## 1 Introduction  
Inherited retinal dystrophies (IRDs) are a group of disorders characterized by progressive vision loss. This is due to degeneration of the light-sensing cells of the retina, the photoreceptors. Rod-cone dystrophy is the most common IRD form, more commonly known as Retinitis Pigmentosa (RP), which affects \(\sim\)1/4000 people worldwide [1]. RP is initially characterized by night blindness and peripheral visual field loss, and subsequently by central vision loss, due to the sequential degeneration of rod and cone photoreceptors [2]. RP is caused by mutations in over 80 genes and it can be transmitted in autosomal dominant (adRP; one mutant allele is sufficient for disease manifestation), autosomal recessive (two mutant alleles are required), and X-linked inheritance patterns [1]. Furthermore, mutations in the same IRD gene can cause both autosomal dominant and recessive forms, and mutation hotspots can result in elevated disease prevalence in certain populations [3]. The most common mutation that is responsible for adRP is the missense mutation c.68C>A (p.Pro23 His; P23H) in _RHO_, the gene encoding rhodopsin, the visual pigment of rod photoreceptors. The second most common mutation for adRP is the c.166G>A (p.Gly56 Arg;G56R) mutation in _NR2E3_. The G56R mutation is exclusively responsible for all _NR2E3_-associated adRP cases and, alone, accounts for 1-2% of total adRP cases in America and 3.5% in Europe [4; 5; 6]. NR2E3 (Nuclear Receptor subfamily 2 group E member 3) is a photoreceptor-specific transcription factor and key player in the development and maintenance of rod photoreceptors [7; 8; 9]. More specifically, NR2E3 acts in a complex with CRX, NRL, and NR1D1 to promote the transcription of rod genes, such as _RHO_, while repressing the transcription of cone genes [8; 10]. NR2E3 has a typical nuclear receptor structure with two main domains, a DNA Binding Domain (DBD) and a Ligand Binding Domain (LBD) [11]. In addition to DNA binding, the DBD is responsible for the interaction of NR2E3 with CRX [9]. By contrast, the LBD mediates the formation of NR2E3 homodimers, which are necessary in transcriptional repression [12; 13]. The highly conserved glycine residue at position 56 is localized within the DBD of NR2E3. The disease mechanism of the G56R variant remains elusive. Some of the hypotheses are that the G56R mutation reduces DNA binding and subsequent _RHO_ activation [14; 15; 16], weakens CRX binding [16], or decreases homodimerization [15] of NR2E3. Currently, there is no treatment for _NR2E3_-associated adRP or other adRPs. However, the advent of the powerful CRISPR/Cas technology provides hope for genome editing as a therapeutic approach [17; 18; 19]. The CRISPR/Cas system comprises two elements, a Cas endonuclease and a 20-nt guide RNA (gRNA). The gRNA is situated next to a 3-nt sequence, which is known as a protospacer adjacent motif (PAM) [17]. The most commonly used Cas is Cas9 from _Streptococcus pyogenes_ (Sp), which recognizes an NGG PAM sequence. The combination of the PAM and gRNA molecule guides the Cas9 to the target sequence in the host DNA, where it induces a double-strand break (DSB). The DSB is then repaired by the cell machinery by one of two main pathways [20]. The first pathway is homologous-directed repair (HDR), which takes place during the S/G2 phase of dividing cells [21]. HDR is exploited for gene correction by providing a DNA sequence repair template along with the CRISPR/Cas system [22]. The second pathway is non-homologous end joining (NHE), which is recruited during all phases of the cell cycle in the absence of a repair template. In most cases where genome-editing is envisaged, the ideal choice would be to correct a mutant allele by the HDR pathway. However, this can be challenging in post-mitotic cells, such as photoreceptors. By contrast, knocking out a mutant allele could be efficient and clinically relevant, especially for an autosomal dominant disorder.