PURPOSE: 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.
PURPOSE: To quantify the retinal disease in Rpe65-deficientmice 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 humanRPE65-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. HumanRPE65-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 humanRPE65-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: Astra Dinculescu; Jackie Estreicher; Juan C Zenteno; Tomas S Aleman; Sharon B Schwartz; Wei Chieh Huang; Alejandro J Roman; Alexander Sumaroka; Qiuhong Li; Wen-Tao Deng; Seok-Hong Min; Vince A Chiodo; Andy Neeley; Xuan Liu; Xinhua Shu; Margarita Matias-Florentino; Beatriz Buentello-Volante; Sanford L Boye; Artur V Cideciyan; William W Hauswirth; Samuel G Jacobson Journal: Hum Gene Ther Date: 2012-01-26 Impact factor: 5.695
Authors: Samuel G Jacobson; Artur V Cideciyan; Ramakrishna Ratnakaram; Elise Heon; Sharon B Schwartz; Alejandro J Roman; Marc C Peden; Tomas S Aleman; Sanford L Boye; Alexander Sumaroka; Thomas J Conlon; Roberto Calcedo; Ji-Jing Pang; Kirsten E Erger; Melani B Olivares; Cristina L Mullins; Malgorzata Swider; Shalesh Kaushal; William J Feuer; Alessandro Iannaccone; Gerald A Fishman; Edwin M Stone; Barry J Byrne; William W Hauswirth Journal: Arch Ophthalmol Date: 2011-09-12
Authors: Shiho Kawamura; Moritz Gerstung; Alejandro T Colozo; Jonne Helenius; Akiko Maeda; Niko Beerenwinkel; Paul S-H Park; Daniel J Müller Journal: Structure Date: 2013-02-21 Impact factor: 5.006
Authors: Kristin L Gardiner; Artur V Cideciyan; Malgorzata Swider; Valérie L Dufour; Alexander Sumaroka; András M Komáromy; William W Hauswirth; Simone Iwabe; Samuel G Jacobson; William A Beltran; Gustavo D Aguirre Journal: Mol Ther Date: 2019-09-03 Impact factor: 11.454
Authors: Artur V Cideciyan; Samuel G Jacobson; William A Beltran; Alexander Sumaroka; Malgorzata Swider; Simone Iwabe; Alejandro J Roman; Melani B Olivares; Sharon B Schwartz; András M Komáromy; William W Hauswirth; Gustavo D Aguirre Journal: Proc Natl Acad Sci U S A Date: 2013-01-22 Impact factor: 11.205
Authors: Charles B Wright; Micah A Chrenek; Stephanie L Foster; Todd Duncan; T Michael Redmond; Machelle T Pardue; Jeffrey H Boatright; John M Nickerson Journal: Invest Ophthalmol Vis Sci Date: 2013-07-30 Impact factor: 4.799