Gene Therapy and Hematopoietic Stem Cell Research to Treat Inherited Primary Immune Deficiencies

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

This project is focused on developing curative allogeneic HSC transplants and autologous HSC gene therapies (that include lentivector gene therapy, adeno-associated virus donor CRISPR editing gene therapy, single strand oligonucleotide donor CRISPR, base-editing CRISPR gene therapy, and prime editing CRISPR gene therapy) for primary immune deficiencies (PIDs) and primary immune regulatory disorders (PIRDs). Our laboratory program is designed to facilitate the translation of our laboratory efforts into therapeutic clinical trials of transplant and gene therapy. The project also must include clinical studies to understand the basic physiology, genetic defects, clinical problems, and management issues affecting the patient groups for which we are developing gene therapies. We use a variety of cell lines, primary patient cells, and animal models to develop these gene and cell therapy treatments; and a variety of tools including integrating and non-integrating gene transfer vectors, as well as gene editing reagents/approaches; as well as methods to transiently correct function in mature immune cells by transfection with mRNA. We also study means of enhancing HSC engraftment and preventing GVHD. Our 16 ongoing therapeutic, lab and clinic facilitating, and natural history clinical trials listed elsewhere in this report are a central element to progress of our research initiatives. The 20 publications associated with this report include outcomes of clinical trials of transplant and gene therapy as well as preclinical gene therapy advances, and reports of infection management in PID patients (primary chronic granulomatous disease) as well as management of inflammatory bowel disease in CGD. Some key highlights of these reports include: A first report of a clinical trial of successful lentivector gene therapy for artemis SCID published in the New England Journal of Medicine (Cowen MJ, et al. NEJM 387:2344). A report of both the utility and problems of granulocyte transfusions for CGD patients with severe infections going to allogeneic transplant (Arnold DE, et al. J Clin Immunol 42:1026). Reports of the utility of ustekinumab in management of inflammatory bowel disease in CGD patients (Bhattacharya S, et al. Clin Gastroenterol Hepatol 20:461. A report of the preclinical development of CRISPR gene editing to correct X-linked severe combined immune deficiency (Brault J, et al. Front Immunol 13:1067417). A Primary Immune Deficiency Treatment Consortium definitive report on the fact that geneotype, oxidase status, preceding infection or inflammation dotho significant affect outcome of allogeneic transplant for CGD (Blood In press).