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K. Mancuso, M. Neitz, W. W. Hauswirth, Q. Li, T. B. Connor, Jr., J. Kuchenbecker, M. C. Mauck, J. Neitz; Colorblindness Cure: Gene Therapy Confers a New Sensation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3252. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Among members of the primate species, Saimiri sciureus (squirrel monkey), a subset of females are trichromatic while males have dichromatic color vision. The dichromats are an ideal model of red-green colorblindness in humans that results from the absence of either the long- (L) or middle- (M) wavelength-sensitive photopigment genes. While normal trichromats have four main hue percepts - red, green, blue, and yellow, - dichromats can discriminate blues and yellows from gray, but lack percepts of red and green. We asked if the addition of a third photopigment would allow dichromatic monkeys to become fully trichromatic, in order to answer whether a single genetic change in the retina can result in a new sensory capacity in adults.
A recombinant adeno-associated virus vector containing an L-opsin gene was injected subretinally. The goal was to exploit the capricious nature of viral infection to transduce only a subset of cones, producing a retinal region with two randomly-interspersed cone types absorbing in the middle-to-long wavelengths. To evaluate transgene expression at the level of the retina, we developed an LED-based wide-field color multifocal electroretinogram (ERG) apparatus. The effects of the treatment on color vision behavior were measured using a computerized color vision test, the Cambridge Colour Test, which was adapted for use with the monkeys.
Before treatment, the monkeys’ discrimination was tested for 16 different hues. Their behavior was highly reliable and they always failed to make "red-green" discriminations, as predicted from their known cone complement. Following gene therapy, successful L-opsin expression and modified cone physiology were readily detected with the color multifocal ERG as an increase in sensitivity to long-wavelength light. In turn, comparisons of pre- and post-therapy color vision test results indicated that the animals also gained a new sensory capacity, red-green color vision, in response to gene therapy.
Conventional wisdom has held that "critical periods" exist for the development of new visual capacities, raising the concern that treating adults with congenital conditions could be impossible. The successful treatment of adult monkeys that had a color vision defect from birth is encouraging for the possibility of using gene therapy to treat a variety of inherited vision disorders that involve cone photoreceptors in humans.
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