Gait phenotype in Batten disease: A marker of disease progression

Østergaard, John R.

doi:10.1016/j.ejpn.2021.09.004

Cited by 10 publications

(8 citation statements)

References 72 publications

(98 reference statements)

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“…Female CLN3 Δex7/8 animals showed less differences over a similar time period, having a more consistent, symmetrical step length, compared to wild-type miniswine ( Figure 3C, F ). Taken together, this data indicates that the front feet of CLN3 Δex7/8 animals show altered stepping and center-of-pressure dynamics, similar to the decreased stability observed in individuals with CLN3 disease 50,51 .…”

Section: Resultssupporting

confidence: 65%

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

Swier

White

Johnson

et al. 2022

Preprint

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Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span, and inconsistent, subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, limiting their utility in preclinical studies. Here we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with vision impairment and motor abnormalities, similar to deficits seen in human patients. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease modifying therapeutics.

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Section: Resultssupporting

confidence: 65%

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

Swier

White

Johnson

et al. 2022

Preprint

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“…This may be related to the less severe and delayed onset of spinal cord pathology in Cln2 R207X versus Cln1 –/– mice but may also be due to the effects of TPP1 deficiency on other brain regions. These data are also unexpected given that severe gait decline is seen in patients with CLN2 disease ( 49 ). Untreated Cln2 R207X mice may die because of seizure-related fatality, before their gait abnormalities become severe enough to prevent them from accessing food and water.…”

Section: Discussionmentioning

confidence: 90%

“…We demonstrate that a single ICV injection of AAV9.hCLN2 vector effectively attenuates many of these defined neuropathological phenotypes, effectively prevents seizures, reduces interictal epileptiform activity, and significantly extends survival in Cln2 R207X mice. During this extended survival period, treated mice also showed markedly improved gait performance, another test that is used clinically to assess disease progression in children with CLN2 disease ( 49 ). Given this robust preclinical efficacy and the documented safety of the AAV9.hCLN2 vector in a nonhuman primate, AAV9.hCLN2 gene therapy is now a candidate for further clinical investigation.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

Takahashi¹,

Eultgen²,

Wang³

et al. 2023

Journal of Clinical Investigation

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Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2 R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9–mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2 R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

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“…This may be related to the less severe and delayed onset of spinal cord pathology in Cln2 R207X vs. Cln1 -/- mice. These data are also unexpected given that severe gait decline is seen in patients with CLN2 disease [54]. This raises the possibility that Cln2 R207X mice may die due to other causes, such as seizures, before their gait abnormality becomes severe enough to prevent them from accessing their food and water.…”

Section: Discussionmentioning

confidence: 98%

Cortical interneuron loss and seizure generation as novel clinically relevant disease phenotypes in Cln2^R207X mice

Takahashi

Eultgen

Wang

et al. 2022

Preprint

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Aims: CLN2 disease is a fatal inherited childhood neurodegenerative disorder. Although a disease-modifying therapy now exists, a fundamental lack of understanding of disease pathogenesis has hampered development of more effective therapies. To better understand the cellular pathophysiology of CLN2 disease, we investigated the nature and progression of neuropathological and neurological changes in the recently generated Cln2R207X mouse. Methods: We have detailed microglial activation, astrogliosis, cytokine and chemokine expression, and neuron loss across the forebrain and spinal cords of Cln2R207X mice, along with quantitative gait analysis. We also performed long-term electroencephalography (EEG) recordings to characterize seizure activity, a clinically-relevant phenotype yet to be defined in any CLN2 disease model. Results: Histology revealed early localized microglial activation months before neuron loss in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. These pathological changes were more pronounced and occurred in the cortex before the thalamus or spinal cord. There were early-onset and progressive changes in the expression of specific chemokines and cytokines including IL-33, IP-10, and MIP-1α. Gait analysis revealed impaired performance only at disease end stage. EEG recordings revealed robust and progressive epileptiform activity from disease mid-stage including spontaneous seizures, which were accompanied by a profound loss of cortical GABAergic interneurons. Conclusions: Our data reveal novel phenotypes in Cln2R207X mice that differ markedly in their timing and progression through the CNS from other NCL mouse models. Our findings provide new insights on CLN2 disease pathogenesis and clinically-relevant readouts for future therapeutic studies.

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Gait phenotype in Batten disease: A marker of disease progression

Cited by 10 publications

References 72 publications

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

Cortical interneuron loss and seizure generation as novel clinically relevant disease phenotypes in Cln2^R207X mice

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Gait phenotype in Batten disease: A marker of disease progression

Cited by 10 publications

References 72 publications

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

Cortical interneuron loss and seizure generation as novel clinically relevant disease phenotypes in Cln2R207X mice

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Cortical interneuron loss and seizure generation as novel clinically relevant disease phenotypes in Cln2^R207X mice