Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

Abstract

Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end‐stage disease at ≤24 months of age. Despite very different gene products, mutations, and subcellular localizations, the pathogenic cascade was remarkably similar for all three disease models. Glial activation was present at birth in affected sheep and preceded neuronal loss, with both spreading from the visual and parieto‐occipital cortices most prominently associated with clinical symptoms to the entire cortical mantle by end‐stage disease. In contrast, the subcortical regions were less involved, yet lysosomal storage followed a near‐linear increase across the diseased sheep brain with age. Correlation of these neuropathological changes with published clinical data identified three potential therapeutic windows in affected sheep—presymptomatic (3 months), early symptomatic (6 months), and a later symptomatic disease stage (9 months of age)—beyond which the extensive depletion of neurons was likely to diminish any chance of therapeutic benefit. This comprehensive natural history of the neuropathological changes in ovine CLN5 and CLN6 disease will be integral in determining what impact treatment has at each of these disease stages.

Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease

“…Natural history studies have shown that the cerebellum does not significantly degenerate in CLN5 −/− sheep ( Mitchell et al, 2023 ) and there was also no apparent cerebellar thinning in any treated sheep over the study ( Figure 5 ; Supplementary Table S2 ).…”

“…By 6 months of age, neuroinflammation in the CLN5 −/− sheep brain is pronounced and spread across the cortical mantle, although the primary visual and parieto-occipital cortices remain the most affected regions ( Mitchell et al, 2023 ). Both GFAP and GSB4 staining of early symptomatic treated brains indicated a halt or slowing of further astrocytosis, brain macrophage formation and recruitment.…”

Efficacy of dual intracerebroventricular and intravitreal CLN5 gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease

“…Natural history electroretinography studies in untreated CLN5 −/− sheep showed that retinal dysfunction begins around 5 months of age ( Russell et al, 2021 ), and this dysfunction is accompanied by progressive loss of vulnerable neurons in the primary visual cortex and outer nuclear layer and photoreceptor cells in the retina ( Murray and Mitchell, 2022 ; Mitchell et al, 2023b ). IVT administration alone was not sufficient to prevent vision loss in CLN5 −/− sheep, likely due to cortical blindness since the CNS remained untreated ( Murray et al, 2021 ).…”

“…Given the progressive nature of CLN5 Batten disease, early intervention is predicted to be the most efficacious; however, most human cases are diagnosed when patients are already symptomatic. Therefore, the effect of combined ICV and IVT scAAV9/oCLN5 administration was assessed at three previously identified disease stages–pre-symptomatic (3 months of age), early symptomatic (6 months of age), and advanced symptomatic (9 months of age) ( Mitchell et al, 2023b ). All sheep received the same IVT dose and pre-symptomatic sheep received the previously efficacious ICV dose ( Mitchell et al, 2023a ).…”

A one-health approach to using sheep in research, with a focus on neuroscience studies

“…Large animal models for this disease primarily include dogs and sheep [65,66] . Both genetically modified and naturally occurring sheep models are available [61,[65][66][67][68] .…”