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Andras M. Komaromy, Simone Iwabe, Jessica S. Rowlan, Alison D. Duncan, Shilpa Rao, Annie Oh, Rong Wen, Gustavo D. Aguirre; Cntf Induces A Transient Restoration Of Cone Function And Day Vision In Cngb3-achromatopsia. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5351.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal bolus injection of CNTF leads to deconstruction and regeneration of photoreceptor outer segments in normal dogs, and improves the success rate of viral CNGB3 gene replacement therapy in older dogs (> 1 year) with CNGB3-achromatopsia. The present work evaluates the effect of intravitreal CNTF alone on retinal gene expression and function in dogs with CNGB3-achromatopsia.
Five CNGB3-mutant dogs (age: 10 months) and 5 normal control dogs (age: 8 months) were injected unilaterally with 12 µg of intravitreal CNTF; the contralateral eyes served as controls and were injected with PBS. ERGs were recorded at baseline and at 1 week post injection, when retinas were collected for RNA extraction. Retinal gene expression was evaluated by qRT-PCR and Agilent Canine Oligo Microarray, containing 42,034 60-mer oligonucleotide probes. Three additional mutant dogs (ages 10, 13 and 45 months) were treated with intravitreal CNTF and followed by ERG, visual behavior testing, and gene and protein expression evaluated by qRT-PCR and IHC at 1, 7, and 94 weeks post treatment.
CNTF treatment severely reduced ERG amplitudes at 1 week in both normal and CNGB3-mutant dogs. However, cone function and day vision were transiently restored in the mutant dogs. At 5-weeks following treatment, scotopic retinal function normalized but cone function and day vision deteriorated back to baseline. In both normal and mutant retinas, these functional observations were associated with marked, but transient shortening of photoreceptor outer segments and decrease in photoreceptor-specific gene expression at 1 week. The most up-regulated genes at 1 week post CNTF included FGG, C3, and AQP3; examples of the most down-regulated genes were ARR3 and GUCA1A.
The CNTF-induced changes in photoreceptor morphology and retinal gene expression are similar between normal and CNGB3-mutant retinas at 1 week. However, mutant retinas transiently regain cone function reminiscent of the 3-4 week old developing CNGB3-mutant retina. Since functional beta subunits of the cone CNG channels are lacking, CNTF might have facilitated the alpha subunits to form functional homotetrameric channels in the cone outer segments, resulting in restored cone function.
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