Publications by authors named "Simon M Petersen-Jones"

Objective: To map the disease locus for familial ocular melanosis (OM) in the Cairn Terrier.

Animals Studied: Cairn Terriers with OM and normal control dogs.

Procedure: A genome-wide association study (GWAS) was performed using 63 OM-affected and 31 control Cairn Terriers, followed by haplotype analysis.

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Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration.

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Subretinal injections are not commonly performed during clinical treatment of animals but are frequently used in laboratory animal models to assess therapeutic efficacy and safety of gene and cell therapy products. Veterinary ophthalmologists are often employed to perform the injections in the laboratory animal setting, due to knowledge of comparative ocular anatomy between species and familiarity with operating on non-human eyes. Understanding the different approaches used for subretinal injection in each species and potential complications that may be encountered is vital to achieving successful and reproducible results.

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Article Synopsis
  • The fundus provides a unique, noninvasive view of the eye's blood vessels and nervous tissue, allowing for the detection of systemic diseases and monitoring treatment responses.
  • Changes in the retina's vasculature, thickness, and presence of abnormalities can indicate various health issues, with some retinal signs being specific to certain systemic illnesses.
  • The examination of the fundus is critical in veterinary medicine for identifying diseases classified under the DAMNIT-V acronym, while also addressing normal variations in retinal structure.
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Companion animals, namely dogs, cats, and horses, can be affected with many forms of hereditary retinal disease. The number of such diseases characterized in the last decade has increased substantially, and nomenclature is nonstandardized, heterogenous, and confusing. We provide in this viewpoint article consensus guidelines for naming of companion animal hereditary retinal diseases, either prospectively or retrospectively.

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Article Synopsis
  • Advances in long-read sequencing technology have facilitated high-quality genome assemblies for dogs and wolves, with 8 assemblies published recently.
  • The study presents 3 new assemblies for specific dog breeds (2 Bernese Mountain Dogs and 1 Cairn Terrier) due to their association with unresolved genetic disorders.
  • The analysis revealed missing conserved genes across all assemblies and confirmed the effectiveness of nanopore sequencing for detailed genetic and epigenetic profiling of canine genomes.
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CRX is a transcription factor essential for normal photoreceptor development and survival. The CRX cat has a naturally occurring truncating mutation in CRX and is a large animal model for dominant Leber congenital amaurosis. This study investigated retinal remodeling that occurs as photoreceptors degenerate.

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Purpose: Mutations in the CRX transcription factor are associated with dominant retinopathies often with more severe macular changes. The CRX-mutant cat (Rdy-A182d2) is the only animal model with the equivalent of the critical retinal region for high-acuity vision, the macula. Heterozygous cats (CRXRdy/+) have a severe phenotype modeling Leber congenital amaurosis.

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Naturally occurring inherited retinal diseases (IRDs) in cats and dogs provide a rich source of potential models for human IRDs. In many cases, the phenotypes between the species with mutations of the homologous genes are very similar. Both cats and dogs have a high-acuity retinal region, the area centralis, an equivalent to the human macula, with tightly packed photoreceptors and higher cone density.

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In this study, we investigate a gene augmentation therapy candidate for the treatment of retinitis pigmentosa (RP) due to cyclic nucleotide-gated channel beta 1 (CNGB1) mutations. We use an adeno-associated virus serotype 5 with transgene under control of a novel short human rhodopsin promoter. The promoter/capsid combination drives efficient expression of a reporter gene (AAV5-RHO-eGFP) exclusively in rod photoreceptors in primate, dog, and mouse following subretinal delivery.

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The genes CNGA1 and CNGB1 encode the alpha and beta subunits of the rod CNG channel, a ligand-gated cation channel whose activity is controlled by cyclic guanosine monophosphate (cGMP). Autosomal inherited mutations in either of the genes lead to a progressive rod-cone retinopathy known as retinitis pigmentosa (RP). The rod CNG channel is expressed in the plasma membrane of the outer segment and functions as a molecular switch that converts light-mediated changes in cGMP into a voltage and Ca signal.

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Objective: To describe the clinical, preliminary electroretinographic and optical coherence tomography features of a newly identified form of progressive retinal atrophy (PRA) in German Spitzes, and identify the causal gene mutation.

Animals: Thirty-three client-owned German Spitz dogs were included.

Procedures: All animals underwent a full ophthalmic examination, including vision testing.

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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.

