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(Investigative Ophthalmology and Visual Science. 2004;45:2420-2430.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-1342
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Encapsulated Cell-Based Intraocular Delivery of Ciliary Neurotrophic Factor in Normal Rabbit: Dose-Dependent Effects on ERG and Retinal Histology

Ronald A. Bush,1,2 Bo Lei,1,3,4 Weng Tao,5 Dorit Raz,2 Chi-Chao Chan,6 Terry A. Cox,6 Maria Santos-Muffley,2 and Paul A. Sieving1,2,6

1From the Department of Ophthalmology and Visual Science, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; 5Neurotech USA, Lincoln, Rhode Island; the 2National Institute of Deafness and Communication Disorders and the 6National Eye Institute, National Institutes of Health, Bethesda, Maryland; and the 3Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, and the 4Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri.

PURPOSE. ERG and histologic changes were investigated in normal rabbits after intravitreal implantation of encapsulated cell technology (ECT) devices releasing ciliary neurotrophic factor (CNTF).

METHODS. Fifteen adult New Zealand White albino rabbits had ECT devices secreting CNTF at 22, 5, or 0 ng/d implanted in the superior temporal quadrant of the left eye. The low dose has been shown to produce substantial rescue of photoreceptors in the rcd1 canine 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. Rod a-waves and rod and cone b-waves and outer nuclear layer (ONL) morphology were evaluated at 25 days.

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, although 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 area in high-dose eyes was significantly greater because of increased thickness than in fellow retinas. ONL cell size was significantly increased, and staining density decreased in CNTF-treated retinas.

CONCLUSIONS. CNTF, given by intravitreal ECT device at doses that protect photoreceptors in a canine model of retinal degeneration (5 ng/d), did not adversely affect either rod or cone ERG function of normal rabbit retina. The cone ERG was more sensitive to suppression being reduced, at low flash intensities, by 22 ng/d. Dose-related changes in the ONL and photoreceptor cell nuclei did not represent a toxic effect, because they were not associated with deficits in the rod ERG over a broad range of intensities.




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