Abstract for laypersons

Current gene therapy studies for the treatment of inherited retinal diseases largely focus on the treatment of single genes or even only single mutations in specific genes. Although of great importance for the affected individuals, the broad mass of patients cannot benefit from such approaches. In our project, we plan to develop a gene-independent approach to the treatment of inherited retinal diseases. For this purpose, we will use a sophisticated method to activate specific neuroprotective genes in the target tissue (i.e., the retina) that have the potential to halt disease progression. At the same time, we will evaluate in a feasibility study whether simultaneous activation of neuroprotective genes in combination with targeted silencing of disease-promoting genes will provide additional therapeutic benefits. Millions of patients worldwide could benefit from these results.

Scientific abstract

Currently, most therapeutic approaches for inherited retinal dystrophies (IRDs) focus on single genes or mutations using recombinant adeno-associated viral (rAAV) vectors. A much more attractive alternative is the development of strategies that can halt disease progression independent of the underlying gene or disease mechanism. Expression of neuroprotective genes or knockdown of potentially deleterious genes represents one promising way to achieve this goal. To this end, we will apply the modular CRISPR-Cas9 technology, which is suitable for transcriptional activation of single or multiple genes using locus-specific single guide RNAs (sgRNAs). Different combinations of genes will be compared with each other in a mouse model for retinitis pigmentosa (RP). The therapeutic success of individual combinations will be assessed at various time points post injection at molecular, morphological, functional and behavioral levels. Finally, the most efficient transactivation approach will be combined with the knockdown of genes expected to have deleterious effects on disease progression and evaluated in the RP mouse model using the same readout parameters. Successful implementation of this approach will provide a proof of principle for gene-independent combinatorial gene therapy that could benefit millions of IRD patients worldwide.