Lastly, we show that this targeting strategy can be used for transfer of a therapeutic gene into CD34(+) cells obtained from patients suffering of X-linked chronic granulomatous disease.
Under the latter conditions, lentivector and MFGS achieved significant ex vivo correction of X-CGDCD34(+)PBSCs (18% and 54% of cells expressing gp91(phox), associated with 53% and 163% of normal superoxide production, respectively).
In the current study we demonstrate that the same vector (MFGS-gp91phox) pseudo-typed with RD114 envelope in a 4-day culture/transduction regimen results in a 7-fold increase in correction of NOD/SCID mouse repopulating X-CGDCD34+ PBSCs (14%-22% corrected human neutrophils; human cell engraftment 13%-67%).
Finally, Nox1 partially restores superoxide production in neutrophils differentiating ex vivo from gp91(phox)-deficient CD34(+) peripheral blood-derived stem cells derived from patients with X-linked chronic granulomatous disease.
These findings were recapitulated in human neutrophils derived from transduced X-CGDCD34(+) cells in vivo, and suggest that the chimeric promoter will have utility for gene therapy of myeloid lineage disorders such as CGD.