Project Details
Projekt
Genetic therapy for EYS- and USH2A-associated retinal dystrophy
Applicant
Professor Dr. Knut Stieger
Subject Area
Ophthalmology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 460683443
Inherited retinal diseases (IRDs) are a group of disorders with a prevalence of approximately 1 in 3,000 people, accounting for about 200,000 patients within the European Union. Due to the complexity of the visual system, several hundred proteins are uniquely expressed in the retina, and mutations in over 200 different genes are associated with IRD. Over the last decade, specific advantages of the eye have positioned this organ at the forefront of gene therapeutic development, including gene augmentation therapy using viral vectors for the transfer of correct cDNA copies of mutated genes. Recent success in clinical trials has demonstrated the utility of gene-based therapies in the treatment of IRDs, and patients throughout Europe are now awaiting gene-specific approaches for each genetic subtype of IRD. However, for patients with mutations in large genes, including two genes most frequently mutated in IRD, i.e. EYS and USH2A, clinical translation is hampered due to the limited cargo capacity of adeno-associated virus (AAV) vectors, the current vector of choice in retinal gene therapy. The aim of our proposal is to address this limitation in two ways. First, we will develop alternative therapeutic approaches, which includes the modulation of the splicing machinery and the implementation of therapeutic genome editing approaches using state-of-the-art methods like AON-based splicing modulation, PRIME-editing and newly identified Cas protein variants. Second, we will optimize novel larger vehicles that can ensure a proper delivery of EYS and USH2A coding sequences to the retina, including an intein-based multiple AAV approach, newly identified adenoviral vectors and latest versions of nanoparticles. To remain as close as possible to the patient population, we will mostly employ human cellular model systems, i.e. well-established cell lines and induced pluripotent stem cell-based retinal organoids. Where necessary and justified, we will also employ the zebrafish and the pig as two in vivo systems relevant to disease pathology. Since the partners in the GET READY consortium are at different stages of their career, the close interaction with each other will likely enable the establishment of new ideas and lead to disruptive scientific developments. A close connection to patient advocacy organizations in many partner countries will ensure dissemination of the results to raise awareness of these developments for patients with EYS and USH2A mutations. A successful outcome of GET-READY will significantly advance the development of novel treatment approaches for a non-negligible patient population, and consequently help to improve the life-quality of these patients as well as reduce the socio-economic burden due to progressive vision loss.
DFG Programme
Research Grants
International Connection
Belgium, France, Italy, Lithuania, Netherlands, Switzerland
