Journal article
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(7), pp.1411-1423
04/01/2011
DOI: 10.1093/hmg/ddr022
PMCID: PMC3049361
PMID: 21245082
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.
Details
- Title: Subtitle
- 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
- Creators
- Artur V Cideciyan - University of PennsylvaniaRivka A Rachel - National Eye Institute, National Institutes of HealthTomas S Aleman - University of PennsylvaniaMalgorzata Swider - University of PennsylvaniaSharon B Schwartz - University of PennsylvaniaAlexander Sumaroka - University of PennsylvaniaAlejandro J Roman - University of PennsylvaniaEdwin M Stone - University of Iowa Carver College of MedicineSamuel G Jacobson - University of PennsylvaniaAnand Swaroop - National Eye Institute, National Institutes of Health
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.20(7), pp.1411-1423
- Publisher
- Oxford University Press
- DOI
- 10.1093/hmg/ddr022
- PMID
- 21245082
- PMCID
- PMC3049361
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 04/01/2011
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; John and Marcia Carver Nonprofit Genetic Testing Laboratory; Ophthalmology and Visual Sciences
- Record Identifier
- 9984070600702771
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