1e
19
1
49
2
2
18
1b
1d
18
35
52
1d
2 29
1d
25
Katherine A. High, M.D.
78
52
Emeritus Professor of Pediatrics (Hematology)
28
73
3
61
Attending Physician, The Children's Hospital of Philadelphia
76
Attending Physician, Hospital of the University of Pennsylvania
70
Attending Physician, Presbyterian Hospital Medical Center
98
Director, Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia
11
Department: Pediatrics
4
1
b
1d
46
Contact information
54
4
3
3
1d
54
President and Chief Scientific Officer
1a Spark Therapeutics
22 3737 Market St, Suite 1300
3e Member, Center for Cellular and Molecular Therapeutics
32 at The Children's Hospital of Philadelphia
39 Room 5064, Colket Translational Research Building
3a 3501 Civic Center Blvd.
Philadelphia, PA 19104
26
1a Spark Therapeutics
22 3737 Market St, Suite 1300
3e Member, Center for Cellular and Molecular Therapeutics
32 at The Children's Hospital of Philadelphia
39 Room 5064, Colket Translational Research Building
3a 3501 Civic Center Blvd.
Philadelphia, PA 19104
2e
Office: 215-220-9336
32 Fax: 215-790-6248
24
f
32 Fax: 215-790-6248
24
18
Publications
23 a
3
2
29
23 a
Links
15c Search PubMed for articles
43 Cell and Molecular Biology graduate group faculty webpage.
c
4
b
1f
15c Search PubMed for articles
43 Cell and Molecular Biology graduate group faculty webpage.
c
13
Education:
21 9 A.B. 16 (Chemistry) c
28 Harvard College, 1972.
21 9 M.D. 15 (Medicine) c
48 University of North Carolina School of Medicine, 1978.
21 9 Cert 15 (Business) c
4c UNC Business School. Management Institute for Hospital Administrators. 16 , 1989.
21 d MA (hon) c
34 University of Pennsylvania , 1993.
c
3
3
3
3
8b
Permanent link21 9 A.B. 16 (Chemistry) c
28 Harvard College, 1972.
21 9 M.D. 15 (Medicine) c
48 University of North Carolina School of Medicine, 1978.
21 9 Cert 15 (Business) c
4c UNC Business School. Management Institute for Hospital Administrators. 16 , 1989.
21 d MA (hon) c
34 University of Pennsylvania , 1993.
c
2 29
21
1e
1d
24
5e
1c5 The 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.
8
51 Key words: Hemophilia , AAV, Gene Therapy, Factor IX, Factor VIIa.
8
26 Description of Research
7b8 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.
8
8
1e Lab Personnel:
8
21 Xavier Anguela, Post Doc;
32 Etiena Basner-Tschakarjan, Research Assoc;
21 George Buchlis, Post Doc;
24 Yifeng Chen, Research Assoc;
28 Robert Davidson, Research Assoc;
26 Liron Elkouby, Research Assoc;
1d Daniel Hui, Post Doc;
24 Jianhua Liu, Research Tech;
20 Alex Tai, Research Tech;
20 Yi Zhao, Research Tech;
35 Shangzhen Zhou, Director, Research Vector Core
65
1a 29
27
Description of Research Expertise
2b Research Interests1c5 The 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.
8
51 Key words: Hemophilia , AAV, Gene Therapy, Factor IX, Factor VIIa.
8
26 Description of Research
7b8 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.
8
8
1e Lab Personnel:
8
21 Xavier Anguela, Post Doc;
32 Etiena Basner-Tschakarjan, Research Assoc;
21 George Buchlis, Post Doc;
24 Yifeng Chen, Research Assoc;
28 Robert Davidson, Research Assoc;
26 Liron Elkouby, Research Assoc;
1d Daniel Hui, Post Doc;
24 Jianhua Liu, Research Tech;
20 Alex Tai, Research Tech;
20 Yi Zhao, Research Tech;
35 Shangzhen Zhou, Director, Research Vector Core
65
Description of Clinical Expertise
58 Hematology, hemostasis and thrombosis, gene transfer for genetic disease1a 29
23
176 Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ, Yazicioglu M, Elkouby L, Hinderer CJ, Faella A, Howard C, Tai A, Podsakoff GM, Zhou S, Basner-Tschakarjan E, Wright JF, High KA: Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med 5(194): 194ra92, Jul 2013.
10a Buchlis G, Odorizzi P, Soto PC, Pearce OM, Hui DJ, Jordan MS, Varki A, Wherry EJ, High KA: Enhanced T cell function in a mouse model of human glycosylation. J Immunol 191(1): 228-237, Jul 2013.
145 Yazicioglu MN, Monaldini L, Chu K, Khazi F, Murphy SL, Huang H, Margaritis P, High, KA: Cellular localization and characterization of cytosolic binding partners for Gla-containing proteins PRRG4 and PRRG2. J Biol Chem Jul 19 [Epub ahead of print] 2013.
