Gene therapy for color blindness

Gene therapy for color blindness is an experimental gene therapy aiming to convert congenitally colorblinds to trichromats by introducing a photopigment gene that they lack. Though partial color blindness is considered to be a disadvantage, it is a condition that affects many people, particularly males . Complete color blindness, or achromatopsia , is very rare but more severe. While never shown in humans, animal studies have shown that it is possible to confer color by injecting a gene of the missing photopigment using gene therapy. As of 2014, there is no medical entity providing this treatment, and no clinical trials available for volunteers.

Color blindness

Main article: Color blindness

The retina of the human eye contains photoreceptive cells called cones that allow color vision. A normal trichromat individual possesses three different types of cones to be distinguished from the visible spectrum from 380 nm to 740 nm. [1] The three types of cones are designated L, M, and S cones, and each type is sensitive to a certain range of wavelength of light depending on what photopigment it contains. More specifically, the cone absorbs around 560 nm, the M cone absorbs near 530 nm, and the S cone absorbs near 420 nm. [1]Contrary to popular belief, The Peak Absorption Frequency for L, M, and S cones, not exactly corresponding to red, green, and blue wavelength. Rather, the peak frequency for the cone is orange, yellowish green in M ​​cones, and blue-violet in S cones. These cones transduce the retinal bipolar cells and retinal ganglion cells , before reaching the brain . [1]

The signals from different cones are added or subtracted from each other to the color of incoming light. For instance, the color red stimulates the cones more than M cones, the color green stimulates the L and M cones more than the S cones. [1] The colors are perceived in an opponent process , such as red and green are perceived in opposition, as are blue and yellow, black and white. [1]

The gene loci coding for the photopigments: M- opsin and L-opsin are located in close proximity within the chromosome and are highly polymorphic. [1] Among the population, some have a deleted gene for the photopigment in the chromosome (such as in deuteranopia), while others have a mutated form of the gene (such as in deuteranomaly). Individuals who can express only two types of opsins in the cones are called dichromats . Because males have only one copy of the X chromosome, dichromatism is much more prevalent among men. [1]With only two types of cones, dichromats are less capable of distinguishing between two colors. In the most common form of color blindness, deuteranopes have difficulty discriminating between red and green color. [1] This is shown by their poor performance in Ishihara test . Although dichromatism poses little problem for everyday life, dichromats may find some color-coded diagrams and maps difficult to read.

Less common forms of dichromacy include protoanopia (lack of L-cones), and tritanopia (lack of S-cones). If they have two types of photopigments, they are considered monochromats . People lacking the three types of photopigments are said to have complete color blindness or achromatopsia . Color blindness can also result from the visual cortex in the brain. [1]


Experiments using a variety of mammals (including primates), which is possible to confer color vision to animals by introducing an opsin gene that the animal previously lacked. Using a replication-defective recombinant adeno-associated virus (rAAV) as a vector, the cDNA of the opsin gene found in the gold mediator can be delivered to some fraction of the cones within the retina via subretinal injection. Upon gaining the gene, the cone begins to express the new photopigment. The effect of therapy lasts until the cones die or the inserted DNA is lost within the cones.

While gene therapy for humans has been ongoing with some success, a gene therapy for humans to gain color has not been attempted to date. However, demonstrations using multiple mammals (including primates such as squirrel monkey) suggest that the therapy should be feasible for humans as well. It is also theoretically possible for trichromats to be “upgraded” to tetrachromats by introducing new opsin genes.


The goal of the gene therapy is to make some of the cones in the retina of a dichromat individual to express the missing photopigment. Although partial color blindness is considered to be a disadvantage and even to the advantage under certain circumstances (such as spotting camouflaged objects), it can pose challenges for certain occupations such as driving or piloting an aircraft. [2] More generally, color codes and maps may be difficult to read with color blindness.

Because it is a relatively simple gene for photopigment and the gene is only expressed in the retina, it is a relatively easy condition for treating genetic disorders compared to other genetic diseases. However, there remains the question of whether the therapy is worthwhile, for an individual to undergo an invasive subretinal injection to be treated.

However, complete color blindness, or achromatopsia , is very rare but more severe. Indeed, achromats can not see any color, a strong photophobia (blindness in full sun), and reduced visual acuity (generally 20/200 after correction).

