Genetic Immunotherapy Section
Suk See De Ravin, M.D., Ph.D.
Senior Research Physician
Chief, Gene Therapy Development Unit
Specialty(s): Pediatrics Provides direct clinical care to patients at NIH Clinical Center
Major Areas of Research
- Gene therapy
- Inborn Errors of Immunity/Primary Immunodeficiency Diseases; Chronic Granulomatous Disease, X-linked Severe Combined Immunodeficiency, XMEN, WHIM, XLA, STAT3, STAT1, CTLA4.
Program Description
Dr. De Ravin’s primary goal is to develop novel gene therapy and cell therapy approaches for treatment of Inborn Errors of Immunity (IEI) /Primary Immunodeficiency Diseases (PID). Advances in genomic diagnosis and immune-phenotype characterization within National Institutes of Allergy and Infectious Diseases identifies many individuals who will benefit from gene and cell therapy. Current gene therapy for IEI (e.g., X-linked SCID, Chronic Granulomatous Disease (CGD) using lentivectors) has provided clinical benefit to multiple patients. However, the risk semi-random vector insertion causing insertional oncogenesis and the lack of physiological gene expression from inserted exogenous transgenes leave room for improvement. To address these concerns, Dr. De Ravin is working on targeted approaches to insert therapeutic genes in hematopoietic stem and progenitor cells for future gene therapy. Programmable CRISPR-Cas9 nuclease systems can deliver corrective genes or repair mutations efficiently. However, this approach carries risks of genotoxicity although there are mitigating agents. Base editing that side-steps risks associated with double strand DNA breaks and the dependence on homology-directed repair is another promising approach for gene therapy for the near future. For patients with infections difficult to control with current antimicrobials, mRNA transfection of autologous primary cells such as granulocytes provide hopes for a transient therapeutic approach. A better understanding of the immune-phenotype allows rational designs for short-term disease control and ultimately long-term treatment of disease with ideal gene therapy approach.
Biography
Education
Ph.D., Sydney Children’s Hospital/University of New South Wales, Australia
Dr. De Ravin obtained her medical degree and pediatrics subspecialty training in Australia. Upon completion of her Ph.D. at Sydney Children’s Hospital/University of New South Wales, Australia, she continued her training at the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, with Dr. Harry L. Malech. She has continued since working towards translating better and safer gene therapy approaches for treatment of SCIDX1 and CGD, applying similar approaches to treatment of broader spectrum of IEI.
Clinical Studies
NADPH Oxidase Correction in mRNA-transfected Granulocyte-enriched Cells in Chronic Granulomatous Disease (CGD): NCT05189925
Recruitment and Apheresis Collection of Peripheral Blood Hematopoietic Stem Cells, Mononuclear Cells and Granulocytes: NCT00001405
Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID): NCT01306019
Screening and Baseline Assessment of Patients with Abnormalities of Immune Function
A Phase 1 Study to Evaluate the Safety and Tolerability of Tandemly-purified Allogeneic CD34+CD90+ HSC Administered Following Conditioning with JAS 191 to Achieve Engraftment and Immune Reconstitution in Patients with SCID
Selected Publications
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.
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.
Brault J, Meis RJ, Li L, Bello E, Liu T, Sweeney CL, Koontz SM, Dowdell K, Theobald N, Lee J, Allen C, Clark AB, Ravell JC, Lenardo MJ, Dahl GA, Malech HL, De Ravin SS. MAGT1 messenger RNA-corrected autologous T and natural killer cells for potential cell therapy in X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia disease. Cytotherapy. 2021 Mar;23(3):203-210.
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.
De Ravin SS, Wu X, Moir S, Anaya-O'Brien S, Kwatemaa N, Littel P, Theobald N, Choi U, Su L, Marquesen M, Hilligoss D, Lee J, Buckner CM, Zarember KA, O'Connor G, McVicar D, Kuhns D, Throm RE, Zhou S, Notarangelo LD, Hanson IC, Cowan MJ, Kang E, Hadigan C, Meagher M, Gray JT, Sorrentino BP, Malech HL, Kardava L. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016 Apr 20;8(335):335ra57.
De Ravin SS, Reik A, Liu PQ, Li L, Wu X, Su L, Raley C, Theobald N, Choi U, Song AH, Chan A, Pearl JR, Paschon DE, Lee J, Newcombe H, Koontz S, Sweeney C, Shivak DA, Zarember KA, Peshwa MV, Gregory PD, Urnov FD, Malech HL. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol. 2016 Apr;34(4):424-9.