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Curing Color Blindness—Mice and Nonhuman Primates

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Curing Color Blindness—Mice and Nonhuman Primates Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Curing Color Blindness—Mice and Nonhuman Primates Maureen Neitz and Jay Neitz Department of Ophthalmology, University of Washington, Seattle, Washington 98109 Correspondence: [email protected] It has been possible to use viral-mediated gene therapy to transform dichromatic (red-green color-blind) primates to trichromatic. Even though the third cone type was added after the end of developmental critical periods, treated animals acquired red-green color vision. What happened in the treated animals may represent a recapitulation of the evolution of trichro- macy, which seems to have evolved with the acquisition of a third cone type without the need for subsequent modification to the circuitry. Some transgenic mice in which a third cone type was added also acquired trichromacy. However, compared with treated primates, red-green color vision in mice is poor, indicating large differences between mice and monkeys in their ability to take advantage of the new input. These results have implications for understanding the limits and opportunities for using gene therapy to treat vision disorders caused by defects in cone function. isual experience-dependent neural plastici- genital vision disorders would be ineffective un- Vty is a recognized property of the developing less administered to the very young. However, in cortex, but what purpose is served by the ability recent experiments using adult red-green color- of sensory processes to remodel their function deficient primates, addition of a third opsin was in response to changes in experience (Hubel sufficient to produce trichromatic color vision 1988)? An engaging hypothesis is that plasticity behavior (Mancuso et al. 2009), demonstrating relieves the necessity to hard-wire all connec- that trichromacy does not require an early de- tions during development according to genetic velopmental process and that there are excep- www.perspectivesinmedicine.org instructions. In the adult cortex, this could al- tions to the idea that neural inputs to the visual low adaptive adjustments depending on the en- system cannot be appropriately processed un- vironment and could provide a mechanism for less they are established before a critical period recovering from damage (Albright et al. 2000). in development. For example, in a recent study Classic visual deprivation experiments led to of surgical outcome for removal in congenital the expectation that neural connections estab- cataracts in pediatric patients, poor outcomes lished during development would not appro- were associated with surgical intervention after priately process an input that was not present compared with before one year of age (Khanna from birth, and therefore, that treatment of con- et al. 2013). The successes so far provide reason Editors: Eric A. Pierce, Richard H. Masland, and Joan W. Miller Additional Perspectives on Retinal Disorders: Genetic Approaches to Diagnosis and Treatment available at www.perspectivesinmedicine.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a017418 Cite this article as Cold Spring Harb Perspect Med 2014;4:a017418 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press M. Neitz and J. Neitz for optimism that gene therapy can be devel- opsin. Adeno-associated virus serotype 2/5 oped as a viable treatment strategy for adult (rAAV2/5) containing a recombinant human patients with disorders affecting cone photore- L-opsin (RHLOPS) gene under the control of ceptor function, and they open the way for new the recombinant human L/M-opsin enhancer research to explore the possibilities and limits and promoter pR2.1 (Wang et al. 1992) was for gaining function by adding new inputs in delivered to the photoreceptor layer by sub- adults. A better understanding of the ways in retinal injection (Mancuso et al. 2009). Tran- which the adult nervous system changes and scriptional regulatory elements contained in does not change will be key for future develop- pR2.1 direct gene expression in M cones, but ment of therapies to restore visual function. not S cones, rods, or any other retinal cell type (Li et al. 2007). These control elements include CURING COLOR BLINDNESS the locus control region, which is an enhancer IN NONHUMAN PRIMATES that is required for transcription of the opsin genes on the X chromosome (Nathans et al. Experiments using gene therapy in an attempt 1989; Wang et al. 1992; Wang et al. 1999), and to cure congenital red-green color blindness in the proximal promoter for the L-opsin gene. nonhuman primates were performed on adult To provide the receptor basis for trichromacy, squirrel monkeys (Saimiri sciureus). In this spe- animals received three 100-mL injections in cies, as in manyother New Worldprimates, there each eye. This transduced roughly one-third of is a single