Sabatino Laboratory

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.

Denise Sabatino, PhD. is a Research Assistant Professor of Pediatrics at The Perelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of Philadelphia. Dr. Sabatino did her undergraduate studies at The Ohio State University and earned her PhD. in Genetics at The George Washington University/National Institutes of Health in the laboratory of Dr. David Bodine at NHGRI. During her postdoctoral fellowship with Dr. Katherine High at The Children’s Hospital of Philadelphia, she investigated gene transfer for hemophilia B using AAV vectors. Dr. Sabatino joined the faculty at the University of Pennsylvania School of Medicine in 2008 in the Department of Genetics. In 2010 she joined the Department of Pediatrics and became a member of the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP.

Positions

PubMed: Denise Sabatino, PhD