172 Gil-Farina I, DiScala M, Vanrell L, Olagüe, Vales A, High KA, Prieto J, Mingozzi J, Gonzelez-Aseguinolaza G.: IL12-Mediated liver inflammation reduces the formation of AAV transcriptionally active forms but has no effect over preexisting AAV transgene expression. PLoS One 8(7): e67748, Jul 2013.
1a6 Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F.: Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber Congenital Amaurosis Type 2. Ophthalmology 120(6): 1283-1291, June 2013.
184 Callejas D, Mann CJ, Ayuso E, Lage R, Grifoll I, Roca C, Andaluz A, Ruiz-de Gopegui R, Montane J, Munoz S, Ferre T, Haurigot V, Zhou S, Ruberte J, Mingozzi F, High K, Garcia F, Bosch F: Treatment of diabetes and long-term survival following insulin and glucokinase gene therapy. Diabetes 62(5): 1718-1729, May 2013.
d3 Hoffman BA, Ertl HCJ, Terhorst C, High KA, Herzog RW: Gene therapy at the frontiers of viral immunology. Front Microbiol 3: 182, May 2013.
1ee O'Reilly M, Kohn DB, Bartlett J, Benson J, Brooks PJ, Bryne BJ, Camozzi C, Cornetta K, Crystal RG, Fong Y, Gargiulo L, Gopal-Srivastava R, High KA, Jacobson SG, Jambou RC, Montgomery M, Rosenthal E, Samulski RJ, Skarlatos SI, Sorrentino B, Wilson JM, Xie Y, Corrigan-Curay J.: Gene therapy for rare diseases: Summary of a National Institutes of Health workshop, September 13, 2012. Hum Gene Ther 24(4): 355-362, Apr 2013.
111 Parzych EM, Liu H, Yin X, Liu Q, Wu TL, Podsakoff G, High KA, Levine MH, Ertl HC: Effects of immunosupression on circulating AAV capsid-specific T cells in humans. Hum Gene Ther 24: 431-422, Apr 2013.
2c
7
1d
1f
Selected Publications
123 Mingozzi F, Chen Y, Edmonson SC, Zhou S, Thurlings RM, Tak PP, High KA: Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther 20: 417-424, Jul 2013.176 Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ, Yazicioglu M, Elkouby L, Hinderer CJ, Faella A, Howard C, Tai A, Podsakoff GM, Zhou S, Basner-Tschakarjan E, Wright JF, High KA: Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med 5(194): 194ra92, Jul 2013.
10a Buchlis G, Odorizzi P, Soto PC, Pearce OM, Hui DJ, Jordan MS, Varki A, Wherry EJ, High KA: Enhanced T cell function in a mouse model of human glycosylation. J Immunol 191(1): 228-237, Jul 2013.
145 Yazicioglu MN, Monaldini L, Chu K, Khazi F, Murphy SL, Huang H, Margaritis P, High, KA: Cellular localization and characterization of cytosolic binding partners for Gla-containing proteins PRRG4 and PRRG2. J Biol Chem Jul 19 [Epub ahead of print] 2013.
172 Gil-Farina I, DiScala M, Vanrell L, Olagüe, Vales A, High KA, Prieto J, Mingozzi J, Gonzelez-Aseguinolaza G.: IL12-Mediated liver inflammation reduces the formation of AAV transcriptionally active forms but has no effect over preexisting AAV transgene expression. PLoS One 8(7): e67748, Jul 2013.
1a6 Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F.: Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber Congenital Amaurosis Type 2. Ophthalmology 120(6): 1283-1291, June 2013.
184 Callejas D, Mann CJ, Ayuso E, Lage R, Grifoll I, Roca C, Andaluz A, Ruiz-de Gopegui R, Montane J, Munoz S, Ferre T, Haurigot V, Zhou S, Ruberte J, Mingozzi F, High K, Garcia F, Bosch F: Treatment of diabetes and long-term survival following insulin and glucokinase gene therapy. Diabetes 62(5): 1718-1729, May 2013.
d3 Hoffman BA, Ertl HCJ, Terhorst C, High KA, Herzog RW: Gene therapy at the frontiers of viral immunology. Front Microbiol 3: 182, May 2013.
1ee O'Reilly M, Kohn DB, Bartlett J, Benson J, Brooks PJ, Bryne BJ, Camozzi C, Cornetta K, Crystal RG, Fong Y, Gargiulo L, Gopal-Srivastava R, High KA, Jacobson SG, Jambou RC, Montgomery M, Rosenthal E, Samulski RJ, Skarlatos SI, Sorrentino B, Wilson JM, Xie Y, Corrigan-Curay J.: Gene therapy for rare diseases: Summary of a National Institutes of Health workshop, September 13, 2012. Hum Gene Ther 24(4): 355-362, Apr 2013.
111 Parzych EM, Liu H, Yin X, Liu Q, Wu TL, Podsakoff G, High KA, Levine MH, Ertl HC: Effects of immunosupression on circulating AAV capsid-specific T cells in humans. Hum Gene Ther 24: 431-422, Apr 2013.
2c