May 2006
Volume 47, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2006
Retina–Wide and Local Retinal Toxicity in Preclinical Studies of Ocular Therapy: ERG and Morphometric Standards in Non–Human Primates
Author Affiliations & Notes
  • A.J. Roman
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • T.S. Aleman
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • A.V. Cideciyan
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • S.B. Schwartz
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • M.D. Doobrajh
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • A. Sumaroka
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • E.A. M. Windsor
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • A.M. Komaromy
    University of Pennsylvania, Philadelphia, PA
    School of Veterinary Medicine,
  • G.D. Aguirre
    University of Pennsylvania, Philadelphia, PA
    School of Veterinary Medicine,
  • S.G. Jacobson
    University of Pennsylvania, Philadelphia, PA
    Ophthalmology, Scheie Eye Institute,
  • Footnotes
    Commercial Relationships  A.J. Roman, None; T.S. Aleman, None; A.V. Cideciyan, None; S.B. Schwartz, None; M.D. Doobrajh, None; A. Sumaroka, None; E.A.M. Windsor, None; A.M. Komaromy, None; G.D. Aguirre, None; S.G. Jacobson, None.
  • Footnotes
    Support  NIH/NEI; Foundation Fighting Blindness, Macula Vision Research Foundation, Macular Disease Foundation; RPB; Mackall Trust.
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 5685. doi:
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      A.J. Roman, T.S. Aleman, A.V. Cideciyan, S.B. Schwartz, M.D. Doobrajh, A. Sumaroka, E.A. M. Windsor, A.M. Komaromy, G.D. Aguirre, S.G. Jacobson; Retina–Wide and Local Retinal Toxicity in Preclinical Studies of Ocular Therapy: ERG and Morphometric Standards in Non–Human Primates . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5685.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Preclinical studies of treatment for retinal diseases, such as using intraocular gene transfer, require objective and quantifiable measures to detect retinal toxicity. The use of non–human primates in such studies prompts the need for standards in this species.

Methods: : Cynomolgus monkeys (n=9; age 2 yrs) had bilateral simultaneous full–field ERGs under anesthesia (ketamine; xylazine) in 2 recording sessions, 3 months apart. Responses were elicited to mimic an ISCEV protocol: dark–adapted (R) rod (dim blue flash) and (M) mixed cone and rod (single white flash); and light–adapted cone (on white adapting background: C1, white flashes at 1 Hz and CF, flicker at 29 Hz). At necropsy, eyes were taken for histopathology. Retinal morphometry was performed on vertical sections through the globe, sampling central (through the fovea), temporal and nasal retina. Overlapping microscope fields were digitized, montaged and measured at intervals for outer nuclear layer (ONL) thickness. Measures were normalized to thickness at 2 mm eccentricity.

Results: : ERG amplitude and timing parameters were as follows: R–b–wave, mean 101 (SD, 41) µV | 85.6 (12) ms; M–a–wave, 96 (30) µV | 11.5 (0.6) ms; M–b–wave, 169 (59) µV; C1–b–wave, 78 (22) µV | 28.3 (0.9) ms; CF, 93 (24) µV | 25 (0.5) ms. Interocular difference (IOD) variability (SD) was: R–b–wave, 17µV | 2.7ms; M–a–wave, 17 µV | 0.7ms; M–b–wave, 24 µV ; C1–b–wave, 8.5 µV | 0.5ms; CF, 8.7 µV | 0.25 ms. Intervisit difference (IVD) variability was also quantified. Average ONL thickness showed an expected decline with eccentricity towards the periphery. Mean normalized (2mm=100%) ONL thicknesses along the central vertical section were 96, 74, and 44% at loci 4, 6 and 10 mm from center, respectively. Variability at individual loci was similar to the aggregate SD of 11%.

Conclusions: : Human clinical trials for treatment of retinal diseases are benefited by toxicity studies performed on the human–like eyes of monkeys. The current data set serves as a reference for quantitative analyses of future toxicity studies. Of interest, ERG data variability (IOD, IVD) for the monkey corresponds closely to that published for man using similar techniques and the percent decline with eccentricity in ONL thickness relates well to human values from optical coherence tomography.

Keywords: retinal degenerations: hereditary • degenerations/dystrophies 
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