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First Small Molecule Therapy for Retinal Degenerations

Investigators: Mark Humayun; Stan Louie

Retinitis pigmentosa (RP) has been linked to over 200 genetic mutations spanning more than 60 different genes. Despite their genetic differences, there is a common molecular underpinning, where all of these mutations can initiate and promote RP. Recently, RP has been linked to chronic inflammation, where aqueous and vitreous humor from RP patients showed elevation of MCP-1, CXCL-10, and IL-8. These findings suggest that innate immune cells such as neutrophils and microglial cells may play a role in its pathogenesis. Thus the ability to resolve chronic inflammation may be an effective approach for the treatment of RP. Persistent neutrophils in the affected tissue can form chromatin networks (NETs) that can sustain chronic inflammation. However, aspirin trigger lipoxin or lipoxin A4 (LXA4) have been shown to reduce inflammation, through promoting neutrophil apoptosis, and its clearance, thus breaking the cycle of persistent inflammation. We have developed an ALXR agonist, EMX151, that mimics the biological activity of LXA4 but with improved pharmacokinetic properties. Similar to LXA4, EMX151 is able to promote neutrophil apoptosis and its clearance but have a longer ocular and systemic half-life. In this proposal, we will establish the effectiveness of EMX151 in RP rat models. Therefore, we propose to determine the optimal dose and frequency leading to maximal efficacy. In addition, we will dissect the molecular mechanism driving the pharmacologic properties of EMX151. At the conclusion of this study, the team will be poised to enter into IND enabling studies and thus set the stage for Phase I clinical evaluation.