This project studies gene therapy for chronic granulomatous diseases (CGD) and other inherited immune diseases affecting human phagocytes, and also studies use of gene therapy to augment phagocyte host defense against chronic intracellular infections such as tuberculosis and other mycobacterial infections. CGD are a group of 4 distinct genetic disorders with common phenotype characterized by life-threatening recurrent infections caused by failure of blood neutrophils and monocytes to produce superoxide and hydrogen peroxide. CGD results from the failure to produce any of the components of the NADPH oxidase. We now have achieved retrovirus mediated gene transfer to functionally correct all four genetic forms of CGD by transfer of normal oxidase genes into CD34+ hematopoietic myeloid progenitor cells from CGD patients resulting in full correction of superoxide production by 5% to 80% of phagocytes differentiated from the progenitors. A closed plastic bag system for large scale growth and efficient retrovirus transduction of CD34+ progenitors has been developed in collaboration with Baxter Healthcare. Large scale production of the clinical grade replication defective retrovirus substantially free of animal proteins was developed in collaboration with Somatix Therapy Corp. Also, a sensitive FACS analysis system was developed to follow funtional correction of oxidase after gene transfer correction of CGD progenitors. These scientific accomplishments allowed approval by regulatory agencies of a Phase I clinical trial of gene therapy for the p47phox deficient form of autosomal recessive CGD. This clinical trial has begun and analysis of these studies is in progress. The development of an animal protein free growth and transduction regimen together with a completely closed system for growth and transduction of CD34+ blood progenitors is a major advance in enhancing safety of gene therapy and will provide a general platform for other applications of gene transfer technology based on targeting of hematopoietic progenitor cells.
NIH ExPorter
NIH ExPorter