Human molecular geneticsJan 20, 2011

Cone photoreceptors as main targets for gene therapy in NPHP5 or NPHP6 blindness: creating a mouse with mostly cone cells to model human retinal cilia disease

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Updated Apr 4, 2026

Abstract

NPHP5- and NPHP6-LCA are associated with early-onset rapid degeneration of rod photoreceptors in young subjects.

Rod outer segment lamination is disorganized when detectable, indicating abnormal development.
Accumulation of lipofuscin in retinal pigment epithelium suggests that rod photoreceptors existed previously in most subjects.
Despite early rod losses, cone nuclei in the fovea are retained across all ages in NPHP5- and NPHP6-LCA.
The rd16 mouse model shows normal formation of photoreceptors but exhibits rapid degeneration of rod outer segments.
Rd16;Nrl-/- double-mutant mice retain cone photoreceptors but demonstrate disproportionate loss of cone function, reflecting human disease characteristics.
These findings suggest that NPHP5- and NPHP6-LCA could be suitable for cone-directed gene augmentation therapy.

Simplified

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.

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Cone photoreceptors as main targets for gene therapy in NPHP5 or NPHP6 blindness: creating a mouse with mostly cone cells to model human retinal cilia disease

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