A Novel Form of Progressive Retinal Atrophy in Swedish Vallhund Dogs

Peer reviewe

Transient Photoreceptor Deconstruction by CNTF Enhances rAAV-Mediated Cone Functional Rescue in Late Stage CNGB3-Achromatopsia

Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs \u3c0.5 years of age, but treatment is minimally effective in dogs \u3e1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy

Insight from OPN1LW Gene Haplotypes into the Cause and Prevention of Myopia

Nearsightedness (myopia) is a global health problem of staggering proportions that has driven the hunt for environmental and genetic risk factors in hopes of gaining insight into the underlying mechanism and providing new avenues of intervention. Myopia is the dominant risk factor for leading causes of blindness, including myopic maculopathy and retinal detachment. The fundamental defect in myopia—an excessively elongated eyeball—causes blurry distance vision that is correctable with lenses or surgery, but the risk of blindness remains. Haplotypes of the long-wavelength and middle-wavelength cone opsin genes (OPN1LW and OPN1MW, respectively) that exhibit profound exon-3 skipping during pre-messenger RNA splicing are associated with high myopia. Cone photoreceptors expressing these haplotypes are nearly devoid of photopigment. Conversely, cones in the same retina that express non-skipping haplotypes are relatively full of photopigment. We hypothesized that abnormal contrast signals arising from adjacent cones differing in photopigment content stimulate axial elongation, and spectacles that reduce contrast may significantly slow myopia progression. We tested for an association between spherical equivalent refraction and OPN1LW haplotype in males of European ancestry as determined by long-distance PCR and Sanger sequencing and identified OPN1LW exon 3 haplotypes that increase the risk of common myopia. We also evaluated the effects of contrast-reducing spectacles lenses on myopia progression in children. The work presented here provides new insight into the cause and prevention of myopia progression

Standard electroretinograms (ERGs) recorded from normal and affected Swedish vallhund dogs.

<p>Compared to the ERG recordings of a normal dog (top row) both rod- and cone-mediated retinal functions are clearly reduced at <i>Stage 2</i>. ERG amplitudes are further decreased at <i>Stage 3</i> (third row), especially rod-mediated responses, and may not even be recordable in some affected dogs (flat lines in fourth row).</p

Appearance of Swedish vallhund dogs.

<p>The Swedish vallhund is a spitz-type herding breed, recognized since the age of the Vikings (700–1000 A.D.). The breed standard includes erect ears and a medium-length, hard haircoat. Coat color is a sable pattern in grey, red or combinations thereof. Tail may be natural (long, stub or bob) or docked.</p

Swedish vallhund dogs that showed progression with repeated examination.

<p>At the authors' discretion, selected examinations performed by other certified veterinary ophthalmologists were included in the data analysis in order to provide a more complete picture of disease progression.</p><p>Swedish vallhund dogs that showed progression with repeated examination.</p

Swedish vallhund dogs that showed no progression to subsequent disease stages with repeated examination.

<p>Swedish vallhund dogs that showed no progression to subsequent disease stages with repeated examination.</p

Clinical appearance of the ocular fundi of normal and affected Swedish vallhund dogs.

<p>(A–C) Normal appearance of the ocular fundus with the colored tapetum lucidum (responsible for eye shine), the well developed retinal vasculature, and the optic nerve head (arrows). It is not unusual to see a thin halo of altered reflectivity or <i>conus papillaris</i> around the optic nerve head as seen in B and C. (D–F) <i>Stage 1</i> is characterized by multifocal red or brown discoloration of the tapetal fundus (arrows). (G–I) In <i>Stage 2</i>, the retina showed signs of degeneration, indicated by multifocal, geographic thinning (arrow heads), beginning in the periphery and spreading throughout the tapetal fundus. (J–L) <i>Stage 3</i> is defined by a more diffuse retinal thinning recognized by the large, bright (hyperreflective) regions affecting most of the tapetal fundus (arrow heads). The <i>conus papillaris</i> also appears wider in <i>Stage 3</i> (arrows).</p