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Purpose: The rdAc cat has an intronic mutation in the centrosomal 290 kDa (CEP290) gene resulting in a frameshift and a premature stop codon (c.6960 + 9 T > G, p.Ile2321AlafsTer3) predicted to truncate the protein by 157 amino acids.

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Large animal models are valuable for developing and testing translational therapies for inherited retinal dystrophies such as retinitis pigmentosa (RP). Gene augmentation therapy has been developed utilizing such models. Adeno-associated viral (AAV) vectors have been frequently utilized and delivered by intravitreal or subretinal injection.

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Background: The On-Off, or long flash, full field electroretinogram (ERG) separates retinal responses to flash onset and offset. Depending on degree of dark-adaptation and stimulus strength the On and Off ERG can be shaped by rod and cone photoreceptors and postreceptoral cells, including ON and OFF bipolar cells. Interspecies differences have been shown, with predominantly positive Off-response in humans and other primates and a negative Off-response in rodents and dogs.

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Purpose: Mutations in the cyclic nucleotide-gated (CNG) channel beta subunit (CNGB1) are an important cause of recessive retinitis pigmentosa. We identified a large animal model with a truncating mutation of CNGB1. This study reports the persistence of small, desensitized rod ERG responses in this model.

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Objectives: To assess an inherited abnormal negative response electroretinogram (NRE) that originated in a family of Papillon dogs.

Animals Studied: Thirty-eight dogs (Papillons, or Papillon cross Beagles or Beagles).

Procedures: Dogs underwent routine ophthalmic examination and a detailed dark-adapted, light-adapted and On-Off electroretinographic study.

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Purpose: In this study, we assessed several extended electroretinographic protocols using nonstandard stimuli. Our aim was to separate and quantify the contributions of different populations of retinal cells to the overall response, both to assess normal function and characterize dogs with inherited retinal disease.

Methods: We investigated three different protocols for measuring the full-field flash electroretinogram-(1) chromatic dark-adapted red and blue flashes, (2) increasing luminance blue-background, (3) flicker with fixed frequency and increasing luminance, and flicker with increasing frequency at a fixed luminance-to assess rod and cone contributions to electroretinograms recorded in phenotypically normal control dogs and dogs lacking rod function.

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Purpose: While the retinal vasculature can be assessed by simple funduscopy, a more detailed assessment can be performed by conventional angiography using dyes such as fluorescein or indocyanine green. The development of optical coherence tomography angiography (OCT-A) allows a non-invasive detailed examination of posterior segment vasculature. The purpose of this prospective study was to compare imaging of posterior segment vasculature in normal dogs and cats using OCT-A, fluorescein angiography (FA), and indocyanine green angiography (ICGA).

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Background: Despite the common use of topical ophthalmic corticosteroids in dogs, detailed reports on systemic and dermatologic adverse effects are limited.

Results: Nine purpose-bred research Beagles were treated with difluprednate 0.05% ophthalmic emulsion in one or both eyes 2-3 times daily.

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Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5-/- mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.

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Objective: To report the development of focal bullous retinal detachments (bullae) in dogs with different forms of progressive retinal atrophy (PRA).

Procedures: Dogs with three distinct forms of PRA (PRA-affected Whippets, German Spitzes and CNGB1-mutant Papillon crosses) were examined by indirect ophthalmoscopy and spectral domain optical coherence tomography (SD-OCT). Retinal bullae were monitored over time.

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Retinal degenerative (RD) conditions associated with photoreceptor loss such as age-related macular degeneration (AMD), retinitis pigmentosa (RP) and Leber Congenital Amaurosis (LCA) cause progressive and debilitating vision loss. There is an unmet need for therapies that can restore vision once photoreceptors have been lost. Transplantation of human pluripotent stem cell (hPSC)-derived retinal tissue (organoids) into the subretinal space of an eye with advanced RD brings retinal tissue sheets with thousands of healthy mutation-free photoreceptors and has a potential to treat most/all blinding diseases associated with photoreceptor degeneration with one approved protocol.

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Retinitis pigmentosa type 45 (RP45) is an autosomal-recessively inherited blinding disease caused by mutations in the cyclic nucleotide-gated channel subunit beta 1 () gene. In this study, we developed and tested a novel gene supplementation therapy suitable for clinical translation. To this end, we designed a recombinant adeno-associated virus (rAAV) vector carrying a genome that features a novel human rhodopsin promoter (hRHO194) driving rod-specific expression of full-length human (rAAV5.

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