Biography
Mentor: Jeffrey Medin, PhD
Year Entered MCW: 2016
Previous Education: BS, Molecular Genetics & Microbiology, University of Toronto
Year Entered MCW: 2016
Previous Education: BS, Molecular Genetics & Microbiology, University of Toronto
Research Interests
Gene therapies are a promising avenue of treatment for numerous inherited disorders, in particular lysosomal storage disorders. Many lysosomal enzymes are secreted when overexpressed, and secreted enzyme is appropriately modified to be taken up by cells. Modification of some cells using a gene therapy designed to overexpress the deficient enzyme can therefore lead to correction of many unmodified cells. For enduring correction, long-lived stem cell compartments can be modified. To this end, our lab is testing a gene therapy approach in a phase I trial to treat Fabry disease - lentivirus is used to engineer overexpression of the deficient enzyme in hematopoietic stem cells (HSCs) ex vivo, which are transplanted back to provide a source of blood cells that are able to secrete enzyme and correct the disease.
My first aim is to improve upon this strategy by including a component in the viral vector that would allow enrichment of transduced cells in response to a drug, after the transplant has already taken place. This may provide a way to fine-tune the level of enzyme-producing cells circulating in a treated patient, potentially increasing the efficacy of this treatment modality. My second aim is to optimize the use of an alternative cell type to be modified by our viral vectors that can be used in place of or in combination with our established approach. This cell type should retain the benefit of being a circulatory cell but, unlike HSCs, should be readily obtained and have the potential for expansion of cell numbers ex vivo. In this way we hope to combine the benefits of using an autologous cell to deliver the therapeutic protein with the “druggable” potential of banked cells that can be engrafted easily.
Finally, suitable animal models of disease are needed to accurately test gene therapy strategies. We have previously described a mouse with acid ceramidase deficiency, which recapitulates many aspects of Farber disease. Recently, we have established a colony of mice which display phenotypes associated with spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), another disorder caused by acid ceramidase deficiency; no other models of this disease currently exist. We are in the process of characterizing this mouse line after which we hope to test our gene therapy approaches on them.
My first aim is to improve upon this strategy by including a component in the viral vector that would allow enrichment of transduced cells in response to a drug, after the transplant has already taken place. This may provide a way to fine-tune the level of enzyme-producing cells circulating in a treated patient, potentially increasing the efficacy of this treatment modality. My second aim is to optimize the use of an alternative cell type to be modified by our viral vectors that can be used in place of or in combination with our established approach. This cell type should retain the benefit of being a circulatory cell but, unlike HSCs, should be readily obtained and have the potential for expansion of cell numbers ex vivo. In this way we hope to combine the benefits of using an autologous cell to deliver the therapeutic protein with the “druggable” potential of banked cells that can be engrafted easily.
Finally, suitable animal models of disease are needed to accurately test gene therapy strategies. We have previously described a mouse with acid ceramidase deficiency, which recapitulates many aspects of Farber disease. Recently, we have established a colony of mice which display phenotypes associated with spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), another disorder caused by acid ceramidase deficiency; no other models of this disease currently exist. We are in the process of characterizing this mouse line after which we hope to test our gene therapy approaches on them.
Publications
Li et al. “Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target” Proc Natl Acad Sci USA 2019 Oct 1;116(40):20097-20103
Nagree, et al. (Review) “An Update on Gene Therapy for Lysosomal Storage Disorders.” Expert Opin Biol Ther 2019 Jul;19(7):655-670
Yu et al. “Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment.” Am J Pathol 2018 Nov 22. pii: S0002-9440(18)30504-2
Huang et al. “Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease.” Mol Ther Methods Clin Dev. 2017 May 12;5:241-258
Nagree et al. (Review) “Towards in vivo amplification: Overcoming hurdles in the use of hematopoietic stem cells in transplantation and gene therapy.” World J Stem Cells. 2015 Dec 26;7(11):1233-50
Nagree, et al. (Review) “An Update on Gene Therapy for Lysosomal Storage Disorders.” Expert Opin Biol Ther 2019 Jul;19(7):655-670
Yu et al. “Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment.” Am J Pathol 2018 Nov 22. pii: S0002-9440(18)30504-2
Huang et al. “Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease.” Mol Ther Methods Clin Dev. 2017 May 12;5:241-258
Nagree et al. (Review) “Towards in vivo amplification: Overcoming hurdles in the use of hematopoietic stem cells in transplantation and gene therapy.” World J Stem Cells. 2015 Dec 26;7(11):1233-50