A Novel Porcine Model of CLN2 Batten Disease that Recapitulates Patient Phenotypes

Swier, Vicki J.; White, Katherine A.; Johnson, Tyler B.; Sieren, Jessica C.; Johnson, Hans J.; Knoernschild, Kevin; Wang, Xiaojun; Rohret, Frank; Rogers, Christopher S.; Pearce, David A.; Brudvig, Jon; Weimer, Jill M.

doi:10.1007/s13311-022-01296-7

Cited by 9 publications

(28 citation statements)

References 66 publications

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“…FitBark Activity Monitoring: Miniswine were tracked every six months from 24 to 48 months of age over the course of six days using a FitBark2 device (www.fitbark.com), attached on the neck using a common dog or calf collar as previously described 31,48 . Distance traveled, active time, rest time and sleep quality were analyzed with GraphPad Prism 8.0 using a two-way ANOVA, uncorrected Fisher's LSD post-hoc.…”

Section: Pcr Screen and Cellmentioning

confidence: 99%

“…To determine if CLN3 Δex7/8 miniswine recapitulate the cognitive decline displayed in CLN3 disease patients, animals were trained in a simple T-maze as previously described 32,48 . Briefly, the miniswine are allowed to roam the maze for four days for 10 minutes each day in the acclimation phase.…”

Section: Cln3 δEx7/8 Miniswine Present With Limited Cognitive Dysfunc...mentioning

confidence: 99%

“…Simple T-maze: Memory and learning capabilities were monitored using a simple T-maze as previously described 32,48 , with the exception of using dry animal pellets as a reward. Briefly, during the acquisition phases (two days of testing), animals learned which arm a food reward was located in.…”

Section: Pcr Screen and Cellmentioning

confidence: 99%

“…Gait assessment: Motor performance was analyzed using a pressure-sensor mat as previously described 48,82 . Briefly, animals were trained to walk on a 4.87x0.6m Zeno Electronic Walkway (ZenoMetrics Peekskill, NY) every