## 1 Introduction  
Since the creation of the first genetic knockout rabbits with the CRISPR/Cas9 method in 2014 [1], the number of publications on CRISPR/Cas9-modified rabbits has increased, touching on a wide array of topics such as improving meat quality [2], altering fur color [3], studying the metabolic features [4, 5], modeling human diseases [6], producing recombinant proteins [7], and improving the methodology [8, 9, 10]. Compared to rodents, rabbits are phylogenetically more closely related to humans, and many physiological processes, such as lipid and carbohydrate metabolism [11, 12], disease progression in the case of atherosclerosis [13, 14], cardiac diseases [15], and obesity [16, 17], are more similar to those in humans. In addition, because of their similar anatomy and bigger size,experimentation is more achievable with rabbits, and they are hence considered to be a better subject for studies in translational medicine [18]. CRISPR/Cas9 technology in animal transgenesis has undergone great improvements in recent years. Prior to the employment of this technique, it was a big challenge to knockout a gene in rabbits because of the lack of suitable embryonic stem cells [19; 20; 21] and the low efficiency and difficulties associated with rabbit somatic cell nuclear transfer [22]. Now, with the almost completely sequenced rabbit genome and expertise available, CRISPR/Cas9 is a relatively robust technology that can be used to knockout almost any gene in rabbits. Knocking out a gene with CRISPR/Cas9 is based on targeted cutting of double-stranded DNA and the cells' own mechanism of DNA damage repair by nonhomologous end joining (NHEJ), resulting in indels at the target site that usually result an early stop codon that leads to fast degradation of mRNA [23; 24]. In order to reduce the number of experimental animals and test mutations rapidly, embryo culturing and testing for mutations at the blastocyst stage are suitable alternatives. In mice, in vitro cultured preimplantation stage blastocysts have been appropriate for testing the fidelity of CRISPR/Cas9-mediated genome editing [25]. Concerns remain about the unwanted off-target effects of CRISPR/Cas9 technology. However, modified Cas9 enzymes with higher specificity and improved algorithms that allow researchers to choose the most suitable guide RNA (gRNA) provide a stable background to overcome this challenge [26; 27]. Genetic mosaicism of founder animals is a known phenomenon in CRISPR/Cas9-mediated gene editing, as summarized in the review of [PERSON] et al. [28]. CRISPR/Cas9 is directly injected into the cytoplasm or pronuclei of fertilized oocytes. As zygotes develop, cells continuously divide, and the CRISPR-directed Cas9 enzyme is able to cut the targeted locus at further stages of development. As a consequence, somatic and/or germline mosaicism develops in the founder animals [28]. Mosaticism was investigated in mice, for example, as described by the authors of [29; 30], following the injection of CRISPR/Cas9 components targeting the tyrosinase gene locus, revealing the occurrence of diverse allelic modifications of the tyrosinase gene and also affecting the germline of the founder animals. However, in most cases, the germline cells of the founder animal carry only one type of modified allele. Interestingly, mosaicism in founder transgenic rabbits appears more frequently than in mice. Early rabbit embryos undergo a rapid series of cell divisions and can reach the four-cell stage within half a day [31]. In humans, rodents, and livestock animals, this takes 30-40 h after fertilization. The early timing of differentiation can explain the high mosaicism rates during rabbit transgenesis [32]. Despite the high rate of mosaicism in transgenic rabbits, to our best knowledge, a germline multiallelic knockout rabbit has not previously been described. NADPH oxidase 4 (NOX4) is an important and widely expressed member of the NADPH oxidase family that is responsible for the production of reactive oxygen species (ROS).