A387/3415

Topical Application of Novel Quinazolinone OC-10X Does Not Adversely Affect the Retina: Multifocal Electroretinogram and Visual Evoked Response Analysis

Tuesday, Apr 29, 2008, 3:00 PM - 4:45 PM

Hall B/C

104 age-related macular degeneration: basic mechanisms - RC

S.S. Samudre, F.A. Lattanzio, Jr., A. Hosseini, P.B. Williams. Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA.

412 age-related macular degeneration, 510 electroretinography: non-clinical, 577 laser

Introduction: During drug development, visual function cannot be directly measured in preclinical animal models. Multifocal electroretinogram (MFERG) and visual evoked response (VER) are emerging tools to assess drug efficacy and toxicity at the retina and optic nerve respectively. MFERG and VER were used to assess retinal function and toxicity after topical application of OC-10X, a new drug for age-related macular degeneration (AMD).
Methods: For MFERG analysis, contact lens electrodes and stimuli with a 254 non-scaled hexagonal pattern were used. For VER analysis, sub-dermal Pt needle electrodes were placed near the visual cortex and stimulated with 8x8 square pattern. Full-field ERG (FF) was measured with corneal electrodes. To demonstrate detection of retinal damage by MFERG over 30 laser spots were placed in opposing quadrants and monitored for 2 wk. In the Brown Norway rat AMD model, choroidal neovascularization was stimulated by applying 8 radial laser photocoagulation spots at a constant distance from the optic disk. In this AMD model, some rats were treated with 1.0% OC-10X or vehicle control three times a day for up to 6 wk. Other rats without laser damage were also treated with OC-10X for up to 6 wk to examine for toxic effects on retina and optic nerve. To demonstrate detection of laser damage by FF, laser damage was compared with intravitreal injection of NMDA (40 nM).
Results: In the rat AMD model, MFERG identified laser damaged quadrants as areas of retinal dysfunction and was able to differentiate individual laser spot damage corresponding to approximately 5 non-responsive hexagons (NRH). There were no corresponding changes in VER or FF. Results were corroborated with fluorescein angiography and histology. NMDA treatment significantly reduced FF a-wave amplitude to 171±10.4 µV compared to the contralateral untreated eye (241±14.0 µV; p=0.03). Although in the untreated AMD rats, NRH progressed over a 2 wk period from 5 to 8 hexagons with ~20% decrease in N1 and P1 amplitude, this was not the case with OC-10X treatment. In normal rats, treatment with OC-10X for up to 6 wk had no adverse effect on FF a-, b-wave, oscillatory potential, or flicker response (amplitude or latency) or VER (P1, N1 and P2).
Conclusions: In an AMD model, electroretinography can quantify the extent of damage to retina or optic nerve. By this measure sustained topical application of OC-10X was not toxic to either retina or optic nerve. In addition, OC-10X appeared to retard retinal damage.

 S.S. Samudre, None; F.A. Lattanzio, Ocucure Therapeutics Inc., C; A. Hosseini, None; P.B. Williams, Ocucure Therapeutics Inc., C.

Ocucure Therapeutics Inc.