Report Summary

Gene Therapy Fully Restores Vision to the All-Cone Nrl - / -Gucy2e- / - Mouse Model of Leber Congenital Amaurosis-1

Study Summary

Overall Study Design 
Mutations in GUCY2D are the cause of Leber congenital amaurosis type 1 LCA1 GUCY2D encodes retinal guanylate 
cyclase-1 retGC1 a protein expressed exclusively in outer segments of photoreceptors and essential for timely recovery 
from photoexcitation Recent clinical data show that despite a high degree of visual disturbance stemming from a loss of 
cone function LCA1 patients retain normal photoreceptor architecture except for foveal cone outer segment abnormalities 
and in some patients foveal cone loss These results point to the cone-rich central retina as a target for GUCY2D 
replacement LCA1 gene replacement studies thus far have been conducted in rod-dominant models mouse or with 
vectors and organisms lacking clinical translatability Here we investigate gene replacement in the Nrl-  - Gucy2e-  - 
mouse an all-cone model deficient in retGC1 We show that AAV-retGC1 treatment fully restores cone function cone-
mediated visual behavior and guanylate cyclase activity and preserves cones in treated Nrl-  -Gucy2e-  - mice over the 
long-term A novel finding was that retinal function could be restored to levels above that in Nrl-  - controls contrasting 
results in other models of retGC1 deficiency 
We attribute this to increased cyclase activity in treated Nrl-  -Gucy2e-  - mice relative to Nrl-  - controls Thus Nrl-  -
Gucy2e-  - mice possess an expanded dynamic range in ERG response to gene replacement relative to other models 
Lastly we show that a candidate clinical vector AAV5-GRK1- GUCY2D when delivered to adult Nrl-  -Gucy2e-  - 
mice restores retinal function that persists for at least 6 months 
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