Intravitreal gene therapy preserves retinal function in a canine model of CLN2 neuronal ceroid lipofuscinosis.

CLN2 neuronal ceroid lipofuscinosis is a rare hereditary neurodegenerative disorder characterized by deleterious sequence variants in TPP1 that result in reduced or abolished function of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Children with this disorder experience progressive neurological decline and vision loss starting around 2-4 years of age. Ocular disease is characterized by progressive retinal degeneration and impaired retinal function culminating in total loss of vision. Similar retinal pathology occurs in a canine model of CLN2 disease with a null variant in TPP1. A study using the dog model was performed to evaluate the efficacy of ocular gene therapy to provide a continuous, long-term source of human TPP1 (hTPP1) to the retina, inhibit retinal degeneration and preserve retinal function. TPP1-/- dogs received an intravitreal injection of 1 x 1012 viral genomes of AAV2.CAG.hTPP1 in one eye and AAV2.CAG.GFP in the contralateral eye at 4 months of age. Ophthalmic exams, in vivo ocular imaging and electroretinography were repeated monthly to assess retinal structure and function. Retinal morphology, hTPP1 and GFP expression in the retina, optic nerve and lateral geniculate nucleus, and hTPP1 concentrations in the vitreous were evaluated after the dogs were euthanized at end stage neurological disease at approximately 10 months of age. Intravitreal administration of AAV2.CAG.hTPP1 resulted in stable, widespread expression of hTPP1 throughout the inner retina, prevented disease-related declines in retinal function and inhibited disease-related cell loss and storage body accumulation in the retina for at least 6 months. Uveitis occurred in eyes treated with the hTPP1 vector, but this did not prevent therapeutic efficacy. The severity of the uveitis was ameliorated with anti-inflammatory treatments. These results indicate that a single intravitreal injection of AAV2.CAG.hTPP1 is an effective treatment to inhibit ocular disease progression in canine CLN2 disease.

Visual system pathology in a canine model of CLN5 neuronal ceroid lipofuscinosis.

CLN5 neuronal ceroid lipofuscinosis is a hereditary neurodegenerative disease characterized by progressive neurological decline, vision loss and seizures. Visual impairment in children with CLN5 disease is attributed to a progressive decline in retinal function accompanied by retinal degeneration as well as impaired central nervous system function associated with global brain atrophy. We studied visual system pathology in five Golden Retriever littermates homozygous for the CLN5 disease allele previously identified in the breed. The dogs exhibited signs of pronounced visual impairment by 21-22 months of age. Electroretinogram recordings showed a progressive decline in retinal function primarily affecting cone neural pathways. Altered visual evoked potential recordings indicated that disease progression affected visual signal processing in the brain. Aside from several small retinal detachment lesions, no gross retinal abnormalities were observed with in vivo ocular imaging and histologically the retinas did not exhibit apparent abnormalities by 23 months of age. However, there was extensive accumulation of autofluorescent membrane-bound lysosomal storage bodies in almost all retinal layers, as well as in the occipital cortex, by 20 months of age. In the retina, storage was particularly pronounced in retinal ganglion cells, the retinal pigment epithelium and in photoreceptor cells just interior to the outer limiting membrane. The visual system pathology of CLN5-affected Golden Retrievers is similar to that seen early in the human disease. It was not possible to follow the dogs to an advanced stage of disease progression due to the severity of behavioral and motor disease signs by 23 months of age. The findings reported here indicate that canine CLN5 disease will be a useful model of visual system disease in CLN5 neuronal ceroid lipofuscinosis. The baseline data obtained in this investigation will be useful in future therapeutic intervention studies. The findings indicate that there is a fairly broad time frame after disease onset within which treatments could be effective in preserving vision.

Intravitreal enzyme replacement inhibits progression of retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis.

