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.2009 Oct 8;461(7265):784-7.
doi: 10.1038/nature08401. Epub 2009 Sep 16.

Gene therapy for red-green colour blindness in adult primates

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Gene therapy for red-green colour blindness in adult primates

Katherine Mancuso et al. Nature..

Abstract

Red-green colour blindness, which results from the absence of either the long- (L) or the middle- (M) wavelength-sensitive visual photopigments, is the most common single locus genetic disorder. Here we explore the possibility of curing colour blindness using gene therapy in experiments on adult monkeys that had been colour blind since birth. A third type of cone pigment was added to dichromatic retinas, providing the receptoral basis for trichromatic colour vision. This opened a new avenue to explore the requirements for establishing the neural circuits for a new dimension of colour sensation. Classic visual deprivation experiments have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that the treatment of congenital vision disorders would be ineffective unless administered to the very young. However, here we show that the addition of a third opsin in adult red-green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour. Thus, trichromacy can arise from a single addition of a third cone class and it does not require an early developmental process. This provides a positive outlook for the potential of gene therapy to cure adult vision disorders.

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Figures

Fig. 1
Fig. 1
rAAV2/5 vector produced functional L-opsin in primate retina. a, Molecular map; TR = terminal repeats; LCR = locus control region; PP = proximal promoter; SD/SA = splice donor/acceptor; RHLOPS = recombinant human L opsin cDNA; PA1 = polyadenylation signal. b, Red light mf-ERG stimulus. c, Mf-ERG 40 weeks after two injections (yellow circles) of a mixture of L-opsin- and GFP-coding viruses. Grey lines show borders of highest response; for comparison, inset = mfERG 16 weeks post-injection; there was no reliable signal from L-opsin, unchanged from baseline. High responses in far peripheral retina were measured reliably and may have originated from offshoot of one of the injections. d, Fluorescence photographs from a similar retinal area as c; grey lines from c were copied in d. e, Confocal microscopy revealed a mosaic pattern of GFP expression in 5–12% of cones. Because GFP-coding virus was diluted to 1/3 compared to L-opsin virus, an estimated 15–36% of cones in behaviourally tested animals express L-opsin. f, Mf-ERG from a behaviourally tested animal 70 weeks after 3 injections of L-opsin virus.
Fig. 2
Fig. 2
Pre-therapy colour vision and possible treatment outcomes. a, Colour vision stimuli examples. b, Pre-therapy results, monkey 1. Hues tested are represented as dominant wavelengths (DWs) rather thanu', v' coordinates. If a hue could not be reliably distinguished at even the highest saturation, the extrapolated threshold approached infinity. c, Pre-therapy results, monkey 2. de, Possible experimental outcomes: Monkeys could have a relative increase in long-wavelength sensitivity, but remain dichromatic (dashed lines, d); theoretical colour spectrum appearances for a dichromat and a possible “spectral shift” are shown. Alternatively, dichromatic monkeys could become trichromatic. Results from a trichromatic female control monkey are plotted (dashed line, e; error bars = SEM and n varied from 7–11).
Fig. 3
Fig. 3
Gene therapy produced trichromatic colour vision. a, Time course of thresholds for the blue-green confusion colour, DW = 490 nm (circles), and a yellowish colour, DW = 554 nm (squares). A logarithmic scale was used to fit high thresholds for DW = 490 nm; significant improvement occurred after 20 weeks. Enclosed data points = untreated dichromatic monkey thresholds, DW = 490 nm (triangle) and DW = 554 nm (diamond). b–c, Comparison of pre-therapy (open circles, solid line) and post-therapy thresholds (solid dots, dashed line). Enclosed data points are DW = 490 nm thresholds when tested against a red-violet background (DW = −499 nm); pink triangles = trichromatic female control thresholds. Error bars = SEM; n varied from 7–11.
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