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

Abstract 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.