Cellular and molecular studies of ciliary neurotrophic factor receptor alpha expression and ciliary neurotrophic factor mediated neuroprotection in the canine retina
Over the past decades, extensive new knowledge on the cellular and molecular mechanisms of vision has been acquired. During the genomic era, numerous genes involved in retinal function have been identified, some of which have been causally associated with various forms of retinal disorders. Despite this rapid progress in the understanding of retinal biology, retinal degeneration, the most common cause of blindness in the developed world remains an untreatable condition. A therapeutic strategy that has been tested in several animal models of retinal degeneration has been to deliver intraocularly a survival factor, ciliary neurotrophic factor (CNTF), in an attempt to rescue photoreceptor cells prior to cell death. To begin addressing the question about the mechanism of CNTF-mediated neuroprotection, the retinal expression of the specific receptor for CNTF (CNTFRalpha) was characterized. Using different molecular approaches, we found that photoreceptor cells from non-rodent mammalian species (including dog and human) express CNTFRalpha. This led to the conclusion that in these species, a CNTF- mediated photoreceptor rescue effect would most likely result from the direct activation of a pro-survival response in rods and cones. The underlying expectation in testing CNTF as a potential treatment for retinitis pigmentosa (RP) and allied disorders is that it may provide a means of protecting photoreceptor cells regardless of the genetic and/or environmental causes of the disease. This hypothesis is based on the evidence that CNTF rescues photoreceptors in several non-allelic animal models of RP. One such model has been rcd1, a canine form of early-onset and rapidly progressing retinal degeneration caused by a mutation in the PDE6B gene. In this work, we evaluated whether CNTF could also rescue photoreceptors in XLPRA2, another early-onset canine model of RP caused by a mutation in a different gene (RPGR exon ORF15). The characterization of the histological stages of the disease, and the examination of the kinetics of cell death provided time-points to optimally test CNTF's neuroprotective effect in this model. Intravitreal injections of CNTF in XLPRA2 at these determined ages failed to show any significant rescue from cell death, and caused some abnormal peripheral retina remodeling that was disease- and age-specific.
neuroprotection; retina; CNTF; canine; CNTFRalpha; dog; photoreceptor
dissertation or thesis