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Katherine A. High, M.D.Professor of Pediatrics
Attending Physician
Attending Physician
Adjunct Faculty Member
Attending Physician
Director, Center for Cellular and Molecular Therapeutics
Department: Pediatrics
Contact information
Children's Hospital of Philadelphia
302 D Abramson Research Center 3615 Civic Center Boulevard Philadelphia, PA 19104
Office: 215-590-4521
Fax: 215-590-3660 Email: HIGH@EMAIL.CHOP.EDU
Graduate Group Affiliations
Publications
Education:
A.B. (Chemistry) Harvard College, 1972. M.D. (Medicine) University of North Carolina School of Medicine, 1978. Cert (Business) UNC Business School. Management Institute for Hospital Administrators. , 1989. MA (hon) University of Pennsylvania , 1993.
Post-Graduate Training
Intern in Medicine, North Carolina Memorial Hospital, 1978-1979. Assistant Resident Physician, North Carolina Memorial Hospital, 1979-1981. Hematology Fellow, Yale University School of Medicine, 1981-1984. Cold Spring Harbor Course on Protein Purification and Characterization, Cold Spring Harbor, 1995-1995.
Certifications
Permanent linkAmerican Board of Internal Medicine , 1981. American Board of Internal Medicine, Hematology Section, 1986. Description of Research ExpertiseResearch InterestsThe focus of the laboratory was initially on the molecular basis of blood coagulation, and the use of novel genetic therapies to treat hemophilia. More recently we have pioneered safe and effective clinical translation of genetic therapies for inherited disorders. These clinical trials have led to short-term correction of disease in hemophilia B, and long-term improvements in Leber’s congenital amaurosis, a hereditary cause of blindness. Key words: Hemophilia , AAV, Gene Therapy, Factor IX, Factor VIIa. Description of Research Major areas of investigation include: 1) structure-function analysis of Factors VII, IX and X through the study of naturally occurring mutant proteins and recombinant proteins produced using site-directed mutagenesis and a mammalian expression system, 2) study of the regulation of expression of the genes encoding the vitamin K dependent clotting factors. These genes manifest tissue-specific expression; they are expressed only in the liver. We have isolated the 5' flanking sequences of all three genes, characterized promoter activity and determined, using DNase footprinting, the location of protein binding sites within these promoters. In the case of Factor X, we have determined through a variety of approaches the identity of the transcription factors binding to the promoter and are in the process of carrying out similar studies on the promoters of VII and IX, 3) studies designed to establish an experimental and clinical basis for gene therapy of hemophilia, a bleeding disorder that results from a deficiency of functional Factor IX. We are currently using both viral vectors to introduce the Factor IX cDNA into target cells of interest. My colleagues and I have several active projects, including a study on the generation and use of recombinant AAV vectors expressing Factor IX to treat hemophilia B. In particular, we are investigating novel methods of delivering vector to target tissues, and are also exploring the use of alternate serotypes and optimized expression cassettes in order to maximize gene expression. Other work focuses on safety problems, including determinants of the immune response to the transgene product, and assessment of risk of germline transmission of vector sequences. In other experiments, we are investigating the function of coagulation proteins through the use of targeted disruption of clotting factor genes. Current areas of interest include completion of clinical trials of an AAV-mediated, liver directed approach. Rotation Projects for 2009-2010 1. Gene transfer for hemophilia B 2. Immunological aspects of viral vector-based gene transfer 3. Novel approaches to the treatment of hemophilia Lab Personnel: Anand Bhagwat, Pre Doc George Buchlis, Pre Doc Yifeng Chen, Research Assoc Harre Downey, Research Tech Jonathan Finn, Post Doc Virginia Haurigot, Post Doc Mark Hensley, Pre Doc Daniel Hui, Post Doc Hojun Li, Pre Doc Jianhua Liu, Research Tech Yi-Lin (Emily) Liu, Research Assoc Katherine Marcucci, Post Doc Paris Margaritis, Research Assoc Federico Mingozzi, Director, Translational Research Alex Tai, Research Tech Yi Zhao, Research Tech Shangzhen Zhou, Director, Research Vector Core Mustafa Yazicioglu, Post Doc Description of Clinical ExpertiseHematology, hemostasis and thrombosis, gene transfer for genetic diseaseSelected PublicationsManno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, High KA, Kay MA: Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.[erratum appears in Nat Med. 2006 May;12(5):592 Note: Rasko, John [corrected to Rasko, John JE]; Rustagi, Pradip K [added]]. Nature Medicine 12(3): 342-347, Mar 2006.Manno CS, Chew AJ, Hutchison S, Larson PJ, Herzog RW, Arruda VR, Tai SJ, Ragni MV, Thompson A, Ozelo M, Couto LB, Leonard DGB, Johnson FA, McClelland A, Scallan C, Skarsgard E, Flake AW, Kay MA, High KA, Glader B: AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101(8): 2963-72, Apr 15 2003. Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying G-s, Rossi S, Fulton A, Marshall KA, Banfi S, Chung DC, Morgan JIW, Hauck B, Zelenaia O, Zhu X, Raffini L, Coppieters F, DeBaere E, Shindler KS, Volpe NJ, Surace EM, Acerra C, Lyubarsky A, Redmond TM, Stone E, Sun J, Wellman McDonnell J, Leroy BP, Simonelli F, Bennett J: Age-dependent effects of REP65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose escalation trial. Lancet 2009 Oct. 23 [Epub ahead of print] Maguire AM*, Simonelli F*, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell’osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A,* High KA*, Bennett J*: Safety and efficacy of gene transfer for Leber’s Congenital Amaurosis. New England Journal of Medicine 358: 2240-2248, 2008 Notes: *Co-senior authors. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, Glader B, Chew AJ, Tai SJ, Herzog RW, Arruda V, Johnson F, Scallan C, Skarsgard E, Flake AW, High KA: Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector.[see comment]. Nature Genetics 24(3): 257-61, Mar 2000. Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JEJ, Ragni MV, Manno CS, Sommer J, Jiang H, Pierce GF, Ertl HCJ, High KA: CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nature Medicine 13(4): 419-22, Apr 2007. Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, Edmonson SA, Hui DJ, Sabatino DE, Zhou, S, Wright JF, Jiang, H, Pierce GF, Arruda VR, High KA: Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110(7): 2334-41, Oct 1 2007. Margaritis P, Roy E, Aljamali MN, Downey HD, Giger U, Zhou S, Merricks E., Dillow A, Nichols TC, High KA.: Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 113: 3682-3689, 2009. Pien GC, Basner-Tschakarjan E, Hui DJ, Mentlik A, Finn JD, Hasbrouck HC, Zhou S, Murphy SL, Maus MV, Mingozzi F, Orange JS, High KA: Capsid antigen presentation flags hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clinical Investigation 119: 1688-1695, 2009. High KA and Brenner MK: Gene Transfer for Hematologic Disorders. Hematology: Basic Principles and Practice. Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (eds.). Elsevier Science, Page: 1723-1734, 2009 Notes: 5th Edition, Chapter 110.
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