Chronic Intravitreous Infusion of Ciliary Neurotrophic Factor Modulates Electrical Retinal Stimulation Thresholds in the RCS Rat

Retinitis pigmentosa (RP) is a clinical term that refers to a heterogeneous group of inherited or sporadic retinal dystrophies that affect 1 in 4000 worldwide.1-3 This degeneration is characterized by a progressive loss of photoreceptors in the outer retina and later, a remodeling of higher-order neuronal circuits within the relatively spared inner retina.4-6 Ultimately, patients with RP may become blind due to failure of the retina to process visual input as a consequence of these changes. Although there are currently no effective treatments for these diseases, patients who have lost their vision because of retinal degeneration may benefit from a retinal prostheses designed to restore sensory inputs to the remaining retinal circuits. Pioneering human trials have demonstrated that electrical stimulation of the retina can produce rudimentary visual percepts, called electrophosphenes.7-9 These studies have also revealed, however, that electrophosphene thresholds are significantly higher in patients with more advanced stages of retinal degeneration. In addition, electrical stimulation studies of retinal wholemounts in rd1 mice have confirmed that more advanced stages of retinal degeneration are associated with higher electrical stimulation thresholds.10 Thus, as a patient’s retinal degeneration progresses, the effectiveness of a sensory replacement retinal prosthesis may progressively diminish. Increased electrophosphene thresholds constrain the resolution of sensory replacement retinal prosthetics by necessitating larger electrodes with greater charge-carrying capacity. Heat generation may also increase as the currents required for electrophosphene percepts rise. Consequently, we hypothesized that methods for retinal neuroprotection may preserve or enhance retinal sensitivity to electrical stimulation. Electrical stimulation devices have, in the past, been shown to be neuroprotective against a multitude of neuronal injuries and disease states, including those that afflict the eye. After transection of the optic nerve, the ganglion cells of the retina rapidly succumb to apoptosis within weeks.11,12 However, transcorneal electrical stimulation was found to rescue axotomized retinal ganglion cells for 1 to 2 weeks after injury.13,14 In addition to rescue of ganglion cells, electrical stimulation may be neuroprotective against inherited retinal degenerations.15 Pardue et al.15 found that subretinal implantation of a microphotodiode array in the RCS rat preserves electroretinograms (ERGs) for up to 6 weeks after surgery. The treatment effect was transient, however, and no significant functional preservation was seen at postoperative week 8. The mechanisms of neuroprotection after electrical stimulation most likely include the modulation of endogenous growth factors. A multitude of growth factors have long been shown to enhance survival of retinal neurons.16 After injury or stress, activated microglia and Muller cells have demonstrated increased expression of CNTF, glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF or FGF2), which act to enhance photoreceptor survival.17,18 Expanding on the knowledge that growth factor upregulation has a protective effect, a number of groups have administered exogenous growth factors intraocularly to rodent models of RP and found that they reduced the degree of retinal degeneration.19-22 The neurotrophin CNTF has been found to be efficacious in slowing the progression of retinal degeneration, with prolonged administration to the RCS rat, S334ter-3 rat, and rcd1 canine animal models of retinal degeneration.21,22 Recently, a phase I clinical trial demonstrated the safety of chronic intravitreous delivery of CNTF over a 6-month period in patients with RP.23 These clinical trials have now entered phase II in patients with RP and dry aged-related macular degeneration. The lack of adverse outcomes from chronic CNTF delivery is an encouraging finding, suggesting that CNTF may be an efficacious treatment to slow the progression of RP. The purpose of this study was to determine whether retinal neuroprotection in the RCS rat via chronic intravitreous infusion of CNTF is associated with a reduction in electrically evoked cortical potential (EECP) stimulation thresholds.