This project involves the conduct of a therapeutic clinical trial using autologous blood stem cell gene therapy to treat X-linked severe combined immune deficiency. 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. Our goal is to investigate the safety and efficacy of gene transfer treatment as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant(s). In our now closed earlier protocol that provided background to the current lentivector protocol, we used gamma-retroviral vector to mediate the gene transfer without any conditioning regimen, which did not achieve sustained correction and expansion of the genetically corrected lymphoid cells. We have in April 2016 published the first report of the first five of six older subjects with partially corrected X-SCID, treated using a integrating lentivector mediated gene transfer combined with mild/moderate dose of busulfan 6mg/kg total for myeloconditioning (De Ravin SS, et al. Sci Transl Med April 2016) that is the major scientific accomplishment for this report. This vector is developed in collaboration with extramural investigators (Dr Brian Sorrentino and Dr John Gray) at St Jude Children's Research Hospital, Memphis. To date no serious adverse events have been observed. Significant levels of myeloid gene marking is observed, and in patients with sufficient length of follow-up, the gene marking in T and B cells continues to improve, with associated clinical benefits. To date, the gene integration pattern appears polyclonal. Formal assessment for clinical benefit from the therapy is performed at two years after treatment.

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10
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2016
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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
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
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
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

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