Subventions et des contributions :

Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier (2017-2018 à 2018-2019).

Transforming growth factor beta (TGF-ß) is a pleiotropic cytokine with essential roles in normal embryonicx000D
development and tissue homeostasis. The role of excessive TGF-ß action in fibrosis is well documented.x000D
Therefore, it is of interest to develop drugs that block TGF-ß signaling for therapeutic benefit. This therapeuticx000D
niche is now being explored by Formation Biologics, a Canadian company focusing on the development ofx000D
TGF-ß inhibitors. Formation has a successful drug development record with one product in phase I clinicalx000D
trials, and a second in IND-enabling development. To continue its efforts in the development of specific TGF-ßx000D
inhibitors (i.e. specific to each isoform within the TGF-ß superfamily), Formation Biologics is now interestedx000D
in exploring promising alternatives to antibody-based therapeutics. The proposed research thus focuses onx000D
harnessing the TGF-ß-neutralizing potential of TGF-ß receptor extracellular domains to develop potent TGF-ßx000D
antagonists. More specifically, the proposal is to physically combine various receptor extracellular domains tox000D
improve their TGF-ß binding and sequestration efficiency while taking advantage of their binding specificity. Ifx000D
performed with a classical experimental approach (i.e., the design of chimeric proteins corresponding to thex000D
fusion of two distinct receptors, their purification and related assays), such a study would be extremelyx000D
time-consuming if one considers the number of TGF-ß isoforms, the number of receptors they bind to, as wellx000D
as the number of resulting receptor combinations. Using a unique molecular adaptor strategy emanating fromx000D
previous work performed in De Crescenzo's lab, the inhibition of TGF-ß signaling by different TGF-ß receptorx000D
combinations will be tested more rapidly by setting an innovative mix-and-match strategy. The expectedx000D
outcome is a competitive and novel strategy to inhibit TGF-ß signaling. Successful completion of this projectx000D
will provide Formation Biologics with a new therapeutic avenue to inhibit TGF-ß signaling, hence promotingx000D
the development of new drugs, and thus directly benefiting the Canadian patient population and economy.