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

Whiting, Rebecca E.H.; Kick, Grace Robinson; Ota-Kuroki, Juri; Lim, Stefanie; Castaner, Leilani J.; Jensen, Cheryl A.; Kowal, Joseph B.; Nguyen, Annalisa; Corado, Carley R.; O’Neill, Charles; Katz, Martin L.

doi:10.1016/j.exer.2020.108135

Cited by 14 publications

(3 citation statements)

References 28 publications

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“…This contrasts with the canine TPP1 null variant, where retinal degeneration is described as a progressive loss of inner retinal function, affecting the rod system more profoundly than the cone system [ 40 , 41 ]. In particular, the canine ERG is profoundly electronegative, with a-wave amplitudes declining later in the disease progression [ 40 , 41 ]. The canine model more closely resembles the ERG of human CLN1 and CLN3 disease, [ 5 , 28 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the canine ERG is profoundly electronegative, with a-wave amplitudes declining later in the disease progression [ 40 , 41 ]. The canine model more closely resembles the ERG of human CLN1 and CLN3 disease, [ 5 , 28 , 41 ]. Canine models of other human cone disease show reduced cone ERGs and preservation of rods ERGs [ 42 ], and the reason for this disparity in CLN2 is unclear, but it is an important consideration when piloting human eye treatments based on the canine model.…”

Section: Discussionmentioning

confidence: 99%

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An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

Thompson

Handley

Henderson

et al. 2021

Eye

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Background Late infantile neuronal ceroid lipofuscinosis (CLN2 Batten disease) is a rare, progressive neurodegenerative disease of childhood. The natural history of motor and language regression is used to monitor the efficacy of CNS treatments. Less is known about CLN2 retinopathy. Our aim is to elaborate the nature, age of onset, and symmetry of CLN2 retinopathy using visual electrophysiology and ophthalmic imaging. Subjects and methods We reviewed 22 patients with genetically confirmed CLN2 disease; seventeen showing classical and five atypical disease. Flash electroretinograms (ERGs), flash and pattern reversal visual evoked potentials (VEPs), recorded from awake children were collated. Available fundus images were graded, optical coherence tomography (OCT) central subfoveal thickness (CST) measured, and genotype, age, clinical vision assessment and motor language grades assembled. Results ERGs show cone/rod system dysfunction preceded by localised macular ellipsoid zone disruption on OCT from 4.8 years. Electroencephalogram (EEG) time-locked spikes confounded both pattern 6/17 (35%) and flash VEPs 12/16 (75%). Paired right eye (RE) and left eye (LE) ERG amplitudes did not differ significantly for each flash stimulus at the p 0.001 level, Wilcoxon ranked signed test. Cone ERGs show a functional deficit before CST thinning in classical disease. Optomap hyper fundus autofluorescence (FAF) at the fovea was noted in three patients with normal ERGs. The oldest patient showed an ovoid aggregate above the external limiting membrane at the fovea, which did not affect the PERG. Conclusion ERG findings in CLN2 retinopathy show symmetrical cone-rod dysfunction, from 4y10m in this series, but a broad range of ages when ERG function is preserved.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

Thompson

Handley

Henderson

et al. 2021

Eye

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“…Therapeutic trials are in progress aiming to prevent retinal degeneration in animal models using intravitreal gene or enzyme therapy ( 103 , 104 ). These approaches represent powerful therapeutic systems suitable for translation into NCL patients.…”

Section: Selected Clinical Featuresmentioning

confidence: 99%

Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview

Simonati

Williams

2022

Front. Neurol.

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The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.

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