Gene therapy for color blindness
Encyclopedia
Gene therapy for color blindness is an experimental gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

 aiming to convert congenitally colorblind
Color blindness
Color blindness or color vision deficiency is the inability or decreased ability to see color, or perceive color differences, under lighting conditions when color vision is not normally impaired...

 individuals to trichromats by introducing a photopigment
Photopigment
Photopigments are unstable pigments that undergo a chemical change when they absorb light. The term is generally applied to the non-protein chromophore moiety of photosensitive chromoproteins, such as the pigments involved in photosynthesis and photoreception...

 gene that they lack. Though partial color blindness is considered only a mild disability and is controversial whether it is even a disorder, it is a condition that affects many people, particularly males
Sex linkage
Sex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance...

. Complete color blindness, or achromatopsia
Achromatopsia
Achromatopsia , is a medical syndrome that exhibits symptoms relating to at least five separate individual disorders. Although the term may refer to acquired disorders such as color agnosia and cerebral achromatopsia, it typically refers to an autosomal recessive congenital color vision disorder,...

, is very rare but more severe. While never demonstrated in humans, animal studies have shown that it is possible to confer color vision
Color vision
Color vision is the capacity of an organism or machine to distinguish objects based on the wavelengths of the light they reflect, emit, or transmit...

 by injecting a gene of the missing photopigment using gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

. As of 2011 there is no medical entity offering this treatment, and no clinical trials available for volunteers.

Color Blindness

The retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

 of the human eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...

 contains photoreceptive cells called cones
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...

 that allow color vision. A normal trichromat individual possesses three different types of cones to distinguish different colors within the visible spectrum
Visible spectrum
The visible spectrum is the portion of the electromagnetic spectrum that is visible to the human eye. Electromagnetic radiation in this range of wavelengths is called visible light or simply light. A typical human eye will respond to wavelengths from about 390 to 750 nm. In terms of...

 from 380 nm to 740 nm. 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 L cone absorbs around 560 nm, the M cone absorbs near 530 nm, and the S cone absorbs near 420 nm. Contrary to popular belief, the peak absorption frequency for L, M, and S cones do not exactly correspond to red, green, and blue wavelength. Rather, the peak frequency for the L cone is orange, yellowish green in M cones, and blue-violet in S cones. These cones transduce
Transduction (physiology)
In physiology, transduction is the conversion of a stimulus from one form to another.Transduction in the nervous system typically refers to stimulus alerting events wherein a mechanical/physical/etc stimulus is converted into an action potential which is transmitted along axons towards the central...

 the absorbed light into electrical information to be relayed to neurons in the retina such as retinal bipolar cells and retinal ganglion cells, before reaching the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

.

The signals from different cones are added or subtracted from each other to process the color of incoming light. For instance, the color red stimulate L cones more than M cones, whereas the color green stimulates the L and M cones more than the S cones. The colors are perceived in an opponent process
Opponent process
The color opponent process is a color theory that states that the human visual system interprets information about color by processing signals from cones and rods in an antagonistic manner...

, such that red and green are perceived in opposition, as are blue and yellow, black and white.

The gene loci coding for the photopigments: M-opsin
Opsin
Opsins are a group of light-sensitive 35–55 kDa membrane-bound G protein-coupled receptors of the retinylidene protein family found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical...

 and L-opsin are located in close proximity within the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...

 and are highly polymorphic. Among the population, some have a deleted gene for the M photopigment in the X chromosome (such as in deuteranopia), whereas 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. 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. This is shown by their poor performance in Ishihara test. Although dichromatism poses little problem for daily 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 a person lacks two types of photopigments, they are considered monochromats. People lacking the three types of photopigments are said to have complete color blindness or achromatopsia
Achromatopsia
Achromatopsia , is a medical syndrome that exhibits symptoms relating to at least five separate individual disorders. Although the term may refer to acquired disorders such as color agnosia and cerebral achromatopsia, it typically refers to an autosomal recessive congenital color vision disorder,...

. Color blindness can also result from damages to the visual cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....

 in the brain.

