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 hematopoietic stem cell (HSC) transplants and autologous HSC gene therapies (that include lentivector gene therapy, 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 with inborn error of immunity for which we are developing gene therapies. We use a variety of cell lines including induced pluripotent stem cells or EBV transformed B-cell lines derived from patient blood cells, primary patient cells that include HSCs, T-lymphocytes and monocytes, and animal models including immunodeficient mice that can support human marrow xenografts to develop these gene and cell therapy treatments; and a variety of tools including integrating and non-integrating gene transfer lentivectors, as well as gene editing reagents/approaches including base-editing and prime-editing; 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 9 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 fungal infection management in PID patients (primary chronic granulomatous disease) as well as management of inflammatory bowel disease in CGD. Also included in these publications are reviews of consensus conference discussions of approaches to platform and umbrella trials to facilitate regulatory approvals of gene editing treatments of rare inherited disorders (Kassim SH, et al. Nat Biotechnol 43, 1047-1049. and Urnov F, et al. Cytotherapy, in press). Some key highlights of these reports about transplant and gene therapy include: We completed and published pre-IND studies demonstrating efficient and persistent CRISPR base editing correction of CYBB gene mutations in patient hematopoietic stem cells (HSCs) leading to high level correction of oxidase activity in neutrophils progeny differentiated from these base-edited X-CGD HSCs (Bzhilyanskaya V, et al. Sci Transl Med 16, eadj6779) that supported the opening of a clinic trial. We have demonstrated that allogeneic donor bone marrow transplantation can be a safe and effective treatment of life-threatening invasive fungus infection unresponsive to conventional medical management in patients with chronic granulomatous disease (Kline A, et al. Bone Marrow Transplant 60, 191-200). An extensive review of the outcome of allogeneic hematopoietic stem cell transplants since 1995 for the p47phox deficient form of CGD by the multicenter Primary Immune Deficiency Treatment Consortium (PIDTC) demonstrated that this group of CGD patients significantly benefits from transplant in terms of amelioration of infection risk and cure or significant improvement in inflammation complications of CGD (Grunebaum E , et al, 2024. J Allergy Clin Immunol 153:1423). Pre-clinical studies provided proof that correction of the immune defects associated with RAG1 deficiency can be achieved by gene editing (Castiello MS, et al. 2024. Sci Transl Med 16, eadh8162). Gene editing correction of WHIM syndrome in a mouse model (Gao JL, et al. 2023. Blood 142, 23). We participated in a consortium collaborative assessment and demonstration of a high symptom burden observed to manifest in female carriers of X-linked CGD (Miranda MA, et al. Clin Immunol 268, 110364).