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

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

This project is focused on developing curative allogeneic HSC transplants and autologous HSC gene therapies 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 14 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. A summary of research accomplishments published during the reporting period for this report and deriving from studies in our lab and clinic, and in collaboration with other investigative teams follows below. The numbering refers to the number of the citation included in the Bibliography section associated with this report: Reference # 1. A novel definitive report about the use of allogeneic granulocyte transfusions to support patients with CGD undergoing bone marrow transplant, noting both the utility and the problems with development of anti-HLA antibodies in some patients receiving such transfusions before chemotherapy. 2. A definite report of the range of diagnostics findings using computerized tomography to delineate GI disease occurring in patients with CGD. 3. This is a report of the safety and efficacy of ustekinumab to treat severe inflammatory bowel disease in patients with CGD showing that some patients safely achieve significant benefit, but others either may not benefit or the improvement can be transient. 4. Improved methods of gene editing used to demonstrate functional correction of T cells and hematopoietic stem cells from patients with MAGT1 deficiency. 5. This is a report of development of a method of optimum conditions for CRISPR/Cas9 gene editing of human hematopoietic stem cells. 6. This report delineates the effect of a cryptic splice site present in a lentivector being used to treat patients with IL2RG deficient X-linked SCID, demonstrating the transient emergence of myeloid lineage benign clones in which the vector has inserted into the HMGA2 gene causing truncation of the HMGA2 gene product fusion with the virus vector. 7. Important gene editing methods patent application applying the methods of gene editing. 8. A novel artificial thymic organoid system combined with included pluripotent stem cells a an extraordinarily informative system for examining both the immune defect in RAG-2 deficiency and as a model to test methods to correct this immune deficiency. 9. Correction to reference #8 above 10. This is a report of the safety and efficacy of vedolizumab to treat severe inflammatory bowel disease in patients with CGD showing that some patients safely achieve significant benefit, but others either may not benefit or the improvement can be transient. 11. Definitive correction of Adenosine deaminase deficient SCID with lentivector gene therapy. 12. Editorial providing some history of gene editing as applied to treatment of hemoglobinopathies. 13. A review of the history of gene therapy targeting hematopoietic stem cells. 14. Biochemical study of the CGD pathogen Granulobacter bethesdensis. 15. Definitive study of a single center NIH experience with bacterial infections associated with transplant of patients with CGD. 16. Definitive report of the long term outcomes of gene therapy for ADA SCID using murine gamma retrovirus vectors indicating a broad range of degree of immune correction. 17. Categorization of mutations found to cause autosomal recessive CGD 18. Categorization of mutations found to cause X-linked CGD 19. A new clinical lentivector to treat the autosomal recessive p47phox deficient CGD has been developed that appears to be safe and effective and that will be used in a clinical trial in development that will open for recruitment in the next year. 20. NCF1 Arg90His mutations do not cause CGD but are associated with early onset autoimmune problems caused by interferon. 22. First demonstration of high level correction of X-linked CGD by gene editing using a AAV donor encoding the CYBB gene cDNA. 23. First demonstration of efficient gene editing correction of the sickle mutation in human patient blood stem cells in vitro and in a mouse/human xenograft model; and use of the same gene editing methods targeting the homologous genetic site to create the sickle trait in non-human primates. 24. This is a definitive report of showing that mutation of the IL37 gene can be a cause of infantile onset severe inflammatory bowel disease.