The ERG becomes nonrecordable thereafter. Functionally, it is thus apparent that the cone system is primarily affected in the disease. Morphological studies have shown that affected individuals already demonstrate abnormal and retarded photoreceptor development at 22 days as observed by electron microscopy.
Neither rods nor cones develop normally. There is defective synaptogenesis, with degeneration beginning in the central retinal regions and progressing toward the periphery 98, Recently it was clarified that the Rdy defect is a cone-rod dystrophy 8 : The earliest ophthalmoscopic changes are observed in the area centralis region, an area of the feline retina in which the concentration of cones is high in comparison with that of rods.
Further, as the electrophysiological studies described above have shown, the cone system is nonfunctional at a time when functional activity is still induced by the rod system 8 , a fact previously also noted in the original electrophysiological studies performed in the Rdy cat However, at the time of the initial studies, the disease was designated a rod-cone dysplasia, since changes were thought to affect the rod system earlier than the cone system, but with later affection of both types of photoreceptors.
The causative mutation for Rdy was characterized as a single-base deletion in the last exon of the cone rod homeobox CRX gene n. Domains are drawn to scale. Reproduced from Reference 8. The putative truncated peptide retains domains previously characterized in humans as responsible for promoter binding and nuclear localization, but it lacks the two domains critical for transcriptional transactivation In addition, Deckman et al. We thus hypothesized that the truncated CRX peptide possibly could compete with binding and activity of the wild-type CRX transcription factor in the Rdy cat.
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Electrophoretic mobility shift assays have since demonstrated binding of the truncated feline CRX peptide with two CRX-binding recognition sequences located in the rhodopsin promoter region Ret-4 and BAT-1 , , The development of an assay to measure the transcriptional transactivation activity of wild-type and Rdy-truncated CRX peptides is currently ongoing. These studies have improved our understanding of the molecular mechanisms underlying feline Rdy pathology. The Rdy model provides a valuable large mammal model to explore protein function and therapeutic interventions that have potential relevance not only to CRX-related disorders but for other autosomal dominant conditions in humans, as reviewed by Seyhan To date, there are no large mammal models for developing therapies, gene-therapy based or nonviral based, for autosomal dominant vision disorders.
Large mammals have a longer life span and ocular structures more similar to humans than rodent models Therefore, the feline Rdy model is one of the first large mammal models that can be used to extend the initial mouse impdh1, rho, and peripherin 2 and rat rho autosomal dominant therapy studies — Determining the biological mechanism of pathology in blinding diseases in animal models for Leber congenital amaurosis, RP, and cone-rod dysplasia has led to successful therapeutic genetherapy treatments , as witnessed by the recombinant adeno-associated virus rAAV based treatments for canine RPE65 autosomal recessive disorder , Immunofluorescence microscopy at two weeks posttransplantation of GFP-labeled feline neural precursor cells.
One profile small arrow is radially oriented and appears to contribute cytoplasmic extensions to the outer limiting membrane. Another profile large arrow lies in the vicinity of the outer plexiform layer and appears to be horizontally oriented. Reproduced with permission from Reference Abbreviation: ONL, outer nuclear layer.
A third murine model for ADRP used a similar siRNA AAV-mediated vector therapy to suppress the expression of mutant peripherin 2 and to express the introduced wild-type peripherin 2 These examples of AAV-based gene therapies have demonstrated successful rescue from photoreceptor cell degeneration in both autosomal recessive and dominant vision disorders. Nonviral gene delivery methods, which employ physical and chemical methods for transgene introduction electroporation, iontophoresis, liposomes, polymers, compacted nanoparticles , are also being investigated in animal models for the treatment of autosomal dominant vision disorders for review, see Reference Finally, an example of non-DNA therapy is the oral administration of a trafficking protein, curcumin, in rat for a rho autosomal dominant disorder This nongene-therapy treatment method has demonstrated the restoration of a functional vision cascade in the rat.
Recent developments in stem cell therapy show promise for the treatment of retinal degenerative disease. Cat models of hereditary retinal dystrophies will be especially valuable to examine the efficacy of these developing methodologies over extended time periods. Stem cells derived from three sources—embryonic, adult, and induced pluripotent stem cells—have shown promise to repair or replace neuroretinal cells for review, see Reference The secretion of neurotrophic factors from transplanted adult stem cells has demonstrated a protective role for degenerative conditions of the RPE, photoreceptors, and ganglion cells.
Induced pluripotent stem cells, which are generated from the reprogramming of adult somatic cells for review, see Reference , offer the increased advantage of development of patient-specific, isogenic lines, thereby decreasing the chance of host rejection of introduced cells, and eliminate ethical issues related to the use of cells derived from human embryos.
The generation of both photoreceptor and retinal pigment epithelial phenotypes from induced pluripotent stem cells has recently been demonstrated , So far, the rdAc model has been used for transplantation of neural precursor cells Figure 3 and for fetal retinal sheet transplantation studies Figure 4 , Additional work is needed to a b c Figure 4 Scanning-laser ophthalmoscopy images were obtained from the nasal part of the central tapetal fundus illustrating the fundus appearance of retinal sheet allograft—transplanted cats during a native infrared imaging, b fluorescein angiography FA , and c indocyanine green angiography ICGA.
Reproduced with permission from Seiler et al.
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An important finding in this work is, however, that the size of the cat eye makes the surgical approach, and the clinical follow-up using more advanced ophthalmic studies Figure 4 and ERG examinations, more analogous to those used with human patients. This is certainly an advantage over using rodents in this type of research. Long-lived, large animal models of homologous human disease are critical for testing the safety and efficacy of new therapeutic modalities. The domestic cat is emerging as a promising resource of phenotypically defined genetic variation of important biomedical significance.
Feline models for specific human ophthalmic diseases may thus become the necessary last step in the process of translational research, i. Challenges in quantifying multisensory integration: alternative criteria, models, and inverse effectiveness. Brain Res. Visual area of the lateral suprasylvian gyrus Clare-Bishop area of the cat. Kirschvink N, Reinhold P. Use of alternative animals as asthma models.
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Related Postnatal Development of the Cat’s Retina (Advances in Anatomy, Embryology and Cell Biology)
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