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Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.

ABSTRACT: CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.

SUBMITTER: Katz ML

PROVIDER: S-EPMC5398942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.

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