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Developing High Affinity Peptides to Target SARS-CoV-2 Spike (S) Protein
August 28, 2020

First Small Molecular for Retinal Degenerations

Year:

Investigators: Stan Louie; Mark Humayun

Investigators: Stan Louie; Mark Humayun

Retinitis pigmentosa (RP) has been linked to over 200 genetic mutations spanning more than 60 different genes. Despite their genetic differences, in most there is a common molecular underpinning where all of these mutations promote RP and sustained inflammation. These findings have been affirmed in RP patients showing elevated levels of MCP-1, CXCL-10, and IL8. These findings suggest that innate immune cells, in particular, neutrophils may play a role in RP pathogenesis. Thus, the ability to resolve chronic inflammation may be an effective approach for the treatment or slowing down the progression of most forms of RP.

Persistent activated neutrophils can sustain chronic inflammation which is evident by neutrophil extracellular traps (NETosis). However, lipoxin A4 (LXA4) binding onto ALXR can initiate apoptosis of neutrophil and trigger macrophage-mediate efferocytosis, thus breaking the cycle of persistent inflammation. We have developed an ALXR agonist, EMX151, a chemically stable LXA4 that is orally bioavailable. Similar to LXA4, EMX151 is able to promote neutrophil apoptosis and its clearance. We have exciting evidence suggesting oral administration of EMX151 can achieve effective concentration in ocular tissues and fluids. At these levels of EMX151, dramatic reduction of inflammatory cytokine expression associated with improvement in histological and ocular coherence tomography imaging data. We propose to identify oral dosing of EMX151 in RP models (e.g. rd10 and RCS) capable of preserving photoreceptors and their function. We will develop PK/PD models defining the molecular mechanism(s) driving EMX151- related properties. At study conclusion, the team will be poised to enter into IND enabling studies, thus setting the stage for Phase I clinical trial to develop the first oral therapy for RP.