Jeffrey A Medin

Jeffrey A Medin, PhD

Our laboratory focuses on basic biomedical research and clinical translation directed towards the 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 preclinical 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 Canadian Institutes of Health Research (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 CIHR and 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 signalling 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, tumour 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 tumour cells. These receptors are composed of a tumour-specific antibody binding domain, that functions to direct cells to the cancer of interest, fused to a signalling domain that will activate the immune cell's killing and proliferative mechanisms. One set of projects here involves the generation of novel CARs for tumour-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 developing a clinical gene therapy trial for an IL-12-based cancer immunotherapy protocol in collaboration with Dr. Christopher Paige's lab at the Princess Margaret Cancer Centre. 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 tumours.
     
  • Virus Vector Core Facility
    We have established a dedicated GLP-grade Virus Vector Core Facility at 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.

Related Links

World J Stem Cells. 2015 Dec 26;7(11):1233-50
Nagree MS, López-Vásquez L, Medin JA
Proteomics Clin Appl. 2009 Mar;3(3):347-58
Symes J, Evangelou A, Ignatchenko A, Fleshner N, Kislinger T, Medin JA
Immunotherapy. 2015 Mar;7(3):271-84
Oldham RA, Berinstein EM, Medin JA
Haematologica. 2015 Feb 14;
Dworski S, Berger A, Furlonger C, Moreau JM, Yoshimitsu M, Trentadue J, Au BC, Paige CJ, Medin JA
World J Stem Cells. 2014 Sep 26;6(4):380-90
Ricci MJ, Medin JA, Foley RS
Cancer Immunol Res. 2014 Aug 25;
Nelles ME, Moreau JM, Furlonger CL, Berger A, Medin JA, Paige CJ
Anal Chem. 2014 Jul 29;
Jones EE, Dworski S, Canals D, Casas J, Fabrias G, Schoenling A, Levade T, Denlinger CE, Hannun YA, Medin JA, Drake RR
J Cell Mol Med. 2013 Nov;17(11):1465-74
Wei LZ, Xu Y, Nelles EM, Furlonger C, Wang JC, Di Grappa MA, Khokha R, Medin JA, Paige CJ

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Professor, Department of Medical Biophysics, University of Toronto