Denise E. Sabatino, Ph.D.

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Research Associate Professor of Pediatrics
Department: Pediatrics
Graduate Group Affiliations

Contact information
Perelman School of Medicine, University of Pennsylvania
The Children's Hospital of Philadelphia
Department of Pediatrics
3501 Civic Center Blvd
Colket Translational Research Blg, Rm 5020
Philadelphia, PA 19104
Office: 267-425-3121
B.S. (Molecular Genetics)
The Ohio State University, 1992.
Ph.D. (Genetics)
George Washington University/National Institutes of Health, 2000.
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Description of Research Expertise

Research Interests

Coagulation factors and gene-based therapies for the treatment of hemophilia


Coagulation factors, hemostasis, hemophilia, adeno-associated viral vectors, gene therapy

Description of Research

The research in the Sabatino Laboratory is focused on the inherited bleeding disorder, hemophilia. The interests of the laboratory include (1) the study of variants of coagulation factor VIII to understand the biochemical properties of these proteins and to identify novel variants with enhanced function and (2) the development of gene-based therapeutic approaches for treating hemophilia.

Hemophilia A is a bleeding disorder caused by mutations in the factor VIII gene. Current treatment for this disease is protein replacement therapy that requires frequent infusion of the factor VIII protein. The major complication of this treatment is the development of an immune response to the factor VIII protein that occurs in ~25% of hemophilia A patients. Using a gene-based approach our goal is to achieve sustained therapeutic levels of factor VIII expression so that patients no longer require frequent protein treatments. The continuous factor VIII expression would prevent bleeding episodes and may ensure that immune tolerance to the protein is established.

In our early work to develop gene therapy for hemophilia A, we used adeno-associated viral (AAV) vectors to deliver factor VIII to hemophilia A dogs. In these studies we achieved long-term expression of therapeutic levels of factor VIII. In a collaborative study, we have also used AAV to deliver factor VIII into hemophilia A dogs that had an immune response to the factor VIII protein treatment prior to the administration of AAV to induce tolerance to the factor VIII as well as achieve sustained levels of factor VIII.

Our current research focuses on further optimizing gene transfer for hemophilia A by modulating factor VIII expression and the use of novel gene transfer vectors. The characterization of factor VIII variants that have high specific activity, stability and/or increased secretion may provide a better understanding of factor VIII function and may improve factor VIII expression in gene-based approaches. We are also interested in understanding the cellular processing of factor VIII that may impact its secretion into the circulation and its expression in the setting of gene transfer. Understanding the relationship between factor VIII expression and the immune response to factor VIII will also be important for translation of novel therapeutic approaches for hemophilia A.

Lab Personnel

Amanda Messer, Ph.D., Postdoctoral Fellow
Giang Nguyen, B.S., Research Technician
Rachel Eisen-McGinn, Veterinary Student

Selected Publications

Nguyen GN, George LA, Siner JI, Davidson RJ, Zander CB, Zheng XL, Arruda VR, Camire RM, Sabatino DE: Novel human factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A J Thromb Haemost 15(1): 110-121, January 2017 Notes: Epub 2016 Nov 25. (Role: Principal investigator of this study funded by a Pfizer ASPIRE Hemophilia Award and NHLBI, NIH. Dr. Sabatino designed the study, analyzed the data and wrote the paper.).

Lange AM, Altynova E, Nguyen G, Sabatino DE: Overexpression of factor VIII after AAV delivery is transiently associated with cellular stress in hemophilia A mice Mol Ther Methods Clin Dev 3(1): 16064, September 2016 Notes: (Role: Principal investigator of this study funded by a Bayer Hemophilia Early Career Development Award. Dr. Sabatino designed the study, analyzed the data and wrote the manuscript.).

Siner JI, Iacobelli NP, Sabatino DE, Ivanciu L, Zhou S, Poncz M, Camire RM, Arruda VR: Minimal modification in the factor VIII B domain sequence ameliorates the murine hemophilia A phenotype. Blood 121(21): 4396-4403, 2013 Notes: Epub 2013 Jan 31 (Role: Study evolved from Dr. Sabatino’s work on the canine factor VIII protein. She assisted in the study design and contributed intellectually to the project.).

Greene TK, Lyde RB, Bailey SC, Lambert MP, Zhai L, Sabatino DE, Camire RM, Arruda VR, Poncz M : Apoptotic effects of platelet factor VIII on megakaryopoiesis: implications for a modified human FVIII for platelet-based gene therapy. J Thromb Haemost 12(12): 2102-12, December 2014 Notes: Epub 2014 Nov 4 (Role: Dr. Sabatino’s canine factor VIII and human factor VIII variant proteins were used in this study targeting factor VIII expression to platelets. In addition, Dr. Sabatino provided guidance on the assays and experimental design of the study.).

Sabatino DE, Nichols TC, Merricks E, Bellinger DA, Herzog RW, Monahan PE: Animal models of hemophilia. Progress in molecular biology and translational science 105(1): 151-209, 2012.

Cao W, Sabatino DE, Altynova E, Lange AM, Casina VC, Camire RM, Zheng XL: Light Chain of Factor VIII Is Sufficient for Accelerating Cleavage of von Willebrand Factor by ADAMTS13 Metalloprotease. Journal of Biological Chemistry 287(39): 32459-66, 2012 Notes: Epub 2012 Aug 1 . (Role: Designed and performed the in vivo experiments and analysis of the factor VIII variants for this study.).

Sabatino DE, Lange AM, Altynova ES, Sarkar R, Zhou S, Merricks EP, Franck HG, Nichols TC, Arruda VR, Kazazian HH: Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Molecular Therapy 19(3): 442-449, 2011 Notes: Epub 2010 Nov 16 . (Role: Lead investigator of this study of AAV-canine factor FVIII gene therapy in hemophilia A dogs. Designed the study, performed the assays and wrote the manuscript.).

Finn JD, Ozelo MC, Sabatino DE, Franck HW, Merricks EP, Crudele JM, Zhou S, Kazazian HH, Lillicrap D, Nichols TC, Arruda VR : Eradication of neutralizing antibodies to factor VIII in canine hemophilia A following liver gene therapy. Blood 116(26): 5842-8, 2010 Notes: Epub 2010 Sep 28 (Role: The AAV-canine factor VIII constructs and data described in Dr. Sabatino’s study in hemophilia A dogs (Sabatino 2011) were the basis for this collaborative study with Dr. V. Arruda. Assays and reagents developed by Dr. Sabatino were used in this study.).

Sabatino DE, Freguia CF, Toso R, Santos A, Merricks EP, Kazazian HH, Nichols TC, Camire RM, Arruda VR: Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model. Blood 114(20): 4562-4565, 2009 Notes: (Role: Conceived this study and was the lead investigator that characterized the canine FVIII protein. Performed the assays, analyzed the data and wrote the paper.).

Sabatino DE, Mackenzie TC, Peranteau W, Edmonson S, Campagnoli C, Liu YL, Flake AW, High KA: Persistent expression of hF.IX after tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice. Molecular Therapy 15(9): 1677-85, 2007 Notes: (Role: Project as post-doctoral fellow).

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Last updated: 06/20/2022
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