title: Retinal disease in Rpe65-deficient mice: comparison to human leber congenital amaurosis due to RPE65 mutations.
abstract: OBJECTIVE
  To quantify the retinal disease in Rpe65-deficient mice across a wide age span and compare the results to those in humans with Leber congenital amaurosis (LCA) caused by RPE65 mutations.
  
  
  METHODS
  Full-field electroretinograms (ERGs) were recorded from wild-type (C57BL/6; Rpe65(+/+)) and Rpe65(-/-) mice at ages ranging from ∼1 month to 2 years. A physiologically based model of rod phototransduction activation was used to determine photoreceptor (P3) cell components of ERG photoresponses. A bipolar (P2) cell component was also derived. Photoreceptor and inner retinal thickness measurements were made by using optical coherence tomography in human RPE65-LCA.
  
  
  RESULTS
  Age-related declines in ERG photoreceptor and bipolar amplitudes were present in the Rpe65(-/-) mouse. The loss of photoresponse amplitude with age in the mutant mice paralleled reported losses of photoreceptor nuclear layer thickness over the same age range. Unexpectedly, the early activation phase of photoresponses in Rpe65(-/-) mice accelerated with age as amplitude decreased; this was not a feature of Rpe65(+/+) mice. Inner retinal dysfunction increased with age in the mutant mice. Human RPE65-LCA patients had retinal degeneration and loss of photoreceptors in the first decade of life. Unlike the mouse model, there were no examples of a normal photoreceptor complement. Abnormal thickening of the inner retina occurred with increasing loss of photoreceptors.
  
  
  CONCLUSIONS
  The differences in time course of murine and human RPE65-deficiency diseases suggests that preclinical efficacy testing of therapeutic modalities would be most informative when the murine disease becomes comparable to early human disease, toward the end of the first year of life in Rpe65(-/-) mice.
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rafael C
authors.initials: RC
authors.lastname: Caruso
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Mullins
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003623:Dark Adaptation; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology*; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology*; D013997:Time Factors; D041623:Tomography, Optical Coherence; D014785:Vision, Ocular / Q000502:physiology; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase