**1. Introduction**

Large animal models for inherited retinal degenerations (IRDs) have been identified within populations of dogs, cats, sheep, horses and, more recently, non-human primates (NHP). Many different IRDs have been identified in pedigree dogs, most of which mimic retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA). The term "progressive retinal atrophy" (PRA) is used to describe this group of photoreceptor degenerations. In some instances, more detailed descriptive terms such as rod–cone dysplasia or progressive rod cone degeneration have been used. Common dog breeding practices have tended to bring out recessive conditions and have made the pedigree dog a rich source of models for inherited disease, including IRDs. Engineered large animal IRD models such as transgenic pigs have also been produced [1]. With advances in gene editing technologies, further models are likely to be produced in species such as pigs and NHPs and possibly even cats and dogs. The advantages of large animal models over laboratory rodent models of IRDs include the similarity in the size of the eye to that of man [2]. This is of particular importance for the development of translational therapies because it allows identical surgical delivery approaches to be used in the animal model to those that will be eventually used in human patients. NHPs are obviously close relatives to humans, making them attractive models. However, only a few spontaneous IRDs in primates have been identified [3,4], although steps are being taken to identify more animals with disease-causing mutations and to use genome editing to generate additional models with mutations in genes of importance, either for

germline transmission (see [5] for a review) or somatic gene knockout [6]. Another major advantage of large animal models is the presence of a retinal region equivalent to the macula. Laboratory mice and rats are nocturnal rodents that do not have a macula equivalent. The macula is of major importance for high acuity vision and some conditions specifically or differentially affect that retinal region compared to the peripheral retina. Macular dystrophies have been associated with mutations in a number of different genes (see [7,8] for reviews), some of which have relevant large animal models which are discussed below, including Stargardt Disease (*ABCA4* mutations), Best Disease (*BEST1* mutations) and in some patients with *RDH5* mutations. Age-related macular degeneration (AMD) is a major cause of vision loss and has genetic and environmental contributors [9,10]. Screening of primate colonies for animals with lesions comparable to AMD have been performed [11] (for a review, including primate models, see Pennesi et al. [12]). The large animal model species considered here have an area centralis with high photoreceptor density, including, importantly, cones that are equivalent to the human macula [13]. While NHP also have a fovea, most of the other model species do not, although the dog has been reported to have a small concentration of cones in the center of the area centralis, referred to as a "bouquet" of cones [14].

There are several important instances where laboratory rodent engineered models fail to recapitulate the human disease; important examples including *ABCA4*-Stargardt disease, *RDH5*-retinopathy, or where the gene involved is not present in the mouse or rat genome e.g., *EYS* [15].

The disadvantages of the large animal model species tend to be cost, generation of sufficient animals due to the slower reproduction, and because of the longer lifespan (compared to laboratory rodents), the disease course may be longer.

Large animal models have also been important in therapy development. The first proof-of-concept gene augmentation therapy that eventually led to the FDA approval of the first gene therapy product, Luxturna, for the treatment of LCA due to *RPE65* mutations, was performed in a dog model [16].

Table 1 shows a list of IRDs in large animal models and their identified mutations. Retinal layers and the genes discussed in detail within the text are shown in Figure 1. This review will cover the models in which the studies have contributed to the understanding of the mechanism of disease and/or protein structure and function in greater detail.




**Table 1.** *Cont.*

development

*STK38L\** dog c.299\_300ins [218;285\_299]; p.Lys63\_Glu103del


**Table 1.** *Cont.*

**Figure 1.** Schematic of retinal layers and associated genes discussed within this review. The left image shows a histologic section of a feline retina (with comparable anatomy to the human retina). The right panel depicts a schematic showing the genes detailed in this review and their site of expression, grouped per biological process. Inner limiting membrane (ILM), nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexifom layer (OPL), outer nuclear layer (ONL), external limiting membrane (ELM), photoreceptor inner segmen<sup>t</sup> (IS), connecting cilium (CC), photoreceptor outer segmen<sup>t</sup> (OS), retinal pigmentary epithelium (RPE). Ganglion cell (GC), amacrine cell (AC), bipolar cell (BC), horizontal cell (HC), rod (R), cone (C).