CLN2 neuronal ceroid lipofuscinosis is a rare recessive hereditary retinal and neurodegenerative disease resulting from deleterious sequence variants in TPP1 that encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Children with this disorder develop normally, but starting at 2-4 years of age begin to exhibit neurological signs and visual deficits. Vision loss that progresses to blindness is associated with progressive retinal degeneration and impairment of retinal function. Similar progressive loss of retinal function and retinal degeneration occur in a dog CLN2 disease model with a TPP1 null sequence variant. Studies using the dog model were conducted to determine whether intravitreal injection of recombinant human TPP1 (rhTPP1) administered starting after onset of retinal functional impairment could slow or halt the progression of retinal functional decline and degeneration. TPP1-null dogs received intravitreal injections of rhTPP1 in one eye and vehicle in the other eye beginning at 23.5-25 weeks of age followed by second injections at 34-40 weeks in 3 out of 4 dogs. Ophthalmic exams, in vivo ocular imaging, and electroretinography (ERG) were repeated regularly to monitor retinal structure and function. Retinal histology was evaluated in eyes collected from these dogs when they were euthanized at end-stage neurological disease (40-45 weeks of age). Intravitreal rhTPP1 injections were effective in preserving retinal function (as measured with the electroretinogram) and retinal morphology for as long as 4 months after a single treatment. These findings indicate that intravitreal injection of rhTPP1 administered after partial loss of retinal function is an effective treatment for preserving retinal structure and function in canine CLN2 disease.

Retinal astrocytoma in a dog.

A miniature schnauzer dog presenting with hyphema and glaucoma of the right eye had a retinal neoplasm. Neoplastic cells stained positively for glial fibrillary acidic protein, vimentin, and S-100 and largely negatively for oligodendrocyte transcription factor 2 by immunohistochemistry. The clinical and histopathological features of canine retinal astrocytomas are discussed.

Astrocytome rétinal chez un chien. Un chien Schnauzer miniature a été présenté avec de l'hyphéma et du glaucome dans l'oeil droit et avait un néoplasme rétinal. Les cellules néoplastiques ont donné un résultat positif par immunohistochimie pour la protéine fibrillaire gliale acide, la vimentine et S-100 et les résultats étaient en grande partie négatifs pour le facteur de transcription 2 des oligodendrocytes. Les caractéristiques cliniques et histopathologiques des astrocytomes rétinaux canins sont discutés.(Traduit par Isabelle Vallières).

Limbal xanthogranuloma in a dog.

A 10-year-old female spayed American Pitt Bull Terrier was presented with a slow growing mass on the temporal limbus area of the right eye. Canine nodular granulomatous episclerokeratitis was suspected, and the affected eye was treated with 1% prednisolone acetate ophthalmic suspension and 0.03% Tacrolimus ophthalmic solution. As the lesion did not respond to the medical treatments and continued to grow, the mass was excised by lamellar sclerokeratectomy. Microscopically, the mass was composed of granulomatous inflammation with intrahistiocytic lipids and lakes of acicular cholesterol clefts, histopathology findings consistent with xanthogranuloma. To the authors' knowledge, this is the first canine report of limbal xanthogranuloma.

Intraocular and periocular lymphoma in dogs and cats: a retrospective review of 21 cases (2001-2012).

OBJECTIVE: To immunologically phenotype and histologically classify canine and feline intraocular and periocular lymphomas. METHODS: The databases of four veterinary medical diagnostic laboratories were searched to identify cases of intraocular or periocular lymphoma in dogs and cats between 2001 and 2012. Hematoxylin and eosin (H&E) stained slides were reviewed for confirmation and classification of lymphoma, and immunohistochemistry for CD3 (T-cell marker) and CD79a and/or CD20 (B-cell markers) was examined to determine the lineage of the neoplastic lymphocytes. RESULTS: Six canine and 15 feline cases of ocular lymphoma were identified. In the canine cases, there were three intraocular and three periocular lymphomas where two intraocular and one periocular lymphomas were B-cell, one of each intraocular and periocular lymphomas were T-cell and one periocular lymphoma was nonreactive with CD3, CD79a or CD20. In the feline cases, there were six intraocular and nine periocular lymphomas where five intraocular and six periocular lymphomas were B-cell, and one intraocular and three periocular lymphomas were T-cell. Only one canine case had concurrent generalized lymphadenopathy, only one canine conjunctival lymphoma had simultaneous cutaneous lymphoma, and only one feline case had bilateral ocular involvement when they were diagnosed. CONCLUSION: Canine and feline intraocular and periocular lymphomas are often of B-cell phenotype. Although in general terms lymphoma is not considered a primary tumor when it occurs in or adjacent to the globe, these tumors frequently first become evident in the globe and/or periocular area. An accurate early diagnostic approach is crucial for the patient's quality of life because B-cell lymphomas are generally more amenable to chemotherapy than T-cell lymphomas.