Genetic Immunotherapy Section
Established in 1986
Harry L. Malech, M.D. (He/Him/His)
Chief, Genetic Immunotherapy Section
Deputy Chief, Laboratory of Clinical Immunology and Microbiology
Specialty(s): Allergy and Immunology, Infectious Disease, Internal Medicine Provides direct clinical care to patients at NIH Clinical Center
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
- Other forms of severe combined immune deficiency
- 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 either ex vivo lentivector transduction or gene editing 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 M. Kang, M.D., Staff Clinician and Chief of the Hematotherapeutics unit of GIS, has a major role in development and implementation of allogeneic and some gene therapy clinical trials in GIS. Suk See De Ravin, M.D., Ph.D., Staff Clinician and Chief of the Gene Therapy Clinical Development Unit has a major role in development and conduct of gene therapy 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.
The bone marrow transplant program led by Dr. Kang 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 lentivectors and CRISPR based gene editing technologies including base editing and prime editing for genetic correction of disorders of immunity in HSCs and iPSCs; and the delineation of immune factors affecting allogeneic transplantation, including prevention and treatment of GVHD. 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.
EducationM.D., 1972, Yale University
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 Genetic Immunotherapy Section (GIS), and Deputy Chief of the Laboratory of Clinical Immunology and Microbiology (LCIM). Dr. Malech’s research and clinical program within LCIM is the 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.
Brault J, Liu T, Bello E, Liu S, Sweeney CL, Meis RJ, Koontz S, Corsino C, Choi U, Vayssiere G, Bosticardo M, Dowdell K, Lazzarotto CR, Clark AB, Notarangelo LD, Ravell JC, Lenardo MJ, Kleinstiver BP, Tsai SQ, Wu X, Dahl GA, Malech HL, De Ravin SS. CRISPR-targeted MAGT1 insertion restores XMEN patient hematopoietic stem cells and lymphocytes. Blood. 2021 Dec 30;138(26):2768-2780.
Sweeney CL, Pavel-Dinu M, Choi U, Brault J, Liu T, Koontz S, Li L, Theobald N, Lee J, Bello EA, Wu X, Meis RJ, Dahl GA, Porteus MH, Malech HL, De Ravin SS. Correction of X-CGD patient HSPCs by targeted CYBB cDNA insertion using CRISPR/Cas9 with 53BP1 inhibition for enhanced homology-directed repair. Gene Ther. 2021 Jun;28(6):373-390.
De Ravin SS, Brault J, Meis RJ, Liu S, Li L, Pavel-Dinu M, Lazzarotto CR, Liu T, Koontz SM, Choi U, Sweeney CL, Theobald N, Lee G, Clark AB, Burkett SS, Kleinstiver BP, Porteus MH, Tsai S, Kuhns DB, Dahl GA, Headey S, Wu X, Malech HL. Enhanced homology-directed repair for highly efficient gene editing in hematopoietic stem/progenitor cells. Blood. 2021 May 13;137(19):2598-2608.
Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013.
De Ravin SS, Brault J, Meis RJ, Li L, Theobald N, Bonifacino AC, Lei H, Liu TQ, Koontz S, Corsino C, Zarakas MA, Desai JV, Clark AB, Choi U, Metzger ME, West K, Highfill SL, Kang E, Kuhns DB, Lionakis MS, Stroncek DF, Dunbar CE, Tisdale JF, Donahue RE, Dahl GA, Malech HL. NADPH oxidase correction by mRNA transfection of apheresis granulocytes in chronic granulomatous disease. Blood Adv. 2020 Dec 8;4(23):5976-5987.
Kohn DB, Booth C, Kang EM, Pai SY, Shaw KL, Santilli G, Armant M, Buckland KF, Choi U, De Ravin SS, Dorsey MJ, Kuo CY, Leon-Rico D, Rivat C, Izotova N, Gilmour K, Snell K, Dip JX, Darwish J, Morris EC, Terrazas D, Wang LD, Bauser CA, Paprotka T, Kuhns DB, Gregg J, Raymond HE, Everett JK, Honnet G, Biasco L, Newburger PE, Bushman FD, Grez M, Gaspar
HB, Williams DA, Malech HL, Galy A, Thrasher AJ; Net4CGD consortium. Lentiviral gene therapy for X-linked chronic granulomatous disease. Nat Med. 2020 Feb;26(2):200-206.
Gene therapy for X-linked Severe Combined Immune Deficiency
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.
The following are clinical protocols in GIS that are actively recruiting patients:
- 11-I-0007 Lentiviral Gene Transfer for Treatment of Children Older Than 2 Years of Age with X-Linked Severe Combined Immunodeficiency
- 000186-I Part B- Phase I/II, Non-randomized, Multicenter, Open-label Study of G1XCGD (Lentiviral Vector Transduced CD34+ Cells) in Patients with X-Linked Chronic Granulomatous Disease
- 16-I-0032 High Dose Peripheral Blood Stem Cell Transplantation with Post Transplant Cyclophosphamide for Patients with Chronic Granulomatous Disease
- 000134-I A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial of Intravenous Zotatifin in Adults with Mild or Moderate Coronavirus Disease 2019 (COVID-19)
- 21-I-0003 A Phase 1/2 Study to Evaluate the Safety, Tolerability and Efficacy, of JSP191 for Hematopoietic Cell Transplantation Conditioning to Achieve Engraftment and Immune Reconstitution in Subjects with SCID
- 22-I-0001 NADPH Oxidase Correction in mRNA transfected Granulocyte-enriched Cells in Chronic Granulomatous Disease (CGD)
- 94-I-0073 Recruitment and Apheresis Collection of Peripheral Blood Hematopoietic Stem Cells, Mononuclear Cells and Granulocytes
- 14-I-0091 Analysis of Patients Treated for Chronic Granulomatous Disease Since January 1, 1995
- 05-I-0213 Screening and Baseline Assessment of Patients with Abnormalities of Immune Function
- 07-I-0183 The Collection of Research Samples and/or Data for Repository from Related or Unrelated Hematopoietic Stem Cell Transplantation Recipients for the National Marrow Donor Program
Information for Prospective Laboratory Trainees
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.
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.