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Hemophilia A is a bleeding disorder caused by mutations in the factor VIII gene. The conventional treatment for this disease involves protein replacement therapy that requires frequent infusion of the factor VIII protein. An immune response to the factor VIII protein is a major complication of this treatment approach, occurring in approximately 25 percent of hemophilia A patients. Novel therapeutics that overcome the limitations of protein replacement therapy are currently being developed to improve the care of hemophilia patients.
The goal of the Sabatino Lab is to develop a gene-based approach 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 early work to develop gene therapy for hemophilia A, the Sabatino Lab used adeno-associated viral (AAV) vectors to deliver factor VIII to hemophilia A dogs. In these studies, the team achieved long-term expression of therapeutic levels of factor VIII. In a collaborative study, the lab has 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.
The lab’s 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. Using novel hemophilia A mouse models, hemophilia A dog models as well as ex vivo approaches, the lab is investigating the potential immunogenicity of factor VIII variants. The team is 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 therapy.
- Biochemical characterization of novel factor VIII variants
Novel human factor VIII variants with increased activity and improved secretion are in development. Biochemical characterization of these purified proteins is investigated in vitro and in vivo.
- Efficacy of novel factor variants in the setting of gene therapy
The efficacy of adeno-associated viral vector delivery of factor VIII variants is investigated in novel hemophilia A mouse and hemophilia A dog models that are tolerant to human factor VIII.
- Understanding the potential immunogenicity of factor VIII variants
It is important to consider the potential immunogenicity of novel proteins that differ from the native protein. In vivo and ex vivo studies are underway to investigate the potential immunogenicity of factor VIII variants.
- Cellular processing of factor VIII
The DNA sequence, protein and cell type may influence the ability of the cell to effectively process and release coagulation factors. The laboratory is investigating how the cellular processing of factor VIII may impact its secretion into the circulation and its expression in the setting of gene therapy.
Denise E. Sabatino, PhD
The research in the Sabatino Laboratory is focused on hemophilia, an inherited bleeding disorder. The interests of the laboratory include 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 the development of gene-based therapeutic approaches for treating hemophilia.