Retroviral Gene Therapy for X-linked Chronic Granulomatous Disease: Results From Phase I/II Trial

Abstract

X-linked chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by a defect in the gp91(phox) gene. In an effort to treat X-CGD, we investigated the safety and efficacy of gene therapy using a retroviral vector, MT-gp91. Two X-CGD patients received autologous CD34(+) cells transduced with MT-gp91 after a conditioning regimen consisting of fludarabine and busulfan. The level of gene-marked cells was highest at day 21 (8.3 and 11.7% in peripheral blood cells) but decreased to 0.08 and 0.5%, respectively, 3 years after gene transfer. The level of functionally corrected cells, as determined by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assay, reached a peak at day 17 (6.5% patient 1 (P1) and 14.3% patient 2 (P2) of total granulocytes) and declined to 0.05% (P1) and 0.21% (P2), 3 years later. Some retroviral vectors were found to have integrated within or close to the proto-oncogenes MDS1-EVI1, PRDM16, and CCND2; however, no abnormal cell expansion or related hematological malignancy was observed. Overall, the gene transfer procedure did not produce any serious adverse effects and was able to convert a significant fraction of blood cells to biologically functional cells, albeit for a short period of time.

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

“…49 This can lead to a defective activation of cellular processes, which has also been observed in clinical trials for X-linked chronic granulomatous disease. Here, the overexpression of CYBB (gp90 phox ), a subunit of the reduced NAD phosphate oxidase enzyme complex, impaired long-term engraftment of HSCs after transplantation 50 resulting from improper ROS production. 51 The use of gene-editing techniques circumvents several of these issues.…”

Development of gene therapy for blood disorders: an update

“…44 Early trials done without myeloablation or limited myeloablation resulted in only transient production of genetically modified neutrophils, although a clinical benefit with clearance of a chronic infection was noted in several of the early patients. 1,5,[54][55][56] The initial clinical trials used g-retroviral vectors with an intact LTR, and not surprisingly, protooncogene activation occurred resulting in myelodysplasia in all of the successfully treated participants (Table 2). 24,57 In contrast to X-SCID, ADA-SCID, and WAS, the gene-corrected cells in CGD do not have an engraftment advantage, and thus, as treatment efforts evolve, regimens are likely to be more fully myeloablative.…”

Current status of haemophilia gene therapy

“…In theory, transduction and transplantation of a single genetically modified HSC can result in the complete repopulation of the haematopoietic compartment, whereby all cells would be genetically modified. In the clinical setting, many diseases have already been treated using lentiviral-modified HSCs, including adrenoleukodystrophy, metachromatic leukodystrophy, Wiskott-Aldrich syndrome, chronic granulomatous disease, SCID-X1, HIV and thalassemia [65][66][67][68][69][70][71].…”