Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease

Abstract

Little is known about the potential for engraftment of autologous hematopoietic stem cells in human adults not subjected to myeloablative conditioning regimens. Five adult patients with the p47 phox deficiency form of chronic granulomatous disease received intravenous infusions of autologous CD34 ؉ peripheral blood stem cells (PBSCs) that had been transduced ex vivo with a recombinant retrovirus encoding normal p47 phox . Although marrow conditioning was not given, functionally corrected granulocytes were detectable in peripheral blood of all five patients. Peak correction occurred 3-6 weeks after infusion and ranged from 0.004 to 0.05% of total peripheral blood granulocytes. Corrected cells were detectable for as long as 6 months after infusion in some individuals. Thus, prolonged engraftment of autologous PBSCs and continued expression of the transduced gene can occur in adults without conditioning. This trial also piloted the use of animal protein-free medium and a blood-bankcompatible closed system of gas-permeable plastic containers for culture and transduction of the PBSCs. These features enhance the safety of PBSCs directed gene therapy.

Abrogation of TGF-β activity during retroviral transduction improves murine hematopoietic progenitor and repopulating cell gene transfer efficiency

“…39,40 This would be desirable in the genetic therapy of congenital non-malignant disorders such as Gaucher disease or chronic granulomatous disease. 41,42 Materials and methods Mice All mice were purchased from the Jackson Laboratories (Bar Harbor, ME, USA). Female C57BL/6J (homozygous for the single ␤-hemoglobin haplotype) mice were used as bone marrow donors.…”

Successes and risks of gene therapy in primary immunodeficiencies

“…The study showed transient restoration of low levels of oxidase activity detectable in 0.06% to 0.2% of peripheral blood neutrophils. 58 These data suggest that gene therapy protocols for CGD and other PIs in which there is no physiologic selective advantage for corrected cells will need either myeloablation, more efficient gene transduction, or both to generate a large enough proportion of corrected cells to be clinically beneficial.…”

Progress and Prospects: Gene Therapy Clinical Trials (Part 1)

“…The first phase I/II gene therapy trials for CGD were conducted in the United States almost 11 years ago. [31][32][33] Although the level of correction achieved was low (0.004-0.6% functionally corrected cells), they provided clear evidence that a gene therapy approach for CGD was feasible and paved the way for further clinical trials. One common feature of these initial trials was the lack of bone marrow conditioning to enhance engraftment of transduced HSCs.…”