Amelioration of both functional and morphological abnormalities in the retina of a mouse model of ocular albinism following AAV-mediated gene transfer.
X-linked recessive ocular albinism type I (OA1) is due to mutations in the OA1 gene (approved gene symbol GPR143), which is expressed in the retinal pigment epithelium (RPE). The Oa1 (Gpr143) knockout mouse (Oa1(-/-)) model recapitulates many of the OA1 retinal morphological anomalies, including a lower number of melanosomes of increased size in the RPE. The Oa1(-/-) mouse also displays some of the retinal developmental abnormalities observed in albino patients such as misrouting of the optic tracts. Here, we show that these anomalies are associated with retinal electrophysiological abnormalities, including significant decrease in a- and b-wave amplitude and delayed recovery of b-wave amplitude from photoreceptor desensitization following bright light exposure. This suggests that lack of Oa1 in the RPE impacts on photoreceptor activity. More interestingly, adeno-associated viral vector-mediated Oa1 gene transfer to the retina of the Oa1(-/-) mouse model results in significant recovery of its retinal functional abnormalities. In addition, Oa1 retinal gene transfer increases the number of melanosomes in the Oa1(-/-) mouse RPE. Our data show that gene transfer to the adult retina unexpectedly rescues both functional and morphological abnormalities in a retinal developmental disorder, opening novel potential therapeutic perspectives for this and other forms of albinism.
Surace
Enrico Maria
EM
Telethon Institute of Genetics and Medicine, Naples, Italy.
Domenici
Luciano
L
Cortese
Katia
K
Cotugno
Gabriella
G
Di Vicino
Umberto
U
Venturi
Consuelo
C
Cellerino
Alessandro
A
Marigo
Valeria
V
Tacchetti
Carlo
C
Ballabio
Andrea
A
Auricchio
Alberto
A
D016117:Albinism, Ocular / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000503:physiopathology / Q000628:therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012160:Retina / Q000000981:diagnostic imaging / Q000503:physiopathology*; D017384:Sequence Deletion; D014463:Ultrasonography
D005136:Eye Proteins; C095276:GPR143 protein, human; C506821:Gpr143 protein, mouse; D008562:Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled