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Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91[sup.phox]. We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD., Author(s): Marion G Ott [1, 16]; Manfred Schmidt [2, 3, 4, 16]; Kerstin Schwarzwaelder [3, 4, 5, 16]; Stefan Stein [6, 16]; Ulrich Siler [7, 16]; Ulrike Koehl [8]; Hanno [...]

An abstract of the article "Correction of Chronic Granulomatous Disease by Gene Therapy," by Manuel Grez, Marion G. Ott, Stefan Stein, Ulrich Siler, Ulrike Koehl, Hana Kunkel, Andrea Schilz, Klaus Kuehlcke, Dieter Hoelzer and Reinhard Seger is presented.

An abstract of the article "Upscaling of Retroviral Vector Production under GMP Guidelines to Generate High Titer Preparations for Clinical Use," by Sandra Jung, Peter Leyendecker, Frank Kogelberg, Christian Wolf, Andrea Schilz, Klaus Kuehlcke and Sonja Naundorf is presented.

Myelosuppression is the main side effect of cancer chemotherapy. An improved rate of retroviral vector-mediated gene transfer to hematopoietic stem cells, shown in more recent clinical trials, has created the basis to test the concept of myeloprotective gene therapy. We transplanted clinical-scale human peripheral blood progenitor cell grafts (n = 2) transduced with retroviral vector SF91m3, which contains the human multidrug resistance 1 gene (MDR1), into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Engrafted mice of one cohort were protected from paclitaxel toxicity (p < 0.05) and we noted a similar trend in the second cohort. In paclitaxel-treated mice that had received gene-transduced cells we found a significant increase in gene marking (p < 0.05 - p < 0.01) or P-glycoprotein expression (p < 0.01) compared with their chemotherapy-naive counterparts. This is the first report showing that cytostatic drug resistance gene therapy can mediate chemoprotection of human clinically relevant stem cell populations with marrow engraftment potential.