Retinitis pigmentosa (RP) is a group of genetic eye diseases characterised by the progressive damage of photoreceptors (mainly rods) and retinal pigment epithelium (RPE). On a functional level, the typical symptoms are the progressive loss of the mid-peripheral visual field and night blindness. It is the most common inherited retinal disease, affecting approximately 1 in 4,000 people. In a minority of cases, it is associated with neurological, metabolic or cardiac disorders, among others
The cause of retinitis pigmentosa is the mutation in one or more genes that are responsible for forming the proteins needed for photoreceptors to develop. At present, more than a hundred of the approximately 260 genes associated with inherited eye diseases are responsible for the appearance of retinitis pigmentosa. Although the appearance of the fundus enables a preliminary diagnosis to be made, the specific mutation and the inheritance pattern of the disease (autosomal dominant, autosomal recessive, linked to the X chromosome) are related to the patient’s visual prognosis.
Currently, identification of the gene responsible for the disease is a key aspect of the clinical management of the patient with retinitis pigmentosa, as has been supported by the American Academy of Ophthalmology. It is estimated that in three out of four cases of inherited eye diseases, the gene responsable can be identified1. This not only means we can confirm the diagnosis, but also establish the genotype/phenotype correlation (linking a specific mutation in a specific gene with a specific fundus appearance), offer a more accurate prognosis and, in the near future, indicate one type of treatment or another.
A good example of this latter aspect is Leber’s congenital amaurosis, a congenital form of retinitis pigmentosa. This disease is caused by mutations in the RPE65 gene and is the first entity for which the FDA (Food and Drug Administration, which is responsible for the approval of new drugs in the US) has approved gene therapy in an eye disease: Luxturna® (voretigene neparvovec, by Spark Therapeutics). Fundamentally, what this treatment does is replace the abnormal gene with a correct copy of RPE65, so that at least part of the lost functionality is regained. This strategy could be applied to other forms of retinitis pigmentosa and there are different clinical trials under way that use this principle.
Gene therapy is highly encouraging when the disease is detected early, before extensive damage to retinal tissue has occurred. Therapeutic alternatives in patients with more extensive damage involve the replacement of lost tissue with new tissue grafts through, for example, the use of stem cells (cells capable of being transforming into any type of tissue, such as photoreceptors or RPE, which then are implanted in the location where the tissue is already degenerated)2. Another alternative for patients with very extensive damage and highly severe loss of vision are artificial vision devices such as Argus II® (Second Sight Medical Products)1, in which patients wear special glasses on which a small camera with a video processor is mounted. This converts images into stimulation patterns that are sent to a microchip implanted in the retina.
Researchers from the Barcelona Macula Foundation (BMF) have started the DRUG4SIGHT* project funded by La Caixa with the Institute for Bioengineering of Catalonia (IBEC) and other state-level entities to develop new drugs in patients with degeneration of the retina. The paradigm of this project varies completely from the other therapeutic approaches. Here, the intention is to discover and characterise a series of drugs that can stimulate proteins still present in the degenerated retina and make the non-degenerated remnant cells act as photoreceptors, light-sensitive cells. The preliminary results are encouraging but need to be confirmed in animal models with a visual system more akin to that of a human being.
- Stone EM et al. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology 2017; 124: 1314-31.
- Gagliardi G et al. Photoreceptor cell replacement in macular degeneration and retinitis pigmentosa: a pluripotent stem cell-based approach. Prog Retin Eye Res 2019; 71: 1-25.
- Da Cruz L et al. Five-year safety and performance results from the Argus II retinal prosthesis system clinical trial. Ophthalmology 2016; 123: 2248-54.
*The project DRUG4SIGHT has received funding from “la Caixa” (ID 100010434), under the agreement LCF/PR/ HR19 / 52160010.
Author: Marc Biarnés OD MPH PhD, member of the BMF research team.