ABSTRACT
OBJECTIVE: To determine the efficacy of intravitreal administration of 9-cis-retinal in restoring visual function in Rpe65-mutant dogs. METHODS: Intravitreal injection of 9-cis-retinal was administered in 1 eye of 7 Rpe65-/- dogs at a range of ages. Electroretinogram analysis and testing of visual performance was used to evaluate outcomes after a single injection and in 2 dogs after a second injection in the same eye. RESULTS: In 5 of 7 injected dogs, 9-cis-retinal injection resulted in increased rod electroretinogram responses and improved functional vision. Three injected dogs exhibited increased 33-Hz flicker amplitudes characteristic of cone-mediated responses. Electroretinogram improvement was no longer evident by week 10 postinjection in 1 dog monitored over time. A second injection of 9-cis-retinal was performed in the same eye of 2 of the 7 dogs and also resulted in rescue of visual function. CONCLUSION: Our findings establish that 9-cis-retinoid therapy can restore visual function in a canine model of human disease resulting from RPE65 mutations. CLINICAL RELEVANCE: These positive proof-of-principle results provide support for the development of intravitreal devices for sustained delivery of 9-cis-retinal as a therapy for conditions resulting from failure of the visual cycle.
Subject(s)
Carrier Proteins/genetics , Disease Models, Animal , Eye Proteins/genetics , Leber Congenital Amaurosis/drug therapy , Mutation , Photoreceptor Cells, Vertebrate/physiology , Retinaldehyde/administration & dosage , Vision, Ocular/physiology , Animals , Dark Adaptation , Diterpenes , Dogs , Electroretinography , Female , Intravitreal Injections , Isomerism , Leber Congenital Amaurosis/genetics , Leber Congenital Amaurosis/physiopathology , Male , Retreatment , Visual Acuity/physiologyABSTRACT
PURPOSE: The use of canine models of retinal disease in the development of therapeutic strategies for inherited retinal disorders is a growing area of research. To evaluate accurately the success of potential vision-enhancing treatments, reliable methods for objectively assessing visual function in canine models is necessary. METHODS: A simple vision-testing device was constructed that consisted of a junction box with four exit tunnels. Dogs were placed in the junction box and given one vision-based choice for exit. The first-choice tunnel and time to exit were recorded and analyzed. Two canine models of retinal disease with distinct molecular defects, a null mutation in the gene encoding the alpha subunit of rod cyclic GMP phosphodiesterase (PDE6A), and a null mutation in the gene encoding a retinal pigment epithelium-specific protein (RPE65) were tested and compared to those in unaffected dogs. RESULTS: With the use of bright light versus dim red light, the test differentiated between unaffected dogs and dogs affected with either mutation with a high degree of certainty. The white-light intensity series showed a significantly different performance between the unaffected and affected dogs. A significant difference in performance was detected between the dogs with each mutation. CONCLUSIONS: The results indicate that this novel canine vision-testing method is an accurate and sensitive means of distinguishing between unaffected dogs and dogs affected with two different forms of inherited retinal disease and should be useful as a means of assessing response to therapy in future studies.
