Drug and gene therapy of hereditary retinal disease in dog and cat models

Petersen‐Jones, Simon M.

doi:10.1016/j.ddmod.2014.01.002

Cited by 4 publications

(4 citation statements)

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“…Cats have cone-rich area centralis, which is analogous to human maculae. The size of an adult cat's eye is very similar to the size of adult human eye [74], enabling easy translation of surgical techniques to patients.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, large-eye animals with inherited RD mutations such as dogs [61,62], cats [63][64][65], and pigs [66][67][68], and primates with induced RD [69][70][71][72] provide better opportunity to translate in vivo findings to blind patients. Both dogs and cats have an area centralis [65,73,74], which is functionally similar to primate macula. Moreover, due to the large size of their eyes, dogs and cats enable the development of surgical skills and approaches for grafting hESC-3D retinal tissue, which can be directly translated to the clinic.…”

Section: Introductionmentioning

confidence: 99%

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Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in the Subretinal Space of the Cat Eye

Singh

Occelli

Binette

et al. 2019

Stem Cells and Development

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To develop biological approaches to restore vision, we developed a method of transplanting stem cell-derived retinal tissue into the subretinal space of a large-eye animal model (cat). Human embryonic stem cells (hESC) were differentiated to retinal organoids in a dish. hESC-derived retinal tissue was introduced into the subretinal space of wild-type cats following a pars plana vitrectomy. The cats were systemically immunosuppressed with either prednisolone or prednisolone plus cyclosporine A. The eyes were examined by fundoscopy and spectral-domain optical coherence tomography imaging for adverse effects due to the presence of the subretinal grafts. Immunohistochemistry was done with antibodies to retinal and human markers to delineate graft survival, differentiation, and integration into cat retina. We successfully delivered hESC-derived retinal tissue into the subretinal space of the cat eye. We observed strong infiltration of immune cells in the graft and surrounding tissue in the cats treated with prednisolone. In contrast, we showed better survival and low immune response to the graft in cats treated with prednisolone plus cyclosporine A. Immunohistochemistry with antibodies (STEM121, CALB2, DCX, and SMI-312) revealed large number of graft-derived fibers connecting the graft and the host. We also show presence of human-specific synaptophysin puncta in the cat retina. This work demonstrates feasibility of engrafting hESC-derived retinal tissue into the subretinal space of large-eye animal models. Transplanting retinal tissue in degenerating cat retina will enable rapid development of preclinical in vivo work focused on vision restoration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in the Subretinal Space of the Cat Eye

Singh

Occelli

Binette

et al. 2019

Stem Cells and Development

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“…difference in body size between the 2 month-old puppies (weigh about 3 to 4 kg) compared to adult humans it seems that we would be more likely to see retinal spill over in the dog than in the human [20,21]. Unexpectedly, the PDE6A -/puppies had a significantly lower plasma cGMP level than the heterozygotes.…”

Section: Plos Onementioning

confidence: 94%

Elevated retinal cGMP is not associated with elevated circulating cGMP levels in a canine model of retinitis pigmentosa

et al. 2022

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Purpose To investigate whether raised levels of retinal cyclic guanosine monophosphate (cGMP) was reflected in plasma levels in PDE6A-/- dogs. Materials and methods Retina was collected from 2-month-old wildtype dogs (PDE6A+/+, N = 6), heterozygous dogs (PDE6A+/-, N = 4) and affected dogs (PDE6A-/-, N = 3) and plasma was collected from 2-month-old wildtype dogs (PDE6A+/+, N = 5), heterozygous dogs (PDE6A+/-, N = 5) and affected dogs (PDE6A-/-, N = 5). Retina and plasma samples were measured by ELISA. Results cGMP levels in retinal samples of PDE6A-/- dogs at 2 months of age were significantly elevated. There was no significant difference in plasma cGMP levels between wildtype and PDE6A-/- or PDE6A+/- puppies. However, the plasma cGMP levels of the PDE6A-/- puppies were significantly lower than that of PDE6A+/- puppies. Conclusion cGMP levels in the plasma from PDE6A-/- was not elevated when compared to control dogs. At the 2-month timepoint, cGMP plasma levels would not be a useful biomarker for disease.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Large Animal Models of Inherited Retinal Degenerations: A Review

Winkler

Occelli

Petersen‐Jones

2020

Cells

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Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.

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Drug and gene therapy of hereditary retinal disease in dog and cat models

Cited by 4 publications

References 50 publications

Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in the Subretinal Space of the Cat Eye

Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in the Subretinal Space of the Cat Eye

Elevated retinal cGMP is not associated with elevated circulating cGMP levels in a canine model of retinitis pigmentosa

Large Animal Models of Inherited Retinal Degenerations: A Review

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