Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy.
Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5-58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.
1 Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104.
Artur V
AV
Cideciyan
Robert B
RB
Hufnagel
Joseph
J
Carroll
Alexander
A
Sumaroka
Xunda
X
Luo
Sharon B
SB
Schwartz
Alfredo
A
Dubra
Megan
M
Land
Michel
M
Michaelides
Jessica C
JC
Gardner
Alison J
AJ
Hardcastle
Anthony T
AT
Moore
Robert A
RA
Sisk
Zubair M
ZM
Ahmed
Susanne
S
Kohl
Bernd
B
Wissinger
Samuel G
SG
Jacobson
D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003117:Color Vision Defects / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D017353:Gene Deletion; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D017299:Rod Opsins / Q000235:genetics*
D017299:Rod Opsins; C095855:long-wavelength opsin; C095854:middle-wavelength opsin