clinical trial of gene therapy for X-SCID using a novel self-inactivating, insulated lentivector with short EF-1a mammalian internal promotor. A protocol for treating older children with X-linked severe combined immunodeficiency with a lentivector mediated gene transfer has been approved by the NIH Recombinant Advisory Committee, IBC, the NIAID IRB as well as the FDA. We will start treating patients in the next few months.

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Punwani, Divya; Kawahara, Misako; Yu, Jason et al. (2017) Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Hum Gene Ther 28:112-124
Brooks, Kristina M; Jarosinski, Paul; Hughes, Thomas et al. (2017) Test Dose Pharmacokinetics in Pediatric Patients Receiving Once-Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach? J Clin Pharmacol :
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
Panch, Sandhya R; Yau, Yu Ying; Kang, Elizabeth M et al. (2015) Mobilization characteristics and strategies to improve hematopoietic progenitor cell mobilization and collection in patients with chronic granulomatous disease and severe combined immunodeficiency. Transfusion 55:265-74
Felsburg, Peter J; De Ravin, Suk See; Malech, Harry L et al. (2015) Gene therapy studies in a canine model of X-linked severe combined immunodeficiency. Hum Gene Ther Clin Dev 26:50-6
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
Malech, Harry L; Ochs, Hans D (2015) An emerging era of clinical benefit from gene therapy. JAMA 313:1522-3
Kiem, Hans-Peter; Baum, Christopher; Bushman, Frederic D et al. (2014) Charting a clear path: the ASGCT Standardized Pathways Conference. Mol Ther 22:1235-1238
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; Su, Ling; Theobald, Narda et al. (2014) Enhancers are major targets for murine leukemia virus vector integration. J Virol 88:4504-13

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