Ffar1 inhibitors that target dysfunctional energy metabolism in the eye to treat retinopathies
Inventors: Jean-Sebastien Joyal, Lois Smith
Invention Types: Therapeutics
Research Areas: Gastrointestinal/Nutrition, Oncology/Hematology, Ophthalmology
Retinopathies are the leading cause of blindness worldwide. Pathological neovascularization in the retina cause retinopathies such as age-related macular degeneration and diabetic retinopathy. At present, there is no cure, the only alternative is the use of invasive procedures consisting mainly in photocoagulation (laser beam to repair leaking blood vessels in the retina), vitrectomy (the surgical removal of the vitreous gel) and the use of VEGF blockers injected into the eye (i.e., Avastin, Lucentis). These invasive procedures results in multiple side effects including some permanent vision loss, mild loss of central vision, reduced night vision, and blocking neuronal stabilization as well as the growth of healthy necessary blood vessels in the eye and at a systemic level.|
Photoreceptors are mitochondria-rich cells with high energy consumption that was thought to rely on glucose as a fuel source. However, Dr. Smith’s team demonstrated that retina also uses fatty acid and identified free fatty acid receptor 1 (Ffar1, also known as GPR40) as a lipid sensor that curbs glucose uptake in presence of lipid abundance. In addition, they showed that when the lipid uptake is defective (extracellular lipid abundance and reduced lipid intake), photoreceptor cells fail to uptake glucose resulting in nutrient scarcity that leads to pathological angiogenesis. Moreover, Ffar1 deficient mice have improved glucose uptake and reduced number of vascular lesions when compared to controls and VLDLR deficient mice with defective lipid uptake. In contrast, Ffar1 agonists prevent glucose uptake and exacerbate the number of vascular lesions in VLDLR deficient mice. Therefore, the data from the research suggest that Ffar1 may be a potential target for therapeutic development and the use of Ffar1 inhibitors could restore metabolic function and prevent pathological vascularization.
• Inhibition of Ffar1 as a novel target for proliferative retinopathy treatment.
• Inhibitors of Ffar1 may also be used for other neovascularization disorders (i.e., cancer and inflammatory disorders)
• Local endogenous inhibition of pathological neovascularization in the retina to avoid the use of exogenous VEGF inhibitors
• Novel finding of Ffar1 as a metabolic sensor regulating glucose intake involved in neovascularization due to a lipid metabolic defect.
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Key Publications: Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med. 2016 Apr;22(4):439-45. doi: 10.1038/nm.4059. Epub 2016 Mar 14. PMID: 26974308
IPStatus: Pat. Pend.