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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2001-12-0165.
Submitted December 6, 2001
Accepted July 23, 2002
3rd Generation Self-Inactivating gp91phox Lentivector Corrects the Oxidase Defect in NOD/SCID Mouse Repopulating Peripheral Blood Mobilized CD34+ Cells from Patients with X-linked Chronic Granulomatous Disease
Joachim Roesler, Sebastian Brenner, Anatoly A Bukovsky, Narda Whiting-Theobald, Thomas Dull, Michael Kelly, Curt I Civin, and Harry L Malech*
Laboratory of Host Defenses, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
Cell Genesys, Inc., Foster City, CA, USA
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* Corresponding author; email: hmalech{at}nih.gov.
HIV-1 derived lentivectors are promising for gene transfer into hematopoietic stem cells, but require pre-clinical in vivo evaluation relevant to specific human diseases. Non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice accept human hematopoietic stem cell grafts providing a unique opportunity for in vivo evaluation of therapies targeting human hematopoietic diseases. We demonstrate for the first time that hematopoietic stem cells from X-linked chronic granulomatous disease (X-CGD) patients give rise to X-CGD phenotype neutrophils in the NOD/SCID model that can be corrected using VSV-G pseudotyped 3rd generation self-inactivating (SIN) lentivector encoding gp91phox. We transduced X-CGD patient mobilized CD34+ peripheral blood stem cells (CD34+PBSC) with lentivector-gp91phox or amphotropic onco-retrovirus MFGS-gp91phox and evaluated correction ex vivo and in vivo in NOD/SCID mice. Only lentivector transduced CD34+PBSC under ex vivo conditions non-permissive for cell division, but both vectors performed best under conditions permissive for proliferation (multiple growth factors). Under the latter conditions both lentivector and MFGS achieved significant ex vivo correction of X-CGD CD34+PBSC (18% and 54% of cells expressing gp91phox, associated with 53% and 163% of normal superoxide production, respectively). However, lentivector, but not MFGS, achieved significant correction of human X-CGD neutrophils arising in vivo in transplanted NOD/SCID mice (20% and 2.4%, respectively). Thus, 3rd generation SIN lentivector-gp91phox performs well as assessed in human X-CGD neutrophils differentiating in vivo, and our studies suggest that the NOD/SCID model is generally applicable for in vivo study of therapies evaluated in human blood cells expressing a specific disease phenotype.
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