Genetic research paving way for treatment

RETINITIS PIGMENTOSA (RP) is acommon cause of inherited blindness. For normal vision, a cascade of biochemical reactions are triggered once photon (light) strikes the photoreceptor (light sensors in the retina).

Mutations affect the structure and function of photoreceptors, proteins of the neuro-retina and retinal pigment epithelium (RPE) layer causing retinal degenerative diseases like RP. In RP, rods are defective and so cause night blindness and affect peripheral (or side) vision. Now, there are 36 known or predicted RP genes, 19 different gene mutations have been identified, but in 17 only chromosomal region has been identified.

The first one involves transplantation of normal photoreceptors and RPE cells. The retinal photoreceptor transplantation can be done in two ways namely taking retina from stem cells or from aborted material.

In the second, retinal cells from aborted material or stem cells are injected into space behind the retina. Similar attempts are made for RPE cell transplantation. Genetic defect in all types of RP (as also various other retinal degenerations) ultimately ends in suicide (apoptosis) of all the photoreceptors; this can be countered by using growth factors - chemicals that induce growth and prevent degeneration.

This could neutralise apoptotic effect and stabilise vision and provide a status quo for the patient and stop further visual deterioration. Growing retinal cells in vitro (outside the body) could be used in RP patients; these cells after growing to an optimum level can be transplanted in the same individuals.

The third approach is by gene therapy where corrective genes will be delivered to defective photoreceptors and RPE cells by means of viral vectors. Gene therapy could possibly be used in inheritances like autosomal recessive and X-linked recessive genetic types.

Recently a promising event that has happened in gene therapy is the treatment given to Briard dogs that had a human disease called Leber congenital amaurosis - a severe form of inherited blindness that affects infants. These dogs were treated with gene therapy and were able to recover sight.

The gene involved is RPE65 that is involved in vitamin A metabolism in the eye. The genetic defect was also successfully treated in mice with supplementation of a form of vitamin A called 9-cis- retinal. These mice subsequently recovered vision. The RPE65 gene defect was first discovered by the group in a severe childhood form of RP.

Ribozymes are `policing' enzymes that maintain `quality control' in the cells and destroy defectively manufactured proteins. This property of the enzyme was successfully exploited to destroy mutated proteins in RP mice models. But this method would only be useful when retinal photoreceptor cells are in an active state. This modality could be useful in autosomal dominant RP. In RP one type of a mutation (cGMP phosphodiesterase) is associated with excessive accumulation of calcium in photoreceptors leading to retinal degeneration. In a mice model of this disease, calcium channel blocker was used restoring vision in these experimental mice.

In RP, photoreceptors are destroyed but other nerve endings, which carry impulse from retina to the brain are intact but are non-functional due to lack of impulse from photoreceptors.

In these circumstances, computer chips kept either above or below the retina are stimulated either by photons or radio waves that in turn can relay signals to the brain.

Cortical implants could also help people see where visual stimulus is processed in a mini-computer and is transmitted to the cortical region of the brain. Computer implants and transplantation research strategies are not a direct offshoot of genetic research.

The logic of molecular therapeutic intervention strategies is a result of two decades of genetic and molecular biological research in retinal degenerative diseases, particularly RP.

Though the experimental therapeutic research strategies look promising, we have to wait before we can see this enter the clinical practice scenario.

Govindasamy Kumaramanickavel

Sankara Nethralaya,

Chennai

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