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Aim: Inherited retinal dystrophies (IRDs) constitute a heterogeneous group of blinding diseases that affect millions of patients worldwide. The most common subtypes include retinitis pigmentosa (RP) and Stargardt disease (STGD). RP can be caused by mutations in over 80 different genes, while STGD is associated almost exclusively with defects in the large ABCA4 gene. Mutations in the MYO7A gene cause the most severe subtype of Usher syndrome (USH1B), a syndromic form of IRDs, leading to combined deafness and blindness due to RP. There is therefore a high unmet medical need for the development of gene-agnostic therapeutic strategies for RP or mutation-independent approaches for the treatment of STGD and RP.

Method: Here, we applied CRISPR/Cas-based transcriptional activation (CRISPRa) in combination with CRISPR/Cas genome editing in two mouse models of RP to establish a combinatorial, gene-agnostic therapy for RP based on cellular reprogramming and neuroprotection. Furthermore, we evaluated a novel mutation-agnostic approach for USH1B and STGD by activating genes, which are homologous to Myo7a/Abca4, in the corresponding mouse model.

Results: In summary, we provide proof-of-concept for two distinct approaches to the combinatorial, gene-agnostic treatment of RP and the mutation-agnostic treatment of USH1B and STGD in mice. All of which showed significant improvement in mouse models for retinitis pigmentosa and Stargardt disease.

Conclusion: Both approaches are the first of their kind and underscore the great therapeutic potential of CRISPRa-mediated epigenome editing.