Asset/Technology Type
Therapeutic Strategy
Description of Invention
The invention is a therapeutic approach for modulating cellular trans-differentiation and potentially angiogenesis by modulating O-glcnacylation (GlcNAc) of proteins, to treat various conditions. The inventors used existing small molecules to prove the concept in vitro and in vivo. The projected use includes (a) wound or fracture healing and treating vascularization (ischemic tissues, coronary, cerebral and peripheral arterial disease) by enhancing O-glcnacylation pathway, potentially enhancing angiogenesis; and (b) treating tumor neovascularization or excess vascularization (age-related macular degeneration, diabetic retinopathy, telangiectasias, AV malformations) by inhibiting glcnacylation pathway, potentially inhibiting angiogenesis.
Stage of Development
In vitro: Transdifferentiation of fibroblasts to endothelial cells was enhanced with the addition of the OGA inhibitor Thiamet-G (increased GlcNAc). Conversely, transdifferentiation was reduced with DON, a glutamine fructose-6-phosphate amidotransferase inhibitor (decreased GlcNAc). Alternatively, transdifferentiation was enhanced when OGA was knocked down by two shRNAs (sgOGA-1 and sgOGA-2) (increased GlcNAc). Additionally, network formation of human umbilical vein endothelial cells (HUVECs) onto a matrigel was enhanced by Thiamet-G and inhibited by the OGT inhibitor OSMI (quinolonone-6-sulfonamide).
In vivo: Thiamet G increased tissue O-glycnacylation, increased capillary density and limb perfusion, and increased the number of fibroblasts transdifferentiating into endothelial cells in ischemic hindlimb mice model. OGT knockout mice exhibited impaired restoration of perfusion after femoral artery ligation. Retinal neovascularization was delayed in newborn OGT KO, confirming the importance of glcnacylation in angiogenesis.
Competitive Landscape
Small molecule therapies encompass pathway-specific targeting agents designed to promote tissue repair. The proposed therapeutic strategy highlights the potential to target O-GlcNAcylation using small molecules in a rapid, tunable, and controlled manner, facilitating therapeutic transdifferentiation for the treatment of ischemic diseases. This approach involves selectively targeting O-GlcNAcylation-related enzymes, understanding the full spectrum of effects on cellular pathways, and ensuring the safety and efficacy of these molecules in clinical settings. However, challenges remain, including achieving precise and selective targeting, fully understanding the broad effects on cellular mechanisms, and ensuring the safety and effectiveness of these molecules in clinical applications.
Competitive Advantages
Intellectual Property (HM Ref. OTT202123)
US patent application has been filed.
Inventors
John P. Cooke and Li LAI
Contact Us
For more information, contact the Office of Technology Transfer at OTT@HoustonMethodist.org