13.10.2022 World Sight Day celebrated annually on the second Thursday of October, is a global event meant to draw attention to blindness and vision impairments. It was originally initiated by the Sight First Campaign of Lions Club International Foundation in 2000. It has since been integrated into VISION 2020 and is coordinated by IAPB in cooperation with the World Health Organization. Every year they have different themes to celebrate World Sight Day. In 2021, The ‘Love Your Eyes’ campaign encourages individuals to take care of their own eye health and draws attention to over a billion people worldwide who have vision loss and do not have access to eye care services.
Vision plays the most important role in seeing this beautiful world. The eye and the brain work together to help in proper vision mechanisms. These include cornea, lens, retina and optic nerves. Cornea is the front layer of the eye and it works by bending the light that enters into the eye. Lens is behind the iris and the pupil and it works with your cornea to focus the light that enters into the eye, much like a camera. The lens brings the image in front of you into a sharp focus, which allows you to see clearly. Retina is located at the back of the eye, which transforms the light into electrical signals. These signals are sent to the brain where they are recognized as images and the optic nerve transmits the electrical signals formed in the retina to the brain. Finally, the brain creates the images with the received electrical signal or stimulus. The photoreceptor cells involved in the visual cycle are the rods, cons the photosensitive ganglion cells. The rods mainly deal with low light level and do not mediate colour vision. On the other hand, the cones can code the colour of an image and contains three different types of cones. Each cone has different opsin so they will respond to a certain wavelength, or colour and light. The classical visual cycle is initiated by the conversion of a single photon of light energy into an electrical signal in the retina. The signal transduction occurs because of opsin which is a G protein-coupled receptor and it contains 11-cis-retinal chromophore. When a photon strikes, the phototransduction mechanism begins along with several cascade mechanisms. 11-cis-retinal undergoes photoisomerization to all-trans-retinal leading to a change in the conformation of opsin GPCR. The collective changes in the receptor potential of rods and cone cells due to phototransduction triggers nerve impulses that our brain interprets as a vision. After the isomerization procedure, and release from opsin, all-trans-retinal is reduced to all-trans-retinol and then transferred to the retinal pigment epithelium. In retinal pigment epithelium cells, several steps take place like esterification and many other that lead to the generation of 11-cis-retinol which is further oxidized to 11-cis-retinal before returning to the photoreceptors to combine with opsin to form rhodopsin.
The vision in vertebrates is completely dependent on the continuous supply of 11-cis-retinal chromophore. There are several enzymes involved in the visual cycle and mutation in the genes of retinoid cycle proteins frequently causes impaired vision. Mutation in retinol dehydrogenase enzyme 5 causes only a mild clinical phenotype defect in the eye but mutation in RPE65 causes the severe blinding disease called Leber congenital amaurosis (LCA). Mutations in the gene rhodopsin are the major cause of Retinal Pigmentosa, in the form of autosomal dominant and recessive retinal pigmentosa. Knockout mice with a mutation in the rod opsin gene stop to form rod outer segment and have no rod electroretinographic (ERG) response but shows a cone response early in life and eventually disappear at three months of age.
The Stargardt Macular Degeneration is the most commonly inherited maculopathy occurs in the young age. The symptoms of this disease start with blurred vision with progressive loss of central vision, central blind spots and a diminished ability to perceive colours. It is characterized by the accumulation of lipofuscin pigment in the RPE cells, which leads to the degeneration and death of the photoreceptor cells. This disease is mainly caused by the mutation in ABCR4 gene.
In the visual cycle, all-trans-retinal is reduced to a less toxic form all-trans-retinol by several alcohol dehydrogenases like RDH8 and RDH12. No mutation in RDH8 has been associated with a retinal dystrophy in humans. Mice with a knockout mutation in the RDH8 gene show normal kinetics of rhodopsin regeneration and delayed recovery of sensitivity following exposure to bright light.
There are three ways to treat the disease caused by mutations in retinoid cycle genes that have been investigated yet. The first is the replacement of defective genes by viral gene therapy. Replacement of the gene has been successful in models organism mice and dogs for LCA caused by a mutation in the RPE65 gene. Clinical trials in humans with RPE65–mediated LCA are set to begin soon.The second strategy involves the pharmacologic replacement of missing chromophore. It is suitable for diseases caused by impaired chromophore biogenesis, such as RPE65-mediated LCA.
As we are already discussed every enzyme/protein has its own significance in the visual cycle, the third strategy for the remedy of visual impairment is to slow down the synthesis of chromophore by inhibiting some steps in the visual cycle or limiting the availability of all-trans-retinol precursors. This approach is applicable to diseases associated with the accumulation of toxic lipofuscin fluorophores such as A2E. By partially depleting rhodopsin, the amount of all-trans-retinal released by light exposure is reduced.
Apart from them, there are so many common diseases associated with vision which are also the leading cause of blindness and low vision at an early stage of life. Some of the prominent diseases are age-related macular degeneration, cataract, diabetic retinopathy and glaucoma. Refractive errors are the most common eye disease reported in a majority of the population. These include myopia (near-sightedness), hyperopia (farsightedness), astigmatism (distorted vision at all distances). These can be rectified/corrected by eyeglasses, contact lenses and laser therapy, which is nowadays also a common approach. Cataract is another disease which is a leading cause of blindness across worldwide. In the cataract, patient observed clouding of the eye’s lens which leads to blurring of the vision. It can be cured with the help of laser therapy but access barriers, treatment costs and lack of awareness in developing and poor countries makes it one of the serious cause of vision loss. Diabetic retinopathy is a common complication generated due to diabetes. In this disease, new fragile blood vessels get generated and they are quite leaky in nature. Diabetic retinopathy usually affects both eyes.
In the current era, few routes of drug delivery are possible to rectify visual impairment or ocular diseases with retinoid analogues. These potentially available retinoid drugs could be delivered by eye drops, intraocular injection into different compartments of the eye, or periorbital injections into the fat surrounding the eye. The major drawback in the field of ophthalmology is not having high-resolution images of retina. But Nowadays the ray of hope is emerging with a new application of two-photon microscopy that exploits the intrinsic fluorescence of retinoids, permits visualization of RPE-cell structures in live animals. With further development, this technique may provide new information about retinoid metabolism and the response to treat the eye disease in humans.
Authorship: Integrated Structural Biology Group
