The purpose of this body of work is to explore possibilities for drug delivery to the posterior segment of the eye, as well as therapeutics applicable for those patients suffering from chronic retinal degenerations and those who have already lost their sight from progressive retinal degenerations.
To target the posterior segment of the rat eye, a chronic intravitreous infusion cannula was designed and implanted in adult Sprague-Dawley rats. Efficacy was assessed by (a) chronic infusion of fluorescein into the vitreous, and subsequent vitreous sampling (b) chronic infusion of 5mM L-glutamate and PBS to determine whether the pharmacodynamic effects of vitreous infusates can be observed within the retina, as evidenced by electroretinograms (ERGs). Caged neurotransmitters were assessed for use in a neuroprosthetic device. Caged glutamate molecules were screened in vitro , prior to chronic intravitreous infusion in vivo in adult Sprague-Dawley rats. ERGs and retinal histology assessed the pharmacodynamic effects of these substances in the retina following a 7-day infusion. The Royal College of Surgeons (RCS) rat model of retinal degeneration was used to assess the therapeutic effects of intravitreous delivery of CNTF, as assessed by analyzing thresholds for electrically-evoked cortical potentials (EECPs) in response to transcorneal electrical stimulation.
Following chronic intravitreous infusion, significant fluorescein levels were detectable in the vitreous and chronic infusion of L-glutamate resulted in abolition of the ERG waveform, relative to baseline ERGs. pHP glutamate was determined by in vitro assessment to be the least neurotoxic. Following chronic intravitreous infusion, L-glutamate resulted in abolition of the ERG waveform while BSS, pHP glutamate and pHP cage infusions maintained ERG waveform morphology. Histologically, the pHP glutamate group demonstrated a increase in retinal thickness relative to other groups. In the RCS rat retinal degeneration model, it was observed that over time, EECP thresholds increased. Eyes treated with CNTF demonstrated significantly greater retinal sensitivity to electrical stimulation
A chronic intravitreous infusion cannula for the rat eye was developed and is effective for delivering substances to the vitreous and retina. In vivo studies demonstrated that physiologically, pHP glutamate was less toxic to the retina that L-glutamate or photoactivated pHP glutamate and may have a role in the development of a neuroprosthetic device. However, the retinal swelling observed with pHP glutamate treated retina may indicated that long-term, this molecule may have deleterious effects on the retina. Over time, the RCS rat model of retinal degeneration loses retinal sensitivity to electrical stimulation. However, retinal sensitivity to electrical stimulation was preserved in animals treated with chronic intravitreous infusion of CNTF.