Moreover, the research may have strong implications towards genetic therapy of other cone diseases. Other congenital diseases such as congenital amaurosis , cone-rod dystrophy , and certain types of maculopathies may be treated using the same techniques as the gene therapy used for color blindness. [3] [4]

Research so far

There has-beens Ongoing research for gene therapy to treat Leber’s congenital amaurosis , a genetic disorder in Photoreceptors That can lead to vision loss and blindness. These treatments use AAV vector and are delivered in the same way as the gene therapy for color blindness. [5] [6]

Jacobs et al. published in the journal: Science in 2007, on their work introducing a human L-cone photopigment in mice . Since the mice possess only S cones and M cones, they are dichromats. [7] The researchers replaced M-opsin with a cDNA of L-opsin in the chromosome of some mice. By breeding these “knock-in” transgenic mice, they generated heterozygous females with both an M cone and an cone. These mice had been assessed and tested, and tested by electroretinogram and behavioral tests. However, this is more difficult to apply in the form of gene therapy.

In a paper published in the journal: Visual Neuroscience by Mauck et al., Researchers used recombinant AAV vector to introduce the green fluorescent protein (GFP) gene in the cones of gerbils . [8] The genetic insert was designed to be expressed in S or M cones, and the study observed the expression of GFP in vivo over time. The study of the time of onset of expression, and also of the expression of the gene expression could stabilize if a high dose of viral vector is given.

Mancuso et al. published in the journal: Nature in 2009, on converting dichromate squirrel monkeys into trichromates using gene therapy. [9] New world monkeys such as squirrel monkeys lack L-opsin gene and are incapable of discriminating between certain shades of red and green. [9] The Researchers used recombinant AAV vector to deliver a human L-opsin gene into the monkey’s retina. Cones that gained the missing genes began expressing the new photopigment. [9]

The researchers raised the possibility that the therapy worked-that the monkeys would remain dichromatic with greater sensitivity for longer wavelength of light, or they would become trichromatic. [9] Electroretinogram recordings demonstrated that they are able to discriminate blue-green from red-violet, and have indeed gained trichromacy. [9] The treated monkeys were also more successful when their color was tested with a modified Ishihara test. [9]

In 2007, Alexander JJ et al. [10] used gene therapy to restore some of the sight of mice with achromatopsia . The results were positive for 80% of the mice treated. Moreover, a paper by Komáromy et al. [11] published in 2010, deals with gene therapy for a form of achromatopsia in dogs. Cone function and day vision has been restored for at least 33 months in two young dogs with achromatopsia. However, this therapy was less efficient for older dogs.

Theoretical questions

According to David H. Hubel and Torsten Wiesel , the study of an irreversible loss of vision in the eye of the eye, even after the suture was removed. [1] [12] The study concluded that the neural circuitryfor vision is a “critical period” in childhood, after which the visual circuit can no longer be rewired to process new sensory input. Contrary to this finding, Mancuso et al.’s success in conferring trichromacy to adulterated monkeys suggests that it is possible to adapt the preexisting circuit to allow greater acuity in color vision. The researchers concluded that the stimulus of the new photopigment was not analogous to vision loss. [9]

It is yet unknown how the animals gain a new photopigment are perceiving the new color. While the article by Mancuso et al. states that the monkey has indeed gained trichromacy and the ability to discriminate between red and green, they claim the knowledge of how the animal internally perceives the sensation. [9]

While red / green color blindness can be treated by introducing M-opsin genes, rare forms of color blindness such as tritanopia can be treated as well. For tritanopia, the S-opsin gene must be introduced instead of M-opsin gene.


Despite the success in animals, there still remains challenges to conducting gene therapy on humans for treating color blindness.


How to deliver the viral vector is probably the main obstacle to making gene therapy. Because the virus has been injected directly into the eye, the treatment may be highly unpleasant and is a risk for eye infection. Noninvasively, the treatment is rather risky for the benefit gained.

It is not always a good idea to maintain the trichromacy between congenitally colorblind individuals. At the time of publication, Mancuso et al. reports that the treated squirrel monkeys have maintained 2 years of color after treatment. [9] If repeat injections are needed, there is also the problem of developing an immune response to the virus. If a body develops susceptibility to viral vector, the success of the therapy may be unfavorably. An editorial by Bennett J. points to Mancuso et al.’s “unspecified postinjection corticosteroid therapy”. [4] Bennett suggests that monkeys may have experienced inflammation due to the injection. [4]However, the virus that is commonly used for this study is non-pathogenic, and the body is less likely to develop an immune response. [13] Needless to say, an extensive review of the safety of the treatment of any human trials.

