Periodic Reporting for period 1 - MyoTreat (Myopia - from genes and environment to cellular responses and treatment)
Période du rapport: 2023-12-01 au 2025-11-30
Myopia (near-sightedness) has become a massive eye health problem in industrialized countries, and not just because of its high prevalence. Traditional treatments, such as single-vision glasses and contact lenses, treat the symptoms of myopia but do not reduce the risk of vision loss associated with the excessive elongation of the near-sighted eye. Since any degree of myopia increases the risk of developing serious eye diseases, innovative research into new therapies is urgently required. Diagnostic methods and treatment options for myopia need to be improved. To this end, several projects within the MyoTreat doctoral network will identify new molecules and signalling pathways that are important for the physiology and pathophysiology of the retina. This will address the unmet need to establish biomarkers that contribute to the early detection of the disease and enable the monitoring of various strategies for treating myopia using non-invasive measurement methods. Therefore, two projects aim to improve measurement methods in order to visualise structural changes in the myopic eye, particularly in the outer periphery of the retina and choroid. It is known that susceptibility to myopia is influenced by both genetic factors and lifestyle factors such as time spent outdoors and educational level. This suggests an interaction between specific genetic variants associated with myopia and certain lifestyle risk factors. Three MyoTreat projects are investigating this topic using state-of-the-art biostatistical analysis methods for large data sets. There is growing evidence that the choroid, a vascular layer of tissue located between the retina and the sclera, plays an important role in regulating eye growth and the development of refractive errors. Choroidal thinning has been found to precede the development and progression of myopia, while choroidal thickening has been found to occur in response to existing treatments for slowing myopia progression. As the mechanisms and biochemical pathways that trigger changes in the response of the choroid are still largely unknown, they are being investigated from a variety of perspectives in MyoTreat.
In the 1st reporting period the six academic groups and one non-academic/industrial group that make up the MyoTreat consortium (https://www.myotreat.eu(s’ouvre dans une nouvelle fenêtre)) have recruited twelve doctoral candidates (DCs) who work in three different areas of translational research namely WP1: To understand the influence of environmental factors (e.g. education level, spectral composition of ambient light) and gene-environment interactions (specific gene variants and their interaction with key lifestyle exposures). WP2: To identify and test new treatment targets and biomarkers. WP3: To understand how choroidal thickness is regulated, and how to improve measuring techniques to visualize changes especially in the far periphery of retina and choroid. In parallel to their research work, MyoTreat doctoral candidates participated in theoretical and practical hands-on training courses. They presented their work at several meetings in the form of papers or posters. These meetings were both national and international, including the largest international conference in the field of vision research, namely the Association for Research in Vision and Ophthalmology (ARVO).
Several papers have already been published and a number of interesting findings have emerged from projects conducted by the DCs. Data sets from large databases were analysed in order to investigate the interaction between specific gene variants and lifestyle factors in myopia. A new pathway was discovered using the method of conditional quantile regression analysis. Participants who inherited specific genetic variants in this pathway were, on average, more susceptible to myopia. The level of susceptibility changed according to the level of education, which points towards an interesting gene-environment interaction. In addition, it was found that heterozygosity for a specific gene haplotype increases the susceptibility to myopia in females. A number of studies already showed that girls are more susceptible to develop myopia. It was also shown before that sex modifies not only myopia prevalence but also the mechanisms through which lifestyle and physiological factors contribute to myopia development. This information and the new results from MyoTreat are important because our aim is to identify genetic and biological markers that can help to detect children at a higher risk of becoming myopic, who would benefit from early treatment and could allow us to give more specific guidance on which lifestyle choices are particularly harmful for a certain child or particularly beneficial. Differentially expressed candidate genes (DEGs), which were found in animal models and that mimic the phenotype of myopia, but that are functionally not/not well characterized, were investigated for their effects on visual processing. We found that myopia may develop when the retina’s ‘ON’ and ‘OFF’ signals are out of balance. The ON pathway becomes active when light increases and signals brightness, while the OFF pathway responds when light decreases and signals darkness. To date, the MyoTreat doctoral candidates have successfully identified and tested new pathways with therapeutic potential and are in the process to find molecular probes that could be used for biomarker purpose. Also, in the choroid, a new interesting pathway was detected. In summary, significant progress was already achieved by the doctoral candidates and more progress will emerge in the near future.
Several papers have already been published and a number of interesting findings have emerged from projects conducted by the DCs. Data sets from large databases were analysed in order to investigate the interaction between specific gene variants and lifestyle factors in myopia. A new pathway was discovered using the method of conditional quantile regression analysis. Participants who inherited specific genetic variants in this pathway were, on average, more susceptible to myopia. The level of susceptibility changed according to the level of education, which points towards an interesting gene-environment interaction. In addition, it was found that heterozygosity for a specific gene haplotype increases the susceptibility to myopia in females. A number of studies already showed that girls are more susceptible to develop myopia. It was also shown before that sex modifies not only myopia prevalence but also the mechanisms through which lifestyle and physiological factors contribute to myopia development. This information and the new results from MyoTreat are important because our aim is to identify genetic and biological markers that can help to detect children at a higher risk of becoming myopic, who would benefit from early treatment and could allow us to give more specific guidance on which lifestyle choices are particularly harmful for a certain child or particularly beneficial. Differentially expressed candidate genes (DEGs), which were found in animal models and that mimic the phenotype of myopia, but that are functionally not/not well characterized, were investigated for their effects on visual processing. We found that myopia may develop when the retina’s ‘ON’ and ‘OFF’ signals are out of balance. The ON pathway becomes active when light increases and signals brightness, while the OFF pathway responds when light decreases and signals darkness. To date, the MyoTreat doctoral candidates have successfully identified and tested new pathways with therapeutic potential and are in the process to find molecular probes that could be used for biomarker purpose. Also, in the choroid, a new interesting pathway was detected. In summary, significant progress was already achieved by the doctoral candidates and more progress will emerge in the near future.
The MyoTreat consortium has already in the 1st reporting period produced a number of research results that go beyond the current state-of-the art. To name some explicitly, cutting-edge biostatistical analysis methods for large data sets, e.g. Mendelian randomization (MR) studies, were used in MyoTreat. During the re-analysis of a selection of published MR studies, e.g. on the relationships between years of full-time education and myopia, the group in Cardiff found that only one had valid results. The reasons were either poorly designed GWAS (genome-wide association study) analyses in which myopia cases and controls were often misclassified or that the researcher did not pay enough attention on the measurement scale of the GWAS summary statistics. The new re-analysis has therefore a huge impact. It gives guidance on how to prevent misclassification and transformation issues and will therefore improve further MR studies in the field of myopia research. In addition, two newly derived sets of myopia summary statistics were made openly available and researchers were encouraged to use these for future MR studies. In addition, two doctoral candidates successfully enhanced scientific equipment and instrumentation through advancement in the field of a new peripheral refractor prototype and an AI algorithm that might serve as a tool for myopia researchers and clinician to reliably quantify experimental effects on the structure and function of the posterior eye.