Project Details
Projekt
USH1C porcine model utilisation: assessing the function of USH1C/harmonin in the retina and conducting preclinical AAV-mediated gene augmentation therapy in the eye
Subject Area
Ophthalmology
Term
since 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 399487434
Usher syndrome (USH) is the most abundant inherited deaf-blindness in humans. Due to the lack of sufficient animal models for the ocular component of the disease, a basic understanding of pathomechanisms in the retina and an ocular therapeutic option for USH1 are still missing. We have developed a genetically tailored porcine model for USH1C that we characterized in the previous grant period. The deficits observed in the inner ear and the progressive visual loss reflect the phenotype observed in USH1 patients. Thus, they also indicate the suitability of our model for evaluating preclinical treatment options for USH1C. These and our other recent findings on the transcriptome and protein expression profile of USH1C/harmonin in the retina, as well as new discoveries in the field, have led us to define the following objectives to further our understanding of disease mechanisms in USH and the potential of AAV-based gene therapy: 1. Supplying experimental animals and intervention infrastructure and standardizing clinical readout parameters. Establishing a continuously producing USH1C breeding herd and a functional intervention platform for ERG and OCT allows the sufficient generation of pigs and their analysis for our project and collaborations. Emphasis will be put in a more detailed characterization of visually guided behavior to discriminate impaired vision from vestibular dysfunction and its comparison with ERG.2. Elaborating the molecular and cellular function of harmonin in retinal cells to enlighten the pathomechanisms underlying USH1C. New fixation techniques will allow more detailed analysis of the striking morphological changes found in retinal cells. Cellular assays and the application of omics approaches will highlight how Muller glia and photoreceptor cells contribute to the disease and reveal novel pathophysiological mechanisms and biomarkers for disease in the eye.3. Clarifying the effect of AAV9-mediated gene therapy in preventing progression of vision loss in USH1C. Based on our preliminary data, we will perform further gene therapy experiments in the eye of USH1C pigs using AAV9 and investigate the effects on ERG signal, vision, molecular and immunological parameters.Overall, we expect that our research programme contributes to a better understanding of USH1C/harmonin deficiency in the eye to reach our ultimate goal of our enterprise which is the development of options to stop or slow down the progressive retinal degeneration and thereby improve the quality of life of USH patients.
DFG Programme
Priority Programmes
