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Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy.
Hum Mol Genet 2011; 20(7):1411-23HM

Abstract

Leber congenital amaurosis (LCA), a severe autosomal recessive childhood blindness, is caused by mutations in at least 15 genes. The most common molecular form is a ciliopathy due to NPHP6 (CEP290) mutations and subjects have profound loss of vision. A similarly severe phenotype occurs in the related ciliopathy NPHP5 (IQCB1)-LCA. Recent success of retinal gene therapy in one form of LCA prompted the question whether we know enough about human NPHP5 and NPHP6 disease to plan such treatment. We determined that there was early-onset rapid degeneration of rod photoreceptors in young subjects with these ciliopathies. Rod outer segment (OS) lamination, when detectable, was disorganized. Retinal pigment epithelium lipofuscin accumulation indicated that rods had existed in the past in most subjects. In contrast to early rod losses, the all-cone human fovea in NPHP5- and NPHP6-LCA of all ages retained cone nuclei, albeit with abnormal inner segments and OS. The rd16 mouse, carrying a hypomorphic Nphp6 allele, was a good model of the rod-dominant human extra-foveal retina. Rd16 mice showed normal genesis of photoreceptors, including the formation of cilia, followed by abnormal elaboration of OS and rapid degeneration. To produce a model of the all-cone human fovea in NPHP6-LCA, we generated rd16;Nrl-/- double-mutant mice. They showed substantially retained cone photoreceptors with disproportionate cone function loss, such as in the human disease. NPHP5- and NPHP6-LCA across a wide age spectrum are thus excellent candidates for cone-directed gene augmentation therapy, and the rd16;Nrl-/- mouse is an appropriate model for pre-clinical proof-of-concept studies.

Authors+Show Affiliations

Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21245082

Citation

Cideciyan, Artur V., et al. "Cone Photoreceptors Are the Main Targets for Gene Therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) Blindness: Generation of an All-cone Nphp6 Hypomorph Mouse That Mimics the Human Retinal Ciliopathy." Human Molecular Genetics, vol. 20, no. 7, 2011, pp. 1411-23.
Cideciyan AV, Rachel RA, Aleman TS, et al. Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Hum Mol Genet. 2011;20(7):1411-23.
Cideciyan, A. V., Rachel, R. A., Aleman, T. S., Swider, M., Schwartz, S. B., Sumaroka, A., ... Swaroop, A. (2011). Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Human Molecular Genetics, 20(7), pp. 1411-23. doi:10.1093/hmg/ddr022.
Cideciyan AV, et al. Cone Photoreceptors Are the Main Targets for Gene Therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) Blindness: Generation of an All-cone Nphp6 Hypomorph Mouse That Mimics the Human Retinal Ciliopathy. Hum Mol Genet. 2011 Apr 1;20(7):1411-23. PubMed PMID: 21245082.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. AU - Cideciyan,Artur V, AU - Rachel,Rivka A, AU - Aleman,Tomas S, AU - Swider,Malgorzata, AU - Schwartz,Sharon B, AU - Sumaroka,Alexander, AU - Roman,Alejandro J, AU - Stone,Edwin M, AU - Jacobson,Samuel G, AU - Swaroop,Anand, Y1 - 2011/01/18/ PY - 2011/1/20/entrez PY - 2011/1/20/pubmed PY - 2011/5/17/medline SP - 1411 EP - 23 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 20 IS - 7 N2 - Leber congenital amaurosis (LCA), a severe autosomal recessive childhood blindness, is caused by mutations in at least 15 genes. The most common molecular form is a ciliopathy due to NPHP6 (CEP290) mutations and subjects have profound loss of vision. A similarly severe phenotype occurs in the related ciliopathy NPHP5 (IQCB1)-LCA. Recent success of retinal gene therapy in one form of LCA prompted the question whether we know enough about human NPHP5 and NPHP6 disease to plan such treatment. We determined that there was early-onset rapid degeneration of rod photoreceptors in young subjects with these ciliopathies. Rod outer segment (OS) lamination, when detectable, was disorganized. Retinal pigment epithelium lipofuscin accumulation indicated that rods had existed in the past in most subjects. In contrast to early rod losses, the all-cone human fovea in NPHP5- and NPHP6-LCA of all ages retained cone nuclei, albeit with abnormal inner segments and OS. The rd16 mouse, carrying a hypomorphic Nphp6 allele, was a good model of the rod-dominant human extra-foveal retina. Rd16 mice showed normal genesis of photoreceptors, including the formation of cilia, followed by abnormal elaboration of OS and rapid degeneration. To produce a model of the all-cone human fovea in NPHP6-LCA, we generated rd16;Nrl-/- double-mutant mice. They showed substantially retained cone photoreceptors with disproportionate cone function loss, such as in the human disease. NPHP5- and NPHP6-LCA across a wide age spectrum are thus excellent candidates for cone-directed gene augmentation therapy, and the rd16;Nrl-/- mouse is an appropriate model for pre-clinical proof-of-concept studies. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/21245082/Cone_photoreceptors_are_the_main_targets_for_gene_therapy_of_NPHP5__IQCB1__or_NPHP6__CEP290__blindness:_generation_of_an_all_cone_Nphp6_hypomorph_mouse_that_mimics_the_human_retinal_ciliopathy_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddr022 DB - PRIME DP - Unbound Medicine ER -