Intravitreal Enzyme replacement therapy attenuates retinal disease progression in a canine model of neuronal ceroid lipofuscinosis type 2 (CLN2)

Abstract

Purpose : CLN2 disease (a form of Batten disease) is an inherited disorder caused by mutations in the TPP1 gene that affects the nervous system, which ocularly manifests in progressive retinal degeneration and vison loss late in disease progression. We tested if enzyme replacement therapy (ERT) to the eye with tripeptidyl peptidase-1 (TPP1) to the eye could attenuate retinal degeneration in a canine model of CLN2 disease. CLN2 disease dogs (TPP1-null) were treated by intravitreal (IVT) injection (100 µL) with human TPP1 (hTPP1, 0.1 mg OS), and formulation vehicle (OD) starting at 3 months of age (prior to ocular disease onset) biweekly with a treatment duration of up to 7 months.

Methods : The eyes were monitored by ophthalmic exams and monthly in vivo assessments included spectral domain optical coherence tomography / scanning laser ophthalmoscopy (sdOCT/SLO) and electroretinography (ERG). Ocular histopathology was conducted post-mortem when the dogs were euthanized at end-stage neurological disease (10 to 11 months of age). Plasma samples were collected at various time points throughout the study for pharmacokinetics and anti-drug antibody analyses.

Results : IVT administration of hTPP1 was tolerated up to several doses before the emergence of immune-mediated vitreal inflammation likely due to heterologous hTTP1. The response was mitigated by increasing the dosing interval and the administration of anti-inflammatories. Relative to the vehicle, IVT hTPP1 attenuated or prevented the progressive disease related effects in ERG responses and retinal anatomical parameters. We have demonstrated that ERT with hTPP1 via repeated IVT administration in TPP1-null dogs prior to disease onset inhibited the progression of disease related retinal degeneration. In one dog, treatment was initiated after a significant decline in retinal function as measured by the ERG. The treatment prevented further decline in ERG responses which normally occurs in untreated dogs.

Conclusions : This study supports proof of concept towards a therapy for CLN2 disease ocular disease manifestations.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.