## 5 Discussion/Insights
To further promote suppression, dCas9 has been fused with transcriptional repressor domains [125]. The biggest advantage of this approach is its reversibility, as no permanent change is introduced in the DNA. CRISPR could be an advantageous alternative to allele-specificinvalidation if there exists a single nucleotide polymorphism in the promoter that distinguishes the mutant from the wild type allele. Otherwise, both promoters would need to be targeted and a wild copy of the gene provided. CRISPR activation (CRISPRa) is based on the same principle as CRISPR[126; 127]. For CRISPRa, dCas9, instead of being fused to a repressor, is fused to a transcription enhancer. In this way gene expression is enhanced. So far, applications have been focused on gene screening but we can envision this approach as an alternative to gene supplementation (Figure 3). A suitable case would be mutations in _PRPF31_. Enhanced transcription of both alleles would lead to higher levels of only the wild type protein, as mutant PRPF31 would still be cleared by NMD. Furthermore, CRISPRa would provide an advantage in the case of genes that are too large to be delivered by AAV vectors. Base editor is another exciting new technology as it allows the direct editing of specific bases. For the base-editor approach, an impaired Cas9 (i.e., a Cas9 that only induces a single-strand break, also called \"nickase\") is fused to a cytidine deaminase, which directly edits C/G bases to T/A and A/T bases to G/C [128; 129; 130]. In this way, it is possible to specifically convert the mutated nucleotide to the wild type one. This would be an attractive alternative to the correction of a mutant allele, due to the low efficiency of HDR in the post-mitotic retinal cells (Figure 3). Despite the advances in CRISPR/Cas9 technology, there are some limitations that remain and should be taken into consideration when designing a therapy. It is well known that Cas9 tolerates mismatches, which means that it induces double-strand breaks on sequences that differ by one or more base pairs from the gRNA sequence, leading to off-target effects [131]. Strategies that have been designed to circumvent this problem include the development of more specific Cas9 molecules and modifying the guide RNA design to increase specificity [132; 133; 134; 135]. Another difficulty is that most Cas9 genes are too big to be delivered by a single AAV vector. However, smaller Cas9 molecules from different species have been discovered more recently that are small enough to be packaged within an AAV [136; 137; 138]. This opens up the possibility of directly administering the Cas9 gene into the retina for in vivo genome editing. To conclude, IRDs are currently incurable diseases but gene [PERSON] holds great promise for developing a cure. This is evidenced by the fact that the first gene [PERSON] drug for an IRD, Luxturna, an AAV2/2 vector carrying the _RPE65_ gene for the treatment of RPE65-associated RP or LCA type 2 [139], has recently reached the market. It is certain that the field will grow exponentially in the future, especially with the aid of novel, CRISPR/Cas9-mediated, genome-editing strategies. Patients and researchers alike are awaiting the progress that is still to be made with excitement. This research was funded by the Labex EpiGenMed \"Investment for the future\" program, grant number ANR-10-LABX-12-01 (Ph.D. fellowship to [PERSON]). The authors thank [PERSON] for critical reading of the manuscript and [PERSON] for help with figure preparations. The authors have no conflict of interest to declare.