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Artur V. Cideciyan, Alexander Sumaroka, Malgorzata Swider, Alejandro J. Roman, Melani B. Olivares, Cristina L. Mullins, Sharon B. Schwartz, Tomas S. Aleman, Edwin M. Stone, Samuel G. Jacobson; Gene Therapy Potential of Human Retinal Degenerations caused by Mutant Photoreceptor Genes CEP290 versus AIPL1. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6603.
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To evaluate and compare the disease expression in human patients with mutations in photoreceptor-expressed genes CEP290 (also called NPHP6) or AIPL1 in order to predict their potential for treatment with gene augmentation therapy.
Patients with Leber congenital amaurosis, LCA (CEP290, n=14, ages=7-48; AIPL1, n=10, ages=1-40), or later-onset retinal degeneration, RD (AIPL1, n=1, serially examined between ages 45 to 67), were studied by ocular examination, retinal cross-sectional and en face imaging, perimetry, full-field sensitivity testing, and pupillometry.
All LCA patients had severe loss of vision from early life, non-detectable electroretinograms and little or no detectable visual fields. Full field sensitivity was severely reduced or undetectable in most patients. In AIPL1-LCA, when detectable, chromatic stimuli revealed retained but impaired rod function, by psychophysics and pupillometry. In CEP290-LCA, retained function was mediated by cones in most patients. RPE health as evaluated with autofluorescence imaging showed abnormalities in the macular regions of AIPL1-LCA; patients with CEP290-LCA on the other hand showed foveal and parafoveal regions of healthy RPE with retained melanin and lipofuscin. Cross-sectional imaging with SD-OCT showed substantially retained foveal and parafoveal cone photoreceptor nuclei in CEP290-LCA, whereas foveal photoreceptors were undetectable and paracentral photoreceptors were only minimally preserved in AIPL1-LCA. The patient with later-onset RD due to AIPL1 retained an ERG into the fifth decade of life with abnormal rod and cone signals; there was progressive loss of central and peripheral function.
AIPL1-LCA, unlike some other forms of LCA with equally severe visual disturbance, shows profound loss of foveal as well as extrafoveal photoreceptors. Primary therapeutic strategies to be considered should include means for photoreceptor regeneration or substitution. CEP290-LCA patients, on the other hand, retain substantial central cone photoreceptors at all ages and they are appropriate targets for cone-directed gene therapy. The late-onset and slower form of AIPL1-RD disease may also be well suited for a gene therapy intervention.
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