Encapsulated Cell–Based Intraocular Delivery of Ciliary Neurotrophic Factor (CNTF) in Normal Rabbit: Dose Dependent Effects on ERG and Retinal Histology

Abstract

Abstract: : Purpose: Controlled continuous delivery of ciliary neurotrophic factor (CNTF) by intravitreally implanted encapsulated cell technology (ECT) devices has been shown to rescue photoreceptors in the rcd1 dog model of retinitis pigmentosa at relatively low dose levels. CNTF at higher doses, given by intravitreal injection or viral mediated gene transfer, increases photorecptor survival in other animal models, but can lead to impaired retinal function, as measured by the ERG, and abnormal changes in photoreceptor nuclei. We investigated the effects of therapeutic and higher levels of CNTF delivered by ECT device on the ERG and histology of normal rabbit retina. Methods: Fifteen adult New Zealand White albino rabbits had ECT devices secreting CNTF at 22 ng/day, 5 ng/day or 0 ng/day implanted in the dorsal temporal quadrant of the left eye. The low dose was previously shown to produce maximal rescue of photoreceptors in the rcd1 dog model of retinal degeneration. Right eyes were untreated. Ganzfeld dark– and light–adapted ERGs and clinical observations were performed at 5, 15, and 25 days after implantation. Statistical evaluation of rod a–waves, rod and cone b–waves and outer nuclear layer (ONL) morphology was done at the 25 day time point. Results: Clinical examination showed minimal changes in a few CNTF treated eyes, including vitreous membranes and engorgement of iris vessels at day 25. Retinas appeared normal. CNTF did not significantly affect the rod a– or b–waves, though the b–wave amplitude tended to be larger in CNTF treated retinas at low flash intensities. The cone b–wave amplitude was significantly reduced in high dose eyes at some flash intensities. The ONL in high dose eyes was thicker and had a significantly greater area than in fellow retinas. ONL nuclei size was significantly increased and nuclear staining intensity decreased in both high and low dose retinas. Conclusions: Therapeutic doses of CNTF given continuously for 25 days (5 ng/day) by intravitreal ECT do not reduce either rod or cone ERG function of normal rabbit retina. Twenty–two ng/day produces decreases in the light–adapted ERG that may reflect changes in cone pathway function. Morphological changes in the ONL nuclei associated with both doses of CNTF can occur in the absence of functional changes detectable by ERG.

Keywords: growth factors/growth factor receptors • neuroprotection • electroretinography: non–clinical