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Konstantin Petrukhin, Boglarka Racz; Pharmacological normalization of the complement system dysregulation in the animal model of enhanced lipofuscin formation.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):277.
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© 2017 Association for Research in Vision and Ophthalmology.
Complement system dysregulation in the retina plays a critical role in pathogenesis of dry AMD. Normalization of the complement system dysregulation may represent a treatment strategy for dry AMD and, potentially, Stargardt disease. It has been recently reported that enhanced accumulation of lipofuscin in the eyes of abca4-/- mice is associated with complement activation. We developed a novel cyclopentyl fused pyrrolidine Retinol-Binding Protein 4 (RBP4) antagonist as a potential drug candidate for Stargardt disease and dry AMD. The compound partially restricts retinol supply to the RPE and induces drastic inhibition of bisretinoid synthesis in the abca4-/- model. Here we report the data on normalization of the complement system dysregulation by this drug candidate in the abca4-/- mouse model of enhanced lipofuscin formation
Abca4-/- mice were treated with the compound formulated into a chow at the dose that induces ~80% of serum RBP4 reduction. Two control groups of vehicle-treated abca4-/- and abca4+/+ animals were included in the study. Compound dosing was conducted for 3 months. Immunoblot analysis of retinal extracts as well as immunofluorescence analysis of retinal sections were conducted in the treatment and control groups to determine levels of expression for C3/C3b, CFH, CFD, MCP-1 as well as for C-reactive protein
Significant dysregulation of C3/C3b, CFH, CFD and C-reactive protein was observed in eyes of the vehicle-treated abca4-/- mice in comparison to the untreated abca4+/+ controls. Expression of C3/C3b, CFD and C-reactive protein was significantly increased in the abca4-/- mice while expression of CFH was significantly decreased. There was no difference in the MCP-1 expression between untreated abca4-/- and abca4+/+ animals. Compound dosing normalized the expression of all dysregulated complement system components in the treatment group
Administration of the optimized RPB4 antagonist normalized complement system dysregulation in eyes of the abca4-/- mice. The effect seems to relate to the ability of the drug candidate to drastically inhibit bisretinoid synthesis in this animal model. In addition, the drug candidate may directly interfere with the retinol-independent pro-inflammatory signaling function of RBP4 that was ascribed to this adipokine in alternative experimental systems
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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