Light in the dark: the search for new treatments for hereditary blindness

One night, Tomás realised something was seriously wrong. He went for a stroll, along the same paths near his village that he had walked along countless times with his friends, their cheerful voices echoing in the still of the night. There were no streetlights, and the paths were illuminated solely by moonlight. This had never been a problem before, but all of a sudden Tomás realised that he couldn’t clearly make out the edges of the path. He stopped, hesitated, and tried to find a reference point, but the edges of his vision blurred. Without realising it, Tomás had just experienced the first symptom of retinitis pigmentosa: the loss of vision in low light, also known as “night blindness”. One in every 4,000 people around the world suffers from retinitis pigmentosa, though if we factor in other rare genetic diseases that affect vision, prevalence can be as high as one in 2,000. How we see light and colour The retina is the neurosensory tissue that lines the back of the eye. It forms during embryonic development as a protrusion of the central nervous system, which opens outwards in a cup-like shape to differentiate into distinct layers of neurons that are perfectly arranged and interconnected. The layer of retinal neurons furthest from the light source is made up of photoreceptor cells, cones and rods, which can be stimulated by the impact of a single photon (light particle). These cells are responsible for receiving light stimulus, converting it first into a chemical signal and then into an electrical signal. In total, the human retina has around 120 million rods and some 7 million cones. Rods are the photoreceptor cells responsible for vision in low light, as they are stimulated by low photon intensity. These photons activate rhodopsin, the light-sensitive molecule. Rods cannot perceive colour, and can only see in black and white. Cones, however, contain opsin proteins that respond to high photon intensity, allowing us to see colours. Representative image of a human retina, which lines the back of the eye, in which the arrangement of neurons in layers can be seen. The outermost layer consists of photoreceptor cells – rods (in blue) and cones (in red) – which are in contact with the retinal pigment epithelium. Sakurra/Shutterstock Uneven distribution Rods are distributed throughout the retina, while cones are concentrated mainly in the macula, which is located in the fovea, the central area of the retina. This high density of cones provides what is known as visual acuity: extreme sensitivity to contrast. At night, in dim light, only the rods are active. This is why we stop seeing colours and cannot read when it gets dark, although our peripheral vision is still good. But if we switch on a torch or stand under a street lamp, the higher concentration of photons activates the cones, and we begin to perceive colours and details as if it were broad daylight. The brain tells us what we see In retinitis pigmentosa, mutations in genes essential for rod function means these cells become damaged, cease to function and eventually kill themselves off in a process known as programmed cell death. As a result, a loss of rods begins and progresses gradually, from the outer to the inner layers. In the case of Tomás the disease had progressed without him realising it, until it reached the point where the loss of rod cells began to affect his visual perception. His night vision was affected, and he began to experience what is known as tunnel vision: he found it difficult to locate objects around him, but he could still read and perceive details because the cones in the macula were still functioning. In the long run, the disease’s progression ends up affecting the cones as well, leading to total blindness. Read more: Our modern vision evolved from an ancient one-eyed worm creature Symptoms emerge in adolescence Patients with retinitis pigmentosa usually begin to notice symptoms in late adolescence or adulthood. However, when mutations affect photoreceptor structural genes or occur during development, the condition may appear in childhood, as is the case with Leber congenital amaurosis. Another congenital condition, achromatopsia, is characterised by the inability to see in colour. The world is quite literally perceived in shades of grey. In other rare retinal disorders, such as Stargardt disease, mutations affect genes related to the cones or the macula, which are the first to die. This allows patients to see in low light, yet they are unable to make out the details of a human face. Read more: What’s the link between tattoos and vision loss? 2 optometrists explain The search for treatments At present, there are no approved treatments that can completely halt the progression of retinitis. In order to design and implement specific advanced therapies, we need to conduct foundational research into the genetic, biochemical and cellular processes that are disrupted when mutations occur in retinal genes. This is where biotechnology comes into play, as it allows us to analyse disease models. This can be done in one of two ways: by creating avatar mice (who have the condition being studied), or using human retinal organoids (the closest we can get to a human retina in a Petri dish). Building on these innovations, we will be able to develop precision treatments targeting diseases caused by specific genes or mutations – such as Luxturna, for RPE65 gene mutations. We will also be able to develop therapies that promote the survival of photoreceptors without focusing on a specific gene or mutations, also known as “agnostic” therapies. These two approaches offer the possibility of treating – and perhaps even curing – Tomás, as well as other patients who, like him, suffer from rare inherited retinal diseases. A weekly e-mail in English featuring expertise from scholars and researchers. It provides an introduction to the diversity of research coming out of the continent and considers some of the key issues facing European countries. Get the newsletter!