## 5 Discussion/Insights  
The scope of this article was to provide an overview of how adRP could be treated in light of emerging technologies. For this purpose, we examined how genome-editing strategies have been or could be applied to the most common genes that cause adRP. We used adRP as an example because it is the most frequent disorder, but the same principles can be applied to other autosomal dominant IRDs, that have similar pathological mechanisms. When designing a genome-editing strategy, it is essential to take into account the pathological mechanism of the mutation of interest. At the same time, the mechanism of other mutations within the same gene is also informative. For example, if null alleles in the heterozygous state do not cause symptoms, this indicates that, regardless of the mutation, haplonsufficiency is not the cause of pathogenicity. Furthermore, it needs to be kept in mind that the mechanisms are not always black and white. Often, symptoms arise from a combination of mechanisms, such as gain-of-function and dominant-negative, which is the case for _RHO_. In these situations, it is better to opt for the safest approach, which would be invalidation of both alleles followed by gene supplementation or correction of the mutant allele. Wild type gene supplementation (without prior invalidation) on the other hand, is a safer option for cases of haplonsufficiency, such as for _PRPF31_. Another crucial point is the threshold of protein levels in the cell. For some proteins there is a fine balance between insufficiency and toxicity (RHO) while for others, such as transcription factors, improper levels, whether they be too high or too low, could disrupt signaling pathways and cause secondary effects [122]. Therefore, following genome editing, it is important to assay the affected pathways for signs of imbalance. Lastly, it is desirable to develop therapies with as high an impact as possible. All mutations that cause IRDs are rare, some only affecting a few families worldwide, and it would not be economically viable to tailor a strategy for each one of them. Therefore, it is advantageous to design strategies that are mutation-independent and even disorder-independent. As a result, a maximum number of patients would benefit from the therapy. CRISPR/Cas is currently the most promising tool for genome editing and it has dramatically changed the field of gene therapy. To date, for non-retinal diseases, CRISPR/Cas-mediated genome editing has already made its way to clinical trials, at least for ex vivo applications. For example, a phase 1/2 study using autologous CRISPR/Cas9-modified CD34+ human hematopoietic stem and progenitor cells for the treatment of beta thalassemia has already been approved ([[https://clinicaltrials.gov/ct2/show/NCT03655678](https://clinicaltrials.gov/ct2/show/NCT03655678)]([https://clinicaltrials.gov/ct2/show/NCT03655678](https://clinicaltrials.gov/ct2/show/NCT03655678))). This is also the case for an ex vivo trial using autologous T-cells with an engineered T-cell receptor that recognize cancer cells ([[https://clinicaltrials.gov/ct2/show/NCT03399448](https://clinicaltrials.gov/ct2/show/NCT03399448)]([https://clinicaltrials.gov/ct2/show/NCT03399448](https://clinicaltrials.gov/ct2/show/NCT03399448))). On the retinal landscape, the positive results on non-human primates for a CRISPR/Cas9 genome-editing strategy for _CEP290_, a gene that causes LCA type 10 [123], will likely soon result in the first genome-editing clinical trial for an IRD. Aside from the more 'traditional' way of editing mutations with CRISPR/Cas9, there are new variants of this tool that can be envisaged for the treatment of IRDs. One example is CRISPR interference (CRISPRi) (Figure 3). CRISPR uses the so-called dead Cas9 (dCas9) molecule, which has been mutated to have no nuclease activity [124]. The dCas9 molecule is coupled with a gRNA that targets the promoter of the gene of interest. As dCas9 cannot cleave DNA it remains bound to the promoter, preventing its transcription.