Combined rod and cone transduction by adeno-associated virus 2/8.
Gene transfer to both cone and rod photoreceptors (PRs) is essential for gene therapy of inherited retinal degenerations that are caused by mutations in genes expressed in both PR types. Vectors based on the adeno-associated virus (AAV) efficiently transduce PRs of different species. However, these are predominantly rods and little is known about the ability of the AAV to transduce cones in combination with rods. Here we show that AAV2/8 transduces pig cones to levels that are similar to AAV2/9, and the outer nuclear layer (mainly rods) to levels that are on average higher, although not statistically significant, than both AAV2/5 and AAV2/9. We additionally found that the ubiquitous cytomegalovirus (CMV), but not the PR-specific GRK1 promoter, transduced pig cones efficiently, presumably because GRK1 is not expressed in pig cones as observed in mice and humans. Indeed, the GRK1 and CMV promoters transduce a similar percentage of murine cones with the CMV reaching the highest expression levels. Consistent with this, the AAV2/8 vectors with either the CMV or the GRK1 promoter restore cone function in a mouse model of Leber congenital amaurosis type 1 (LCA1), supporting the use of AAV2/8 for gene therapy of LCA1 as well as of other retinal diseases requiring gene transfer to both PR types.
1 Telethon Institute of Genetics and Medicine , Naples 80131, Italy .
Anna
A
Manfredi
Elena
E
Marrocco
Agostina
A
Puppo
Giulia
G
Cesi
Andrea
A
Sommella
Michele
M
Della Corte
Settimio
S
Rossi
Massimo
M
Giunti
Cheryl M
CM
Craft
Maria Laura
ML
Bacci
Francesca
F
Simonelli
Enrico M
EM
Surace
Alberto
A
Auricchio
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000628:therapy*; D051379:Mice; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics / Q000628:therapy*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic