11-cis-retinal and Optic-Atrophy--Hereditary--Leber

Retinitis pigmentosa (RP), the group of hereditary conditions involving death of retinal photoreceptors, represents the most prevalent cause of visual handicap among working populations in developed countries. Here we provide an overview of the molecular pathologies associated with such disorders, from which it becomes clearly apparent that RP is one of the most genetically heterogeneous of hereditary conditions for which molecular pathologies have so far been elucidated. While heterogeneity of such magnitude would appear to represent a major impediment to the development of therapeutics, mutation-independent approaches to therapy are being developed to effectively by-pass such diversity in genetic aetiology. The implications of such technologies in terms of therapeutic intervention in RP, and indeed other genetically heterogeneous conditions, will be addressed.

Topics: 3' Untranslated Regions; 5' Untranslated Regions; Animals; Apoptosis; Disease Progression; Eye Proteins; Genes, Dominant; Genes, Recessive; Genetic Heterogeneity; Genetic Linkage; Genetic Therapy; Humans; Mammals; Mice; Mice, Knockout; Models, Animal; Nerve Growth Factors; Optic Atrophy, Hereditary, Leber; Retina; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; RNA, Catalytic; RNA, Messenger; Syndrome; Transcription Factors; X Chromosome

Retinal pigment epithelium-specific protein 65 kDa (RPE65) is a protein responsible for isomerization of all-trans-retinaldehyde to its photoactive 11-cis-retinaldehyde and is essential for the visual cycle. RPE65 mutations can cause severe, early onset retinal diseases such as Leber congenital amaurosis (LCA). A naturally occurring rodent model of LCA with a recessive nonsense Rpe65 mutation, the rd12 mouse, displays a profoundly diminished rod electroretinogram (ERG), an absence of 11-cis-retinaldehyde and rhodopsin, an overaccumulation of retinyl esters in retinal pigmented epithelial (RPE) cells, and photoreceptor degeneration. rd12 mice were injected subretinally at postnatal day 14 with rAAV5-CBA-hRPE65 vector. RPE65 expression was found over large areas of RPE soon after treatment. This led to improved rhodopsin levels with ERG signals restored to near normal. Retinyl ester levels were maintained at near normal, and fundus and retinal morphology remained normal. All parameters of restored retinal health remained stable for at least 7 months. The Morris water maze behavioral test was modified to test rod function under very dim light; rd12 mice treated in one eye performed similar to normally sighted C57BL/6J mice, while untreated rd12 mice performed very poorly, demonstrating that gene therapy can restore normal vision-dependent behavior in a congenitally blind animal.

Topics: Animals; Behavior, Animal; Carrier Proteins; cis-trans-Isomerases; Dependovirus; Disease Models, Animal; Esters; Eye Proteins; Genetic Therapy; Genetic Vectors; Mice; Mice, Inbred C57BL; Optic Atrophy, Hereditary, Leber; Retina; Rhodopsin; Vision, Ocular