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Project TitleLipoxin Mediated Neuroprotection
Track Code17005
Short Description

Lipoxins  LXA4 and LXB4 as potential treatment for glaucoma and other neuronal injury related pathologies


 
Abstract

Neuroprotective agents represent an intensive research field and an area of high interest for pharmaceutical development. Lipoxins are known pro-resolving lipid mediators that act locally in paracrine or autocrine manners to dampen inflammation. A team of researchers from the University Health Network and the University of California at Berkeley have discovered a new role for lipoxin signaling directly on neuronal homeostasis and survival. Both endogenous lipoxins LXA4 and LXB4 demonstrate direct neuroprotective effects in a neuronal cell line, primary cortical neurons, and cultured retinal ganglion cells (RGCs).  Interestingly, the much less well-studied LXB4 demonstrates superior neuroprotective action compared to LXA4 (Fig.1).  In an acute in vivo retinal injury model LXB4 was similarly more potent than LXA4.  Finally, in a challenging 15-week rat model of chronic glaucoma, LXB4 was therapeutically delivered to the eye and via IP injection starting from week 8. RGC function and survival was significantly better in LXB4-treated retinas compared to vehicle, as shown in Figs. 1 & 2.  Importantly, there was no observed effect of LXB4 treatment on intraocular pressure, eliminating a potential indirect effect.

Fig. 1. Therapeutic administration of LXB4 protects RGC function following chronic IOP injury.  (a) Schematic of the experimental design showing ERG and OCT readings every 4 weeks following suture induce IOP.  LXB4 administration started at week 8, and retinal flatmounting and RGC counting was performed at week 15. (b) Average waveforms for RGC (pSTR) responses at week 15 for LXB4 and vehicle groups, and (c) relative change in RGC function across 15 weeks.  Starting at week 12, there was a significant and increasing rescue of LXB4 treated eyes compared to vehicle (* p < 0.05; n=8 per group, bars are S.D., the shaded area indicates the treatment period).

                     

Fig.2. Quantification of RGC density revealed the suture induced loss was significantly rescued by LXB4 treatment compared to vehicle in both the outer and inner retinas (***p < 0.001 compared to vehicle, n=8, bars are S.E.M.).


 
Tagstherapeutics, small molecules, glaucoma, Krembil, Lipoxin Mediated Neuroprotection
 
Posted DateMay 29, 2017 12:59 PM

Potential Applications

  • Neuroprotection

  • Treatment for glaucoma

Principal Investigator

Dr. Jeremy Sivak, University Health Network (lead researcher)

Project Status and Next Steps

  • Screening for compounds with improved Lipoxin action

  • Formulation development and pre-clinical study

Patent Status

Provisional patent application# 62/469,396 on March 9, 2017

Partnering Opportunity

Available for co-development or licensing

Publications

Izhar Livne-Bar, Jessica Wei, Hsin-Hua Liu, Samih Alqawlaq, Alessandra Tuccitto, Karsten Gronert, John G. Flanagan, and Jeremy M. Sivak Lipoxin LXB4 mediates direct neuroprotection from acute and chronic retinal injury (submitted)

For Further Information, Please Contact:

Oksana Akhova, PhD, MBA | Licensing and Commercialization Professional | Technology Development and Commercialization | University Health Network | +1 416-581-8569 | oksana.akhova@uhnresearch.ca  

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