Harry L. Malech, M.D.
Chief, Genetic Immunotherapy Section
Chief, Laboratory of Host Defenses
Harry Malech received his medical degree from Yale University in New Haven in 1972. He completed clinical residency training at the University of Pennsylvania in Philadelphia, followed by basic research post-doctoral fellowship training at NIH in Bethesda. 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 the 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.
Description of Research Program
The research program of the 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 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 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). The 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 the GIS is focused on the biology of human hematopoietic stem cells; the development of new gene transfer vectors and associated methods for gene transfer into hematopoietic stem cells; 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.
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.
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.
Research Group Members
Leadership in the 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, Gilda Linton, M.A., Courtney Lappas, Ph.D., Morvarid Moayeri, M.D., Ph.D., Abigail Harada, M.D., Kristin Berg, Cattlena Changpriroa, and Douglas Kuhns, Ph.D.
Clinical staff include Dianne Hilligoss, R.N., N.P., Martha Marquesen, R.N., N.P., Julia Friend, P.A., Nana Kwatemaa, R.N., Effie Nomicos, R.N., Sandra Maxwell, R.N., Mary Garofalo, R.N., Corin Kelly, R.N., Sandra Anaya-O’Brien, R.N., Susan Foster, R.N., Jean Ulrick, R.N., Tyra Estwick, R.N., and Kara Johnson, R.N.
Information for Prospective Laboratory Trainees
If you wish to inquire about postdoctoral or other positions in the GIS, contact Dr. Malech directly at hmalech@nih.gov. Other information about training at NIAID can be accessed through the NIAID Training Program site.
Clinical Research Protocols
The following are clinical protocols in the GIS that are actively recruiting patients:
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. The NIH Clinical Center's Patient Recruitment Office can provide general information about clinical research protocols across all NIH institutes.
Selected Most Recent Publications
To view a complete listing, search "Malech H" in PubMed.
Kawai T, Choi U, Cardwell L, De Ravin SS, Naumann N, Whiting-Theobald NL, Linton GF, Moon J, Murphy PM, Malech HL: WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus truncated CXCR4. Blood 109:78-84, 2007.
Malech HL, Hickstein DD: Genetics, Biology and Clinical Management of Myeloid Cell Primary Immune Deficiencies: Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency. Curr Opin Hematol 14:29-36, 2007.
Chinen J, Davis J, De Ravin SS, Hay BN, Hsu AP, Linton GF, Naumann N, Nomicos EY, Silvin C, Ulrick J, Whiting-Theobald NL, Malech HL, Puck JM: Gene therapy improves immune function in pre-adolescents with X-linked severe combined immunodeficiency. Blood 110:67-73, 2007.
Brenner S, Ryser MF, Whiting-Theobald NL, Gentsch M, Linton GF, Malech HL: The late dividing population of gamma-retroviral vector transduced human mobilized peripheral blood progenitor cells contributes most to gene-marked cell engraftment in nonobese diabetic/severe combined immunodeficient mice. Stem Cells 25:1807-1813, 2007.
Kawai T, Choi U, Liu PC, Whiting-Theobald NL, Linton GF, Malech HL: Diprotin A Infusion into Nonobese Diabetic/Severe Combined Immunodeficiency Mice Markedly Enhances Engraftment of Human Mobilized CD34(+) Peripheral Blood Cells. Stem Cells Dev 16:361-370, 2007.
Naumann N, De Ravin SS, Choi U, Moayeri M, Whiting-Theobald N, Linton GF, Ikeda Y, Malech HL: Simian immundeficiency virus lentivector corrects human X-linked chronic granulomatous disease in the NOD/SCID mouse xenograft. Gene Therapy 14:1513-1524, 2007.
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