TARGETED MODULATION OF THE GLIAL INFLAMMATORY RESPONSE IN RETINITIS PIGMENTOSA ATTENUATES PHOTORECEPTOR CELL DEATH

DE LA ROSA EJ; JMAEFF S; BARCELONA PF; CATALINA HERNÁNDEZ-SÁNCHEZ; SARAGOVI, HU

Orlando

Congreso; ARVO?s 2014 Annual Meeting (The Association for Research in Vision and Ophthalmology).; 2014

ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises agroup of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent onthe genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed toexplore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. TheproNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, thelevels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor celldeath. Conversely, processed NGF levels were similar in rd10 and WTretinas. ProNGF remained elevated throughout the period ofphotoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. Theneuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinalexplants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminaldeoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outernuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosisand reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, affordedneuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis inthe progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utilityirrespective of etiology.