Natural History of Retinal Degeneration in Ovine Models of CLN5 and CLN6 Neuronal Ceroid Lipofuscinoses

Abstract

Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases with a common set of symptoms including cognitive and motor decline and vision loss. Naturally occurring sheep models of CLN5 and CLN6 disease display the key clinical features of NCL, including a progressive loss of vision. We assessed retinal histology, inflammation, and lysosomal storage accumulation in CLN5 affected (CLN5−/−) and CLN6 affected (CLN6−/−) sheep eyes and age-matched controls at 3, 6, 12, and 18 months of age to determine the onset and progression of retinal pathology in NCL sheep. The retina of CLN5−/− sheep shows progressive atrophy of the outer retinal layers, widespread inflammation, and accumulation of lysosomal storage in retinal ganglion cells late in disease. In contrast, CLN6−/− retina shows significant atrophy of all retinal layers, progressive inflammation, and earlier accumulation of lysosomal storage. This study has highlighted the differential vulnerability of retinal layers and the time course of retinal atrophy in two distinct models of NCL disease. This data will be valuable in determining potential targets for ocular therapies and the optimal timing of these therapies for protection from retinal dysfunction and degeneration in NCL.

Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)

“…The retina of CLN6 affected sheep exhibits severe atrophy of the photoreceptor layer, and the outer nuclear and plexiform layers [ 46 , 48 , 49 ]. Accumulation of lysosomal storage, particularly in the ganglion cell layer is another common feature of the retina in ovine NCL [ 48 , 50 – 52 ]. Affected-like chimeric animals showed levels of atrophy and lysosomal storage similar to that in affected controls, normal-like chimeras showed no signs of retinal atrophy and very little storage, whilst recovering-like animals sat somewhere in between.…”

Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)

“…The retina of CLN6 affected sheep exhibits severe atrophy of the photoreceptor layer, and the outer nuclear and plexiform layers [46,48,49]. Accumulation of lysosomal storage, particularly in the ganglion cell layer is another common feature of the retina in ovine NCL [48,[50][51][52]. Affected-like chimeric animals showed levels of atrophy and lysosomal storage similar to that in affected controls, normal-like chimeras showed no signs of retinal atrophy and very little storage, whilst recovering-like animals sat somewhere in between.…”