Theory

Experiments using a variety of mammals (including primates) demonstrated that it 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
Adeno-associated virus
Adeno-associated virus is a small virus which infects humans and some other primate species. AAV is not currently known to cause disease and consequently the virus causes a very mild immune response. AAV can infect both dividing and non-dividing cells and may incorporate its genome into that of...

 (rAAV) as a vector, the cDNA of the opsin gene found in the L or M cones 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 vision has not been attempted to date. However, demonstrations using several mammals (including primates such as a 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.

Motivation

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 mild disability and even an advantage under certain circumstances (such as spotting camouflaged objects), it can pose challenges for certain occupations such as driving or piloting an aircraft. More generally, color codes in maps and figures may be difficult to read for individuals with color blindness.

Because only a single gene codes for a photopigment and the gene is only expressed in the retina, it is a relatively easy condition to treat using gene therapy 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 temporarily treat a condition that is more of an inconvenience than a disorder.

However, complete color blindness, or achromatopsia
Achromatopsia
Achromatopsia , is a medical syndrome that exhibits symptoms relating to at least five separate individual disorders. Although the term may refer to acquired disorders such as color agnosia and cerebral achromatopsia, it typically refers to an autosomal recessive congenital color vision disorder,...

, is very rare but more severe. Indeed, achromats cannot see any color, have a strong photophobia
Photophobia
Photophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...

 (blindness in full sun), and a reduced visual acuity (generally 20/200 after correction).

Moreover, the research may have strong implications toward genetic therapy of other cone diseases. Other cone diseases such as Leber's congenital amaurosis
Leber's congenital amaurosis
Leber's congenital amaurosis is a rare inherited eye disease that appears at birth or in the first few months of life, and affects around 1 in 80,000 of the population.It was first described by Theodor Leber in the 19th century...

, cone-rod dystrophy, and certain types of maculopathies
Maculopathy
A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision.-Examples Of Maculopathies:...

 may be treatable using the same techniques as the gene therapy used for color blindness.

Research so far

There has been ongoing research for gene therapy to treat Leber's congenital amaurosis
Leber's congenital amaurosis
Leber's congenital amaurosis is a rare inherited eye disease that appears at birth or in the first few months of life, and affects around 1 in 80,000 of the population.It was first described by Theodor Leber in the 19th century...

, a genetic disorder in photoreceptors that can lead to vision loss and blindness. These treatments use AAV vector and is delivered in much the same way as the gene therapy for color blindness.

Jacobs et al. published their research in the journal: Science in 2007, on their work introducing a human L-cone photopigment in mice
House mouse
The house mouse is a small rodent, a mouse, one of the most numerous species of the genus Mus.As a wild animal the house mouse mainly lives associated with humans, causing damage to crops and stored food....

. Since the mice possess only S cones and M cones, they are dichromats. The researchers replaced M-opsin with a cDNA of L-opsin in the X chromosome of some mice. By breeding these “knock-in” transgenic mice, they generated heterozygous females with both an M cone and an L cone. These mice had improved range of color vision and have gained trichromacy, as 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
Green fluorescent protein
The green fluorescent protein is a protein composed of 238 amino acid residues that exhibits bright green fluorescence when exposed to blue light. Although many other marine organisms have similar green fluorescent proteins, GFP traditionally refers to the protein first isolated from the...

 (GFP) gene in the cones of gerbils. The genetic insert was designed to only be expressed in S or M cones, and the study observed the expression of GFP in vivo over time. The study characterized the time of onset of expression, and also demonstrated that gene expression could stabilize if a sufficiently high dose of the viral vector is given.

Mancuso et al. published their research in the journal: Nature in 2009, on converting adult dichromat squirrel monkeys into trichromats using gene therapy. New world monkeys such as squirrel monkeys lack the L-opsin gene and are incapable of discriminating between certain shades of red and green. 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.

