id_817. FROM GENES TO VISION LOSS: A COMPARATIVE STUDY OF RETINAL DYSTROPHY MOUSE MODELS
Anna Gąsiorek1,2, Anna Pacwa1,2,3,4, Monika Katan1,2, Klaudia Mróz1,2, Bartosz Machna1,2, Xiaonan Liu1,2,5, Joanna Lewin-Kowalik1,2,3, Adrian Smędowski1,2,3,6,7
1 Medical University of Silesia, Laboratory for Translational Research in Ophthalmology, Department of Ophthalmology, Faculty of Medical Sciences in Katowice, Katowice, Poland
2 Medical University of Silesia, Department of Ophthalmology, Faculty of Medical Sciences in Katowice, Katowice, Poland
3 Glaucotech Co, Katowice, Poland
4 Medical University of Silesia, Department of Clinical Genetics and Rare Diseases, Faculty of Medical Sciences in Katowice, Katowice, Poland
5 University of Helsinki, Institute of Biotechnology, HiLIFE, Helsinki, Finland
6 Medical University of Silesia, Department of Ophthalmology, Professor K. Gibinski University Clinical Center, Faculty of Medical Sciences in Katowice, Katowice, Poland
7 Medical University of Silesia, Department of Paediatric Ophthalmology, Faculty of Medical Sciences in Katowice, Katowice, Poland
INTRODUCTION: The retina’s excitable part consists of light-sensing photoreceptor cells that play a key role in phototransduction. Retinal dystrophies (RDs) are a group of degenerative disorders leading to photoreceptor damage and progressive vision loss. Regrettably, the majority of RDs are inherited and multiple gene defects have been identified with more than 270 genes, which make the diagnosis very challenging. It is noteworthy that over 25% of individuals with RDs carry mutations in yet unidentified genes, and the development of novel transgenic animal models offers new insight into their discovery.
AIM(S): The aim of this study was to characterize and compare transgenic mouse models of RDs.
METHOD(S): In this study, we used mutant mice (Rpe65, Abca4, Pde6b, Gucy2e, Cep290) that provide models for RDs, such as retinitis pigmentosa, Leber congenital amaurosis or Stargardt macular dystrophy. Retinal function and structure were assessed using electroretinography (ERG), Masson’s trichrome staining, Western blot and immunofluorescence of selected proteins, apoptosis and oxidative stress markers.
RESULTS: Our findings show that, although all the mutants employed pertain to RDs, they exhibit distinct functional impairments in ERG and divergent phenotypic manifestations. ERG changes appeared in juvenile animals, with structural alterations evident in aged mice. Pde6b and Cep290 mutants showed complete photoreceptor loss with absence of the outer retinal layers. We also observed increased photoreceptor apoptosis, indicated by elevated Caspase-8 staining and higher levels of oxidative stress markers (HNE, 8-OHdG).
CONCLUSIONS: Although no universal cure exists, recent advances in gene therapy and stem cell transplantation show promise. Given the polygenic and heterogeneous nature of RDs, the continued development of advanced genetic animal models is vital for understanding disease mechanisms and creating targeted treatments.