Gene therapy for color blindness

Gene therapy for color blindness is an experimental gene therapy of the human retina aiming to grant typical trichromatic color vision to individuals with congenital color blindness by introducing typical alleles for opsin genes. Animal testing for gene therapy began in 2007 with a 2009 breakthrough in squirrel monkeys suggesting an imminent gene therapy in humans. While the research into gene therapy for red-green colorblindness has lagged since then, successful human trials are ongoing for achromatopsia. Congenital color vision deficiency affects upwards of 200 million people in the world, which represents a large demand for this gene therapy.

Color Vision

The retina of the human eye contains photoreceptive cells called cones that allow color vision. A normal trichromat possesses three different types of cones to distinguish different colors within the visible spectrum. The three types of cones are designated L, M, and S cones, each containing an opsin sensitive to a different portion of the visible spectrum. More specifically, the L cone absorbs around 560 nm, the M cone absorbs near 530 nm, and the S cone absorbs near 420 nm.^[1] These cones transduce the absorbed light into electrical information to be relayed through other cells along the phototransduction pathway, before reaching the visual cortex in the brain.^[1]

The signals from the 3 cones are compared to each other to generate 3 opponent process channels. The channels are perceived as balances between red-green, blue-yellow and black-white.^[1]

Color vision deficiency

Color vision deficiency (CVD) is the deviation of an individual's color vision from typical human trichromatic vision. Relevant to gene therapy, CVD can be classified in 2 groups.

Dichromacy

Dichromats have partial color vision. The most common form of dichromacy is red-green colorblindness. Dichromacy usually arises when one of the three opsin genes is deleted or otherwise fully nonfunctional. The effects and diagnosis depend on the missing opsin.

(rare) have no S-opsin. Accordingly, a missing cone means one of the opponent channels is inactive: red-green for protanopes/deuteranopes and blue-yellow for tritanopes. They therefore perceive a much reduced color space. Although dichromacy poses few critical problems in daily life, a lack of access to many occupations (where color vision may be safety-critical) is a large disadvantage.

Anomalous Trichromats are not missing an opsin gene, but rather have a mutated (or chimeric) gene. They have trichromatic vision, but with a smaller color gamut than typical color vision. Regarding gene therapy, they are equivalent to dichromats.

are missing both the L- and M-opsin and therefore have no color vision. They are treated as a subset of dichromacy since a combination of gene therapies for protanopia and deuteranopia would be used.

Achromatopsia

Individuals with congenital achromatopsia tend to have typical opsin genes, but have a mutation in another gene downstream in the phototransduction pathway (e.g. GNAT2 protein) that prevents their cones (and therefore photopic vision) from functioning. Achromats rely solely on their scotopic vision. The severity of achromatopsia is much higher than dichromacy, not only in the lack of color vision, but also in co-occurring symptoms photophobia, nystagmus and poor visual acuity.

Retinal Gene Therapy

Gene therapies aim to inject functional copies of missing or mutated genes into affected individuals by the use of viral vectors. Using a replication-defective recombinant

are much less invasive, but not yet as effective as subretinal injections. Upon gaining the gene, the cone begins to express the new photopigment. The effect is ideally permanent.

Research

The first retinal gene therapy to be approved by the FDA was

Human L-cone photopigment have been introduced into

electroretinogram

and behavioral tests. However, this is more difficult to apply in the form of gene therapy.

Recombinant AAV vector was to introduce the

The genetic insert was designed to only be expressed in S or M cones, and the expression of GFP in vivo was observed over time. Gene expression could stabilize if a sufficiently high dose of the viral vector is given.

In 2009, adult dichromatic

Gene therapy was to restore some of the sight of mice with achromatopsia. The results were positive for 80% of the mice treated.^[7]

In 2010, gene therapy for a form of achromatopsia was performed 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.^[8]

In 2022, 4 young human ACHM2 and ACHM3 achromats were shown to have neurological responses (as measured with

This may be considered the first case of a cure for colorblindness in humans.

In July 2023 a study found positive but limited improvements on congenital CNGA3 achromatopsia[10]^[11]

Challenges

While the benefits of gene therapy to achromats typically outweigh the current risks, there are several challenges before large acceptance of gene therapy in dichromats can occur.

Safety

The procedure - namely the subretinal injection - is quite invasive, requiring several incisions and punctures in the eyeball. This poses a significant risk of infection and other complications. Subretinal injections methods promise to become less invasive with their application in other retinal gene therapies. They could also be replaced by intravitreal injections, which are significantly less invasive and can in theory be performed by a family doctor, but are less effective.^[12]

The permanence of these therapies is also in question. Mancuso et al. reported that the treated squirrel monkeys maintained 2 years of color vision after the treatment.^[6] However, 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".^[13] Bennett suggests that the monkeys may have experienced inflammation due to the injection.^[13] 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.^[14]

Neuroplasticity

According to research by

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.[6]

Ethics

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. These include issues around the governance of the therapy, whether treatment should be available only to those who can afford it, and whether the availability of treatment creates a stigma for those with color blindness. Given the large number of people with color blindness, there is also the question of whether color blindness is a disorder.^[16] Furthermore, 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.

The gene therapy for converting dichromats to trichromats can also be used hypothetically to "upgrade" typical trichromats to

See also

• Color vision
• Gene therapy
• Achromatopsia
• Color blindness
• Gene therapy of the human retina
• Stem cell therapy for macular degeneration

References