Editorial |

Blind Dogs That Can See:  Pharmacological Treatment of Leber Congenital Amaurosis Caused by a Defective Visual Cycle

Krzysztof Palczewski, PhD
Arch Ophthalmol. 2010;128(11):1483-1485. doi:10.1001/archophthalmol.2010.245.
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Petersen-Jones and colleagues performed an important proof-of-principle study titled “Improvement of Visual Performance With Intravitreal Administration of 9-cis-Retinal in Rpe65-Mutant Dogs,”1 published in this issue of the Archives. As a component of comprehensive preclinical studies, its primary goal was to determine the efficacy of 9-cis-retinal in restoring visual function assessed by both electroretinography (ERG) and functional vision testing in Rpe65-mutant dogs. Because dogs generally have high levels of circulating retinoids,2 the researchers injected 9-cis-retinal directly into 1 eye of 7 Briard Rpe65−/−-mutant dogs (Figure, A).3,4 The results were striking. In 5 of 7 dogs, 9-cis-retinal injection resulted in increased rod ERG responses and improved functional vision. Moreover, 3 injected dogs exhibited increased 33-Hz flicker amplitudes characteristic of cone-mediated responses. These positive effects lasted for about 10 weeks. More important, a second injection of 9-cis-retinal at 20 or 29 weeks after the first injection in 2 (dogs 5 and 6) of the 7 dogs partially restored vision again, providing a potential dosing strategy for humans. These encouraging results provide impetus for the development of intravitreal devices that promote sustained delivery of 9-cis-retinal as a therapy for conditions resulting from a genetic blockade of the retinoid (visual) cycle (Figure, B).

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Treatment of Briard Rpe65−/−-mutant dogs with the synthetic cis-retinoids. A, View of a treated Briard Rpe65−/−-mutant dog. B, Chemistry of vision: phototransduction and the retinoid (visual) cycle (reviewed in von Lintig et al3). Mutations in Rpe65 are associated with Leber congenital amaurosis4 because they are required for 11-cis-retinal production. 9-cis-Retinoids can be used to overcome this blockage and regenerate functional visual pigments, called isorhodopsin, in rods that have characteristics similar to rhodopsin. The depicted protein structures are of rhodopsin (left) and Rpe65 (right).

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