opsin gene on the X chromosome, the M cones such that they coexpressed the but there is allelic diversity at the locus (Jacobs transgenic L opsin along with the endogenous 1984; Mollon et al. 1984; Jacobs and Neitz 1985; M opsin, whereas the untransduced M cones Soares et al. 2010; Bunce et al. 2011). One allele expressed only the endogenous M opsin. The encodes the equivalent to a human long-wave- transduced- and wild-type cones were random- length (L) opsin; anotherencodesthe equivalent ly intermixed in a relatively smooth mosaic. Be- to a human middle-wavelength (M) opsin; and fore treatment, monkeys were trained to per- at least one allele encodes an opsin that gives rise form a computer-based color vision test, the to a photopigment that is spectrally intermedi- Cambridge Colour Test (Reffin et al. 1991; Re- ate between human L and M photopigments gan et al. 1994), which had been modified for (Neitz et al. 1991; Jacobs et al. 1993). Because use with animals (Fig. 2) (Mancuso et al. 2006). all male squirrel monkeys have only one X chro- All dichromats, including humans and mon- mosome, they are dichromatic, with one cone keys who are missing either the L- or the M photopigment encoded by the X chromosome photopigment, fail to distinguish from gray www.perspectivesinmedicine.org plus a short wavelength (S)-sensitive cone pho- any colors near the “spectral neutral point” lo- topigment encoded by an autosome. Females cated in the blue-green region of color space. who are homozygous for the cone opsin allele They also fail to distinguish complementary encoded by the X chromosome are also dichro- colors near the “extra-spectral neutral point” matic; however, females who are heterozygous in the red-violet region (Jacobs 1984). Trichro- have trichromatic color vision (Jacobs and Neitz mats experience six basic color percepts that 1987). The process of X inactivation segregates exist as opponent pairs: blue and yellow, red, the expression of the two opsin alleles into sep- and green, and black and white. In contrast, arate populations of cone photoreceptors, giv- dichromats experience only four basic color ing rise to a mosaic containing L, M, and S percepts, nominally blue and yellow, and black cones. and white, but they do not experience the nor- mal sensations of red or green (Schmidt et al. Gene Therapy with L Opsin in Dichromatic 2014). For all dichromats there are two colors Squirrel Monkeys that are indistinguishable from gray, one of The gene therapy trials targeted adult squirrel which appears greenish and the other reddish monkeys that were missing the gene encoding L to normal trichromats. 2 Cite this article as Cold Spring Harb Perspect Med 2014;4:a017418 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Curing Color Blindness Before treatment, two dichromatic monkeys cence was first detected at 9 wk postinjection, completed three complete color vision tests and it continued to increase in area and intensity (Mancuso et al. 2009). Each test examined the for .24 wk (Mancuso et al. 2009). Although animal’s ability to discriminate 16 different faint signs of GFP were first detectable at 9 wk, hues from gray. For each hue, thresholds were L-opsin levels sufficient to produce suprathres- determined for how much color had to be add- hold mf-ERG signals were still not present at ed to a gray stimulus for it to be distinguishable 16 wk postinjection. After GFP fluorescence be- from a gray background. Because 4–6 mo were came robust, the mf-ERG response to red light, required to test all 16 hues, baseline results rep- which indicates responses from the introduced resented testing conducted for .1 yr. As pre- L opsin, showed highly increased response am- dicted, before treatment, the monkeys had low plitudes in the area of treated retina. The two thresholds for colors that represent blues and dichromatic monkeys who participated in be- yellows to their dichromatic eyes. They always havioral tests of color vision were treated only failed to discriminate specific blue-green and with the virus carrying the L opsin gene. The red-violet hues from gray, as is characteristic treatment goal of producing a large homoge- of animals and humans with only S and M cones neous region was accomplished by placing in- (protanopes). Their pretreatment thresholds, jections at three well-spaced locations with cen- extrapolated from psychometric functions, ters corresponding to 10˚ eccentricity from were orders of magnitude higher for colors the fovea. This produced an mf-ERG response that activate the normal red-green system and to red light that covered an area of central retina fall along a “protan line” in color space than for of roughly 100˚ in diameter. The wide-field col- colors that maximally activate the blue-yellow or mf-ERG results showed that gene therapy color opponent system and that fall along a “tri- changed the spectral sensitivity of a subset of tan line” (a color confusion line for people with the cones.
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