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Trinity Scientists Unravel the Complexities of Debilitating Visual Diseases



Imagine not being able to read, use a computer, watch TV or go to the cinema, or even go for a carefree walk to enjoy some fresh air. This is the day-to-day reality facing the 160 million people across the globe who are visually impaired (around 37 million of whom are blind).

Around 70% of the global visual handicap is caused by cataract, glaucoma, corneal opacities and infections (primarily caused by chlamydia bacteria and a parasitic nematode), which are – lamentably – preventable in many cases. In the developed world, where medical assessment and treatment is more readily available, rarer diseases impacting on vision tend to predominate. Clearly, this is a significant problem to which solutions are desperately required.

The most prevalent causes of registered blindness in Ireland involve degeneration of the retina, the highly specialised, light-sensitive part of the eye that links the all-important nerve impulses to the visual centres of the brain via the optic nerve. Primarily, these diseases are retinitis pigmentosa (RP), age-related macular degeneration (AMD), and proliferative diabetic retinopathy (PDR). RP is a classically heritable disease, being transmitted either in a dominant, recessive or sex-linked mode, whereas AMD and PDR are what we term multifactorial, where both genetic and environmental factors conspire to cause disease.

Researchers at Trinity College Dublin’s Institute of Genetics have been at the forefront in the fight against these debilitating diseases, embarking − three decades ago − on a programme of research aimed at identifying their causal factors. Initially, their work focused exclusively on RP, which is the most prevalent cause of registered blindness among those of working age in Ireland, and in other developed countries.

Typically, RP manifests initially in the development of night blindness, which, as the name suggests, involves an inability to see in the dark because the light sensitive cells of the retina that are responsible for perceiving dim light – the rod photoreceptors – are the first to die. Unfortunately, in most cases, daytime vision then becomes affected as the photoreceptors responsible for colour vision – the cone cells – also begin to die; people usually develop ‘tunnel vision,’ and in many cases, go on to lose all effective sight.

The researchers led by Professor Pete Humphries, focused on trying to isolate the genetic factors involved, fueled by the hope that identifying defective genes in individuals living with RP would help them understand the cause of the disease. Such knowledge might then be used to design genetic and molecular therapies that prevent, or slow down the disease process.

Initially, the geneticists faced a gargantuan challenge, given the complexity involved in genetic expression and the sheer volume of genes that together – or alone – had the potential to be involved. As a result, they were figuratively fumbling in the dark in an attempt to solve the same literal problem that affected millions across the globe.

eye test

Genes involved in causing RP began to emerge from the research group’s work in the late 1980s and early 1990s, and a picture of growing genetic complexity began to develop. This research, together with similar work at other institutions throughout the world, generated extensive knowledge of the cause of the disease. The ‘hoped-for’ genetic and molecular therapies that can prevent RP are now much closer to being realities, rather than mythical weapons in a merely theoretical therapeutic armoury; some of these therapies are now at an advanced stage of development as researchers across the globe strive for golden bullets.

More recently, the group at Trinity has extended its focus to further understanding disease mechanisms in AMD, which is hugely prevalent – to the extent that almost all of us know someone living with the condition. Largely affecting the older population, AMD is the most common cause of registered blindness among the retired sector.

AMD leads to degeneration of the central part of the retina (the macula), which functions to provide our daytime vision. What does that mean? Well, if you place a couple of €1 coins directly in front of both of your eyes, you’ll find out: a single, large black spot will block out your forward vision. Unsurprisingly, AMD has huge social and economic significance because it is very debilitating: with compromised forward vision, everyday tasks become deeply challenging.

Scientists have known for some time that non-genetic factors contribute to the disease. For example, smokers have a seven-fold higher risk of developing AMD, while protective pigments - lutein and xeathanthin - are only obtained by eating well (green and yellow vegetables are particularly rich in these components). But the group has also made excellent recent progress in furthering our understanding of molecular pathologies associated with the disease.

The group found that a component of the immune system, 'IL-18', acts as a guardian of eyesight by suppressing the production of damaging blood vessels behind the retina at the back of the eye. In addition, in pre-clinical models, it was shown that 'IL-18' can be administered in a non-invasive way, which could represent a major improvement on the current therapeutic options that are open to patients.

Up to 30,000 people in Ireland could have AMD, or are living with early signs of it, and while therapies are available for one form of the disease, they are far from optimal: imagine going to the doctor once a month to have a medication injected directly into your eye! Prospects now look good for the development of better means of prevention.

Having isolated mutant genes responsible for causing retinitis pigmentosa, the scientists are now also focusing their research on other common diseases of the eye. With such major therapeutic needs still unmet, researchers at the Institute of Genetics continue in their endeavors to probe the molecular cause of these prevalent eye diseases, and to use such knowledge in the development of improved methods of prevention. Hopefully their work will continue to help many people with a visual handicap.