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Jeffrey A Medin, PhD
Senior Scientist, Princess Margaret Cancer Centre & Toronto Western Research Institute (TWRI)
Affiliate Scientist, Toronto General Research Institute (TGRI)
Keywords: gene transfer/therapy, immunotherapy, lysosomal storage disorders, leukemia, lentivirus 

Research Interests
Our laboratory focuses on basic biomedical research and clinical translation directed towards amelioration of inherited and acquired disorders. We are especially interested in applications that interplay with the hematopoietic system.

Current laboratory projects:

Fabry Disease
Fabry disease is a Lysosomal Storage Disorder (LSD) due to a deficiency of the enzyme alpha-galactosidase A (a-gal A) caused by mutations in the galactosidase A (GLA) gene. The enzyme deficiency leads to accumulation of glycosphingolipids such as globotriaosylceramide (Gb3) damaging tissues. Kidney, cardiac, and cerebrovascular disease are the primary manifestations in Fabry patients.

We have been working for a number of years on the pre-clinical development and clinical implementation of gene therapy trials mediated by recombinant lentiviruses targeting hematopoietic stem cells for the sustained systemic correction of Fabry disease. This work has been supported by the CIHR. In one embodiment, we have generated a fully congenic NOD/SCID/Fabry (NSF) mouse model to facilitate the in vivo assessment of human hematopoietic cell-directed therapies for Fabry disease. Recently, we received an Emerging Team Grant in Rare Diseases from the CIHR and the KFC to conduct the first clinical gene therapy trial for Fabry disease.

Modulation of Acid Ceramidase Expression
Acid ceramidase (ACDase) plays a key role in regulating the balance between cellular ceramide and sphingosine-1-phosphate. Depending on the context, these fundamental lipids either promote apoptosis or promote cell proliferation. Projects here involve generating models with increased or decreased levels of ACDase activity and determining biological outcomes as related to a variety of cell types and tissues.

We have recently generated a novel mouse model of ACDase deficiency that manifests characteristic features of Farber disease, an LSD resulting from the build-up of ceramide. This model is helping us to investigate the roles of ACDase and various sphingolipids in cell signaling and cancers. We are also utilizing this model to better understand the pathophysiology of Farber disease and develop new treatment modality for this very severe and fatal LSD.

Cancer Immunotherapy
Immunotherapy offers the potential to eliminate localized cancers, tumor stem cells, and also metastatic disease. One promising modality of immunotherapy for cancer employs chimeric antigen receptors (CARs) that redirect potent immune cells towards the elimination of tumors cells. These receptors are composed of a tumor-specific antibody binding domain, that functions to direct cells to the cancer of interest, fused to a signaling domain that will activate the immune cell's killing and proliferative mechanisms. One set of projects here involves generation of novel CARs for tumor-associated antigens identified from Acute Myelogenous Leukemia, Hodgkin Lymphoma, Multiple Myeloma, and Colorectal Cancer. These CARs will be stably expressed in various subtypes of immune-effector T cells and/or NK cells and tested in animal models of these cancers.

We are also currently in development of a clinical gene therapy trial for an IL-12-based cancer immunotherapy protocol in collaboration with Dr. Christopher Paige's lab at the OCI. Here, leukemic cells are genetically modified using lentiviral vectors to express IL-12, a potent immuno-stimulatory cytokine. We are also extending development of this treatment schema to solid tumors.

Virus Vector Core Facility
We have established a dedicated GLP-grade Virus Vector Core Facility at the TWH to produce viral vectors for research and commercial use. We currently have lentivirus vectors (LVs) with markers such as eGFP, Luciferase, mCherry, and additional cell surface markers. We also have LVs with suicide elements we developed to increase the safety of cell-mediated therapy and LVs that are integration deficient. In addition to the in-house LVs, we also develop custom LVs. We are also in the process of developing recombinant adeno-associated virus vectors.

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  Jeffrey  A Medin
Mailing Address
Primary LAB
Toronto General Hospital
Max Bell Research Centre
5th Floor 406, 407
200 Elizabeth St.
Toronto, Ontario
Canada M5G 2C4

 
Email

Phone Numbers
416-340-4800 ext. 8429 or 6368(LAB)
416-340-4800 ext. 5880(Admin)

 

   
 
 
 
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