Visual Thresholds and ERG Amplitudes Are Impaired by Intraocular Delivery of CNTF

Abstract

Purpose: : Intraocular delivery of ciliary neurotrophic factor (CNTF), a possible treatment for retinal degenerations, results in reduced ERG amplitudes at high concentrations in mutant and normal animals. To determine whether the same treatment causes an impairment of visual function in normal animals, we measured optomotor thresholds and visual acuity following intraocular delivery of CNTF, and correlated the results with the ERG.

Methods: : Optomotor thresholds of normal, adult Long–Evans rats were evaluated before and after intravitreal injection of recombinant rat CNTF protein (rCNTF; 2 mg/ml in 5µl) or subretinal delivery of adeno–associated virus–vectored CNTF (AAV–CNTF) into one eye, using a virtual optomotor system. Visual acuity was also measured in AAV–CNTF injected animals using the Visual Water Task. Contralateral uninjected eyes served as controls. Full–field scotopic and photopic ERG amplitudes were measured from anesthetized rats.

Results: : Optomotor thresholds measured through eyes injected with rCNTF were normal before injection, but decreased by ∼50% within 5–8 days following injection and remained there for ∼50 days, after which time they gradually returned to normal by ∼100 days. ERG amplitudes showed a similar profile, reduction at 6 days following injection, with partial recovery by 21 days, but they remained below normal for an extended period, with photopic b–waves returning to normal only after 85 days postinjection. In eyes injected subretinally with AAV–CNTF, optomotor sensitivity thresholds decreased by ∼50% approximately 2 weeks postinjection and remained impaired for at least 6 months. Visual acuity was also reduced by ∼50%.

Conclusions: : Retinal delivery of CNTF at doses that transiently reduce ERG amplitudes can transiently impair visual function, and sustained delivery by AAV–CNTF can result in sustained reduction of visual function. These findings should be considered for the therapeutic use of CNTF.

Keywords: neuroprotection • photoreceptors • retinal degenerations: cell biology