FOR 5621:  OCU-GT: Addressing the Unmet Needs in Ocular Gene Therapy

• Subject Area: Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513025799

Significant advancements in key technologies like antibody engineering, genome sequencing, gene manipulation, and gene delivery made it possible to develop novel, innovative gene therapy approaches for ocular disorders. This is nicely exemplified in the case of voretigene neparvovec, the first and currently only marketed ocular gene therapy, which offers a treatment option for patients with retinopathy caused by mutations in the gene RPE65. While adeno-associated virus (AAV) vector-based gene supplementation therapy is a valid concept to treat additional autosomal recessive retinal disorders, it cannot be applied to treat more challenging cases such as gain-of-function mutations with autosomal dominant inheritance. Similarly, the limited cargo capacity of AAV vectors does not support transfer of larger genes, which limits the broad applicability of the AAV technology and does not allow to address the challenging cases caused by mutations in large genes. Other remaining challenges relate to retinal diseases with unclear genetic cause such as age-related macular degeneration (AMD) or diabetic retinopathy (DR). Currently available symptomatic treatments for AMD and DR need to be repeatedly administered via intraocular injection and do not halt disease progression. Application of gene therapy concepts could allow to overcome the limitations of available symptomatic treatments and to develop potentially curative one-time treatments for these retinal diseases. To address these unmet needs, the proposed Research Unit will focus on the development of novel techniques and approaches to provide transformative gene therapy solutions for challenging retinal disorders. The consortium will leverage the key expertise and know-how in a focused manner to overcome current hurdles for the broad successful application of gene therapy to treat challenging genetic and acquired retinal diseases.

• DFG Programme: Research Units
• International Connection: Switzerland

Projects

• Coordination Funds (Applicant Michalakis, Stylianos )
• Development of a Gene Therapy for Usher Syndrome Type 1B (USH1B) (Applicant Biel, Martin )
• Development of a one-time gene therapy for age-related macular degeneration targeting CD146 (Applicant Michalakis, Stylianos )
• Development of novel gene therapy strategies for treatment of autosomal dominant retinitis pigmentosa in a pig model (Applicant Klymiuk, Nikolai )
• Evaluation of novel gene therapy approaches for USH2A (Applicant Becirovic, Elvir )
• Integrating Imaging, Clinical and Genetic Data with Machine Learning to Establish Biomarkers for Retinal Diseases (Applicants Priglinger, Siegfried ;  Theis, Fabian )
• Novel AI-based biomarkers for retinal gene therapy outcomes by integrating functional neuroimaging and retinal imaging (Applicants Koutsouleris, Nikolaos ;  Peng, Ph.D., Tingying ;  Schworm, Benedikt )
• Novel targets for gene therapy in diabetic retinopathy (DR) (Applicants Grosche, Antje ;  Hauck, Stefanie M. )
• Retina organoids as models for assessing pathomechanisms and effects of novel treatments in retinal disorders (Applicants Klopstock, Thomas ;  Serwane, Friedhelm )
• RPE plasticity in the context of neurodegenerative diseases: Understanding the limits, pushing the boundaries (Applicant Koch, Susanne )

• Spokesperson: Professor Dr. Stylianos Michalakis