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A combination of factors slows the translation of experimental neuroprotective targets to the clinic.
For glaucoma, critical needs include (1) identification of “large effect” targets mediating both neuronal and glial (inflammatory) pathogenic cascades, (2) moving beyond traditional testing to models more closely mimicking human disease and response to treatment, and (3) a clear path towards a clinical trial with robust outcomes.
The Calkins laboratory demonstrated recently that daily, topical (eye-drop) application of a potent p38 inhibitor prevented the early axon damage endemic to glaucoma (Dapper et al., 2013). In contrast to many neuroprotective targets, p38 signaling in neurons and glia is activated by multiple stressors relevant to glaucoma, including mechanical, inflammatory and oxidative stressors.
Once activated, p38 in turn activates multiple downstream pathways also relevant in glaucoma. These include pro-inflammatory signaling (TNFα, nitric oxide, interleukins) and regulation (NFkB, Stat3), cytoskeletal degradation (tau phosphorylation), calcium dysfunction (NMDA and TRP receptors), heat shock proteins (HSP27, 90) and pro-apoptotic nuclear signals (caspases). Thus, targeting p38 signaling quiets a multitude of pathogenic processes.
Our goal is to validate p38 as a target for a topical neuroprotective therapy in a highly relevant, preclinical model that will establish feasibility and generate interest for human trials.
Article by David J. Calkins, PhD, the Denis M. O'Day Professor of Ophthalmology and Visual Sciences, Vice-Chairman and Director for Research, The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN
In 2014, Dr. Calkins received a follow-on research grant from the Glaucoma Research Foundation to fund this project.
Last reviewed on April 15, 2015
This article appeared in the September 2014 issue of Gleams.Subscribe