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

In 2007, Alexander JJ et al. used gene therapy to restore some of the sight of mice with achromatopsia
Achromatopsia
Achromatopsia , is a medical syndrome that exhibits symptoms relating to at least five separate individual disorders. Although the term may refer to acquired disorders such as color agnosia and cerebral achromatopsia, it typically refers to an autosomal recessive congenital color vision disorder,...

. The results were positive for 80% of the mice treated.
Moreover, a paper by Komáromy et al., published in 2010, deals with gene therapy for a form of achromatopsia
Achromatopsia
Achromatopsia , is a medical syndrome that exhibits symptoms relating to at least five separate individual disorders. Although the term may refer to acquired disorders such as color agnosia and cerebral achromatopsia, it typically refers to an autosomal recessive congenital color vision disorder,...

 in dogs. Cone function and day vision have 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 research by David H. Hubel
David H. Hubel
David Hunter Hubel is the John Franklin Enders Professor of Neurobiology, Emeritus, at Harvard Medical School. He was co-recipient with Torsten Wiesel of the 1981 Nobel Prize in Physiology or Medicine, for their discoveries concerning information processing in the visual system; the prize was...

 and Torsten Wiesel
Torsten Wiesel
Torsten Nils Wiesel was a Swedish co-recipient with David H. Hubel of the 1981 Nobel Prize in Physiology or Medicine, for their discoveries concerning information processing in the visual system; the prize was shared with Roger W...

, suturing shut one eye of monkeys at an early age resulted in an irreversible loss of vision
Ocular dominance
Ocular dominance, sometimes called eye dominance or eyedness, is the tendency to prefer visual input from one eye to the other. It is somewhat analogous to the laterality of right or left handedness; however, the side of the dominant eye and the dominant hand do not always match...

 in that eye, even after the suture was removed. The study concluded that the neural circuitry for vision is wired during a “critical period” in childhood, after which the visual circuitry can no longer be rewired to process new sensory input. Contrary to this finding, Mancuso et al.’s success in conferring trichromacy to adult squirrel monkeys suggests that it is possible to adapt the preexisting circuit to allow greater acuity in color vision. The researchers concluded that integrating the stimulus from the new photopigment as an adult was not analogous to vision loss following visual deprivation.

It is yet unknown how the animals that 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 gained the ability to discriminate between red and green, they claim no knowledge of how the animal internally perceives the sensation.

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

Challenges

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

Safety

How to deliver the viral vector into the retina is probably the main obstacle to making gene therapy a practical treatment for color blindness. Because the virus has to be injected directly by using a needle to penetrate the sclera
Sclera
The sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...

 of the eye, the treatment may be highly unpleasant and is a risk for eye infection. Without a way to deliver the virus noninvasively, the treatment is rather risky for the benefit gained.

As of now there is no knowledge of how frequently the gene needs to be injected to maintain trichromacy among congenitally colorblind individuals. At the time of publication, Mancuso et al. reports that the treated squirrel monkeys have maintained 2 years of color vision after the treatment. If repeat injections are needed, there is also the concern of the body developing an immune reaction to the virus. If a body develops sensitivity to the viral vector, the success of the therapy could be jeopardized and/or the body may respond unfavorably. An editorial by J. Bennett points to Mancuso et al.’s use of an “unspecified postinjection corticosteroid therapy”. Bennett suggests that the monkeys may have experienced inflammation due to the injection. However, the AAV virus that is commonly used for this study is non-pathogenic, and the body is less likely to develop an immune reaction. Needless to say, an extensive review of the safety of the treatment must precede any human trials.

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

Other challenges

As a way to introduce new genetic information to change a person’s 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 or a phenotypic variant in the human population. In fact, dichromacy can even be advantageous under certain circumstances such as when identifying a camouflaged object from the background. Furthermore, even if gene therapy succeeds in converting incomplete colorblind individuals to trichromats, the degree of satisfaction among the subjects is unknown, though who watches black and white television by choice now? The following sentence reflects bias of those not afflicted with color vision deficiency- There probably is little increase in performance on day-to-day tasks, and it is uncertain how the quality of life will improve (or worsen) after the therapy.
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