**9. Conclusions**

IRDs that lead to visual impairment and blindness show considerable heterogeneity, where even similar disease phenotypes can result from mutations in a wide range of di fferent genes. Closer examination of the broad phenotypes such as RP and LCA show the genetic heterogeneity with altered function of a range of genes leading to photoreceptor loss. Large numbers of di fferent mutations within a single gene exist and can result in a range of phenotypic di fferences.

The mechanisms by which the gene mutation leads to cell death di ffers between genes and between mutations within individual genes. Laboratory rodents have been the workhorses for studying disease mechanisms because of the ease with which their genome can be engineered, the short reproductive time and relatively low costs of maintenance. They have allowed identification of disease pathways and allowed the study of how and why degeneration occurs. However, laboratory rodents have very significant shortcomings. Rodents are nocturnal animals with a di fferent pattern of distribution of photoreceptors to humans. The large animal models discussed in this review have retinal photoreceptor distribution that is much closer to that of humans. This is particularly important when considering conditions that have a major e ffect on the macula. Large animal models have also been of value for the development and testing of translational therapies. They are particularly valuable for this because the larger eye size and proportions of lens and vitreous is much closer to that in humans, allowing for identical surgical approaches for trials of translational therapies. The several, mostly spontaneously occurring, large animal models mentioned here have provided valuable information about disease phenotypes and disease mechanisms. They o ffer grea<sup>t</sup> potential for even more detailed studies to understand how photoreceptor function and survivability is a ffected by the gene mutations and to study the extensive inner retinal remodeling and glial cell activation that occurs in IRDs. Modeling of IRDs using retinal organoids developed from induced pluripotent stem cells from IRD patients is an exciting field of research. These potentially allow the study of the e ffect of the exact mutation that is

present in the patient and in a human cultured tissue. However, they do not ye<sup>t</sup> fully recapitulate the specific environment within the retina of a living animal, so, while showing grea<sup>t</sup> promise, they cannot ye<sup>t</sup> replace whole animal studies. Improving our understanding of how and why photoreceptors die may sugges<sup>t</sup> novel therapies to preserve function and slow down vision loss. There remain untapped populations of companion animals (dogs and cats) with spontaneous IRDs, with new potential models being identified with increasing frequency. The advances in gene editing also expand the opportunity to develop additional large animal models with specific mutations that even more accurately model human IRDs.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2073-4409/9/4/882/s1, Table S1: List of mutations in large animal models of inherited retinal disease and references.

**Author Contributions:** All authors contributed to the conception, design and writing of the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** The NIH (EY027285) and the Donald R. Myers and William E. Dunlap Endowment for Canine Health, to Simon Petersen-Jones, provided support for the work done in this review.

**Conflicts of Interest:** The authors declare no conflict of interest.