The subject should first be evaluated to identify which photopigment they need to gain trichromacy. Also, while gene therapy may be congenital color blindness (such as dichromacy), it is not intended to treat non-retinal forms of color blindness as such to the visual cortex of the brain.


As a phenotype, a gene therapy for color blindness is open to the same ethical questions and criticisms as gene therapy in general. Given the large number of people with color blindness, there is also the question of whether color blindness is a disorder. [14] Moreover, even if gene therapy succeeds in converting incomplete colorblind individuals to trichromats, the degree of satisfaction among the subjects is unknown. It is uncertain how the quality of life will improve (or worsen) after the therapy.

See also

  • Color vision
  • achromatopsia


  1. ^ Jump up to:j Kandel ER, Schwartz JH, Jessel TM, eds. (2000). “Ch. 29: Color Vision”. Principles of Neural Science . McGraw-Hill Professional. ISBN  978-0-8385-7701-1 .
  2. Jump up^ “Color blindness treatment” . World Eye Centers Istanbul. Archived fromthe original on 2009-06-18 . Retrieved 2009-07-05 .
  3. Jump up^ Pang, J.-J., J. Alexander, et al. (2010). Achromatopsia as a Potential Candidate for Gene Therapy: 639-646.
  4. ^ Jump up to:c Bennett J. Gene Therapy for Color Blindness. N Engl J Med. 17 December 2009, 2009; 361 (25): 2483-4.
  5. Jump up^ Bennicelli, J., JF Wright, et al. (2008). “Reversal of Blindness in Animal Models of Leber Congenital Amaurosis Using Optimized AAV2-mediated Gene Transfer.” Mol Ther 16 (3): 458-465.
  6. Jump up^ Jacobson, SGB, Sanford L .; Aleman, Tomas S .; Thomas J. Conlon, Caroline J. Zeiss, Alejandro J. Roman, Artur V. Cideciyan, Sharon B. Schwartz, Andras Komaromy, Michelle Doobrajh, Andy Y. Cheung, Sumaroka Alexander, Susan E. Pearce-Kelling, Gustavo D Aguirre, Shalesh Kaushal, Albert M. Maguire, Terence R. Fleet, William W. Hauswirth. (2006). “Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis.” Human Gene Therapy 17 (8).
  7. Jump up^ Jacobs, GH, GA Williams, et al. (2007). “Emergence of Novel Color Vision in Mice Engineered to Express a Human Cone Photopigment.” Science315 (5819): 1723-1725.
  8. Jump up^ Mauck, MC, K. Mancuso, et al. (2008). “Longitudinal evaluation of virally delivered transgenes in gerbil cone photoreceptors.” Visual Neuroscience 25 (03): 273-282.
  9. ^ Jump up to:i Mancuso, K., Hauswirth WW, et al. (2009). “Gene therapy for red, and green color blindness in adult primates.” Nature 461 (7265): 784-787.
  10. Jump up^ Alexander JJ, et al. (2007). “Restoration of cone vision in a mouse model of achromatopsia.” Nat. Med. Jun; 13 (6): 685-7. Epub 21 May 2007.
  11. Jump up^ Komaromy, K., et al. (2010). “Gene therapy rescues cone function in congenital achromatopsia.” Human Molecular Geneticsdoi:10.1093 / hmg / ddq136.
  12. Jump up^ DH Hubel, Wiesel TN, and S. LeVay. Plasticity of Ocular Dominance Columns in Monkey Striate CortexPhil. Trans. R. Soc. Lond. B April 26, 1977 278: 377-409; doi:10.1098 / rstb.1977.0050
  13. Jump up^ Grieger JC, Samulski RJ (2005). “Adeno-associated virus as a vector gene therapy: vector development, production and clinical applications”. Advances in Biochemical Engineering / biotechnology 99: 119-45. doi:10.1007 / 10_005. PMID 16568890
  14. Jump up^ Morgan J. Adam A, JD Mollon. “Dichromats detect color-camouflaged objects that are not detected by trichromats.” Proc Biol Sci. 22 June 1992; 248 (1323): 291-5. PMID 1354367.

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