Ciliary neurotrophic factor (
CNTF) rescues photoreceptors in several animal models of
retinal degeneration and is currently being evaluated as a potential treatment for
retinitis pigmentosa in humans. This study was conducted to test whether
CNTF prevents photoreceptor cell loss in XLPRA2, an early onset canine model of X-linked
retinitis pigmentosa caused by a frameshift mutation in RPGR exon ORF15. Four different treatment regimens of
CNTF were tested in XLPRA2 dogs. Under
anesthesia, the animals received at different ages an
intravitreal injection of 12 microg of
CNTF in the left eye. The right eye served as a control and was injected with a similar volume of
phosphate buffered saline (PBS). Ocular examinations were performed regularly during the treatment periods. At termination, the dogs were euthanatized, eyes collected and the retinas were processed for embedding in optimal cutting temperature (OCT) medium. The outer nuclear layer (ONL) thickness was evaluated on H&E sections and values in both
CNTF- and PBS-treated eyes were compared. Morphologic alterations in the peripheral retina were characterized by immunohistochemistry using cell-specific markers. Cell proliferation in the retinas was examined on semi-thin
plastic sections, and by
BrdU pulse-labeling and Ki67 immunohistochemistry on cryosections. All
CNTF-treated eyes showed early clinical signs of corneal epitheliopathy, subcapsular
cataracts and
uveitis. No statistically significant difference in ONL thickness was seen between the
CNTF- and PBS-injected eyes. Prominent
retinal remodeling that consisted in an abnormal increase in the number of rods, and in misplacement of some rods, cones, bipolar and Müller cells, was observed in the peripheral retina of
CNTF-treated eyes. This was only seen when
CNTF was in injected before the age at which the canine retina reaches full maturation. In XLPRA2 dogs,
intravitreal injections of
CNTF failed to prevent photoreceptors from undergoing cell death in the central and mid-peripheral retina.
CNTF also caused ocular side-effects and morphologic alterations in the periphery that were consistent with cell dedifferentiation and proliferation. Our findings suggest that some inherited forms of
retinal degeneration may not respond to
CNTF's
neuroprotective effects.