Raymond G. Perelman Center for
Cellular and Molecular Therapeutics

Margaritis Laboratory

Paris Margaritis, DPhil

Paris Margaritis, DPhil

Research in my laboratory uses basic biochemical, molecular as well as complex in vivo methodology within the field of coagulation with two goals: (1) to advance our understanding of molecular mechanisms involved in pro- and anti-coagulant reactions; (2) translational research for the treatment of coagulation defects. Despite their different endpoints, these goals exhibit remarkable cross talk since answering mechanistic questions on coagulation impacts the design of therapeutic approaches for coagulation defects.

Our research pivots on a unique model that we have developed, whereby we can enhance the extrinsic pathway of coagulation by raising the circulating levels of activated FVII (FVIIa) in animal models. Such an approach has obvious ramifications as a potential treatment for coagulation disorders that are currently treated with recombinant FVIIa. Indeed, in a series of novel experiments in life models with hemophilia, we showed that expression of FVIIa via gene transfer results in dramatic phenotypic improvements or complete correction. In addition, we developed mouse and canine-specific reagents, assays and endpoints that allow us to monitor in vivo effects in hemostasis resulting from the action of FVIIa. A current line of investigation in our laboratory aims to better define the intricacies of viral transduction-based FVIIa gene expression and its hemostatic effects in animal models of hemophilia.

The general concept of coagulation proteases interacting with factors other than their natural ligands also applies to FVIIa. Its binding to cell-surface receptors other than tissue factor pose intriguing questions on previously unconsidered interactions affecting its function. As a result, part of ongoing work in our laboratory is a new line of investigation that focuses on the molecular interactions between FVIIa and its binding partners and how these relate to the hemostatic and other role(s) of FVIIa in vivo. To address these functions we have developed unique in vitro and in vivo methodologies to define, quantitate and even visualize FVIIa-participating reactions as they occur in real time. Exploiting this information may also form the basis for the rational design FVIIa-based therapeutics, either protein or gene-based, that can be used for the treatment of coagulation defects.

Dr. Margaritis did his undergraduate studies at the University of Newcastle-upon-Tyne (UK) earning a BSc (Hons) in Genetics. He subsequently did his doctorate work in Prof. George G. Brownlee’s laboratory in the Dunn School of Pathology at the University of Oxford (UK). Dr. Margaritis investigated the potential of skin cell viral transduction and subsequent grafting in life models as a means to express human coagulation factor IX for hemophilia gene therapy. Dr. Margaritis continued in the field of hemophilia gene therapy as a post-doctoral fellow in Dr. Katherine A. High’s laboratory at The Children’s Hospital of Philadelphia (PA, United States). He developed a gene therapy approach to treat hemophilia patients with inhibitors using continuous expression of a transgene encoding activated Factor VII (FVIIa), a protein that is extensively used to control bleeding in several types of coagulation defects but has very short half-life and carries considerable cost. Dr. Margaritis joined the Faculty at the Department of Pediatrics (Division of Hematology) in 2010 and is a member of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics. He is also a member of the Blood Center for Patient Care and Discovery and the Orphan Disease Center at the University of Pennsylvania.

Dr. Margaritis is a member of the American Society of Hematology, the North American Society of Thrombosis and Hemostasis, the American Society of Gene and Cell Therapy and the International Society of Thrombosis and Hemostasis.

Principal Investigator

Paris Margaritis, DPhil (PI), margaritis@email.chop.edu
Shannon M. Smith, PhD (post-doc fellow), smithsm@email.chop.edu
Juliana C. Small, PhD (post-doc fellow), smalljc@email.chop.edu

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