Major Areas of Research
- Clinical trials and basic research of gene therapy using ex vivo transduction of autologous CD34+ hematopoietic stem cells
- Allogeneic transplantation using hematopoietic stem cell grafts
- Chronic granulomatous disease
- X-linked severe combined immune deficiency
- Leukocyte adhesion deficiency
- WHIM syndrome
- Acute and chronic graft versus host disease
- Biology of engraftment of hematopoietic stem cells and the role of the CXCR4 chemokine receptor
- Excessive inflammation and associated autoimmune symptoms with primary immune deficiencies (PIDs)
- Induced pluripotent stem cells used to model human immune deficiencies and for development of novel treatments
The research program of GIS includes both clinical trials and basic bench research. Clinical trials include studies of gene therapy using ex vivo transduction of autologous CD34+ hematopoietic stem cells, as well as studies of allogeneic transplantation using matched-sibling donor or matched-unrelated donor (MUD) hematopoietic stem cell grafts with sub-ablative marrow conditioning plus alloimmune tolerance induction regimens. Elizabeth Kang, M.D., staff clinician and chief of the hematotherapeutics unit of GIS, has a major role in development and implementation of clinical trials in GIS. Suk See De Ravin, M.D., staff clinician, has a major role in development and conduct of clinical trials to treat autoimmune and inflammation problems affecting patients with immune deficiencies under study in the GIS.
The GIS gene therapy program has a particular focus at the bench and in the clinic on development of gene transfer treatments for X-linked chronic granulomatous disease (CGD) and X-linked severe combined immune deficiency (X-SCID). Both Dr. Kang and Dr. De Ravin are involved in the conduct of clinical trials of gene therapy for these disorders. GIS also collaborates closely with investigators in the National Cancer Institute who are working toward development of gene therapy for leukocyte adhesion deficiency (LAD).
The bone marrow transplant program is focused on developing improved methods of transplant to treat primary immune deficiencies and includes hematopoietic stem cell transplant using bone marrow, mobilized peripheral blood stem cells, or cord blood from either an HLA-matched sibling or an unrelated donor. Because hematopoietic stem cell transplantation carries a significant risk of causing graft versus host disease (GVHD), the GIS transplant program includes clinical protocols and bench research to develop methods and treatments to prevent or treat acute and chronic GVHD.
Basic laboratory work in GIS is focused on the biology of human hematopoietic stem cells (HSCs) and induced pluripotent stem cells (iPSCs); the development of new gene transfer vectors and associated methods for gene transfer into HSCs and iPSCs; and the delineation of immune factors affecting allogeneic transplantation, including prevention and treatment of GVHD.
Work on stem cells is focused on the biology of hematopoietic progenitor/stem cells in humans (the CD34+ cell) and in mice (the Sca-1+ cell), including studies of the regulation of engraftment of stem cells in the marrow through CXCR4 receptor/SDF-1 ligand interactions. There is also an interest in delineating the biochemical abnormalities seen with the mutant forms of CXCR4 that cause the myelokathexis, neutopenia, and susceptibility to human papilloma-virus infections characteristic of the immune deficiency known as WHIM syndrome.
GIS also has a basic and pre-clinical program of study of induced pluripotent stem cells (iPSC). This work is focused on development of iPSC from patients with immune deficiencies under study in GIS. Recent work from GIS has been reported regarding the development of iPSC from patients with X-linked CGD, the genetic correction of these patient iPSC, and demonstration that neutrophils with normal oxidant production function can be differentiated from these X-linked CGD patient iPSC that have been genetically corrected.
Basic work on gene therapy vectors has a particular focus on the development of self-inactivating, insulated, lentivirus vectors, which may have improved performance and safety characteristics. Current pre-clinical work is aimed at getting lentivectors into the clinic in the near term to treat X-CGD and X-SCID. The laboratory is also working to develop zinc finger nuclease technology to achieve specifically targeted gene correction in patient hematopoietic stem cells and in patient-derived iPSC.
Basic work on GVHD is focused on delineating mechanisms by which tolerance is developed after bone marrow transplant, as well as developing methods to enhance development of tolerance after transplant using rapamycin or other tolerance-inducing agents.
Dr. Malech received his medical degree from Yale University in New Haven, Connecticut, in 1972. He completed clinical residency training at the University of Pennsylvania in Philadelphia, followed by basic research postdoctoral fellowship training at the National Institutes of Health (NIH) in Bethesda, Maryland. After then completing clinical fellowship training in infectious diseases at Yale University, he remained at Yale as assistant and then associate professor until 1986. In 1986, he returned to NIH as a senior investigator in NIAID. He is currently chief of the Laboratory of Host Defenses (LHD). Dr. Malech’s research and clinical program within LHD is the Genetic Immunotherapy Section (GIS).
The mission of GIS is the development of gene therapy and hematopoietic stem cell transplantation approaches to the treatment of a variety of inherited primary immune deficiencies. Associated with that mission is the diagnosis and treatment of the infections, inflammation, autoimmunity, pulmonary dysfunction, and growth failure that may complicate management of a number of primary immune deficiencies.
Leadership in GIS includes Elizabeth M. Kang, M.D.; Suk See Ting DeRavin, M.D., Ph.D.; and Uimook Choi, Ph.D.
Research staff include Narda Theobald; Janet Lee; Sherry Walker; Colin Sweeney, Ph.D.; Hongmei Wang, M.D.; Kyu Lee Han, Ph.D.;Randy Merling, Ph.D.; Ok Jae Koo, D.V.M., Ph.D.; and Douglas Kuhns, Ph.D.
Clinical staff include Dianne Hilligoss, R.N., N.P.; Martha Marquesen, R.N., N.P.; Rosamma DeCastro, R.N., N.P.; Nana Kwatemaa, R.N.; Patricia Littel, R.N.; Sandra Maxwell, R.N.; Mary Garofalo, R.N.; Corin Kelly, R.N.; Sandra Anaya-O’Brien, R.N.; Thomas Di Maggio, R.N.; Jean Ulrick, R.N.; Kim Montgomery-Recht, R.N.; and Debi Grossman, R.N.
Information for Prospective Laboratory Trainees
If you wish to inquire about postdoctoral or other positions in GIS, contact Dr. Malech directly at firstname.lastname@example.org. Other information about training at NIAID can be accessed through the Research Training at NIAID site.
Kang EM, Malech HL. Gene therapy for chronic granulomatous disease. Methods Enzymol. 2012;507:125-54.
Kang EM, Marciano BE, DeRavin S, Zarember KA, Holland SM, Malech HL. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011 Jun;127(6):1319-26.
Zou J, Sweeney CL, Chou BK, Choi U, Pan J, Wang H, Dowey SN, Cheng L, Malech HL. Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting. Blood. 2011 May 26;177(21):5561-72.
De Ravin SS, Zarember KA, Long-Priel D, Chan KC, Fox SD, Gallin JI, Kuhns DB, Malech HL. Tryptophan/kynurenine metabolism in human leukocytes is independent of superoxide and is fully maintained in chronic granulomatous disease. Blood. 2010 Sep 9;116(10):1755-60.
Zhou S, Mody D, DeRavin SS, Hauer J, Lu T, Ma Z, Hacein-Bey Abina S, Gray JT, Greene MR, Cavazzana-Calvo M, Malech HL, Sorrentino BP. A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells.Blood. 2010 Aug 12;116(6):900-8.
Kang EM, Choi U, Theobald N, Linton G, Long Priel DA, Kuhns D, Malech HL. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood. 2010 Jan 28;115(4):783-91.
Information for Patients
If you are considering participation in our clinical studies, we encourage you to first discuss our studies with your personal physician. To determine your eligibility, we generally request a referral letter from your doctor that contains a concise summary of your medical history and relevant laboratory tests. You may also directly contact one of our GIS study coordinators (listed in the column to the right). The NIH Clinical Center's Patient Recruitment Office can provide additional information about participation in clinical studies at NIH.
Information for Referring Clinicians
A patient may be considered for our clinical studies through referral by his or her personal physician. We generally request a referral letter that contains a concise summary of the patient’s medical history and relevant laboratory tests. We encourage you to contact one of the GIS study coordinators (listed in the column to the right) to discuss your patient and answer any questions you may have. TheNIH Clinical Center's Patient Recruitment Office can provide general information about clinical research protocols across all NIH Institutes.
The following are clinical protocols in GIS that are actively recruiting patients:
- Screening and Baseline Assessment of Patients with Abnormalities of Immune Function. # 05-I-0213
- Autologous Transplantation of Genetically Modified Cells for the Treatment of X-Linked Chronic Granulomatous Disease. # 07-I-0017
- Allogeneic and Matched Unrelated Donor Stem Cell Transplantation for Congenital Immunodeficiencies: Busulfan-based Conditioning with Campath- 1H or h-ATG, Radiation, and Sirolimus. # 07-I-0075
- Lentiviral Gene Transfer for Treatment of Children Older Than Twp Years of Age with X-Linked Severe Combined Immunodeficiency. # 11-I-0007
- Recruitment and Apheresis Collection of Peripheral Blood Hematopoietic Stem Cells. #94-I-0073
- Collection of Peripheral Blood Stem Cells Using G-CSF and Plerixafor in Normal Volunteers. #10-I-0095