Polymer-based manufacturing tolerogenic miRNA-based therapeutics

Cellular bioengineering provides an unexpected means by which unwanted immunological responses can be modulated (i.e., immunomodulation). Using a polymer-based bioreactor system composed of unmodified and polymer-modified living cells from genetically different individuals (e.g., mice or humans), complex formulations of biologically active microRNA (miRNA) can be manufactured. miRNA are small forms of ribonucleic acid (found naturally in all living organisms) that have potent regulatory functions. Two families of manufactured miRNA-based therapeutics have been made: TA1 inhibits inflammatory responses while IA1 enhances inflammatory reactions. Both TA1 and IA1 exhibit potent and persistent in vivo and in vitro immunomodulatory effects. The ultimate target of the miRNA is the T lymphocyte (T cells), a key mediator of the immune system. T cells consist of multiple subclasses that can be divided into Effector T cells (Teff) that cause damage and Regulatory T cells (Treg) that turn off the activity of the Teff cells. In autoimmune disease such as Type 1 Diabetes and Multiple Sclerosis, the number of Treg relative to Teff populations is reduced creating the proinflammatory disease process. Current drugs kill Teff cells but also have significant toxicity to normal cells and tissues. In contrast, the manufactured TA1 mimics normal bioregulatory processes to block the production of Teff cells and to increase the generation of Treg cells. In contrast, IA1 exacerbates the proinflammatory response and could prove useful in cancer therapy by enhancing the body's killing of cancer cells. The goals of this study are to: 1) optimize the manufacturing and composition of TA1 and IA1; 2) determine the therapeutic efficacy TA1 and IA1 in murine disease models; and 3) compare TA1 and IA1 to existing therapeutic agents. These studies will provide significant new insights into the potential utility of miRNA-based therapeutics as an approach to treating immune dysfunctions.
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Co-Investigator(s) / Trainee
Canadian Blood Services
Canadian Blood Services-CIHR Partnership Operating Grant Program
British Columbia
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