Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness.
Mutations in the retinal pigment epithelium gene encoding RPE65 are a cause of the incurable early-onset recessive human retinal degenerations known as Leber congenital amaurosis. Rpe65-deficient mice, a model of Leber congenital amaurosis, have no rod photopigment and severely impaired rod physiology. We analyzed retinoid flow in this model and then intervened by using oral 9-cis-retinal, attempting to bypass the biochemical block caused by the genetic abnormality. Within 48 h, there was formation of rod photopigment and dramatic improvement in rod physiology, thus demonstrating that mechanism-based pharmacological intervention has the potential to restore vision in otherwise incurable genetic retinal degenerations.
Van Hooser
J P
JP
Departments of Ophthalmology, Chemistry, and Pharmacology, University of Washington, Seattle, WA 98195, USA.
Aleman
T S
TS
He
Y G
YG
Cideciyan
A V
AV
Kuksa
V
V
Pittler
S J
SJ
Stone
E M
EM
Jacobson
S G
SG
Palczewski
K
K
D000284:Administration, Oral; D000818:Animals; D001766:Blindness / Q000188:drug therapy* / Q000503:physiopathology; D002352:Carrier Proteins; D002648:Child; D004195:Disease Models, Animal; D004224:Diterpenes; D005136:Eye Proteins; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010857:Pigment Epithelium of Eye / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000503:physiopathology; D012172:Retinaldehyde / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D012176:Retinoids / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D013997:Time Factors; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D004224:Diterpenes; D005136:Eye Proteins; D011506:Proteins; D012172:Retinaldehyde; D012176:Retinoids; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C031390:9-cis-retinal