Genetic therapy for EYS- and USH2A-associated retinal dystrophy ("GET-READY")

01 June 2021 → 31 May 2024
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Ophtalmology
    • Drug discovery and development not elsewhere classified
    • Biopharmaceutics
ocular gene therapy
Project description

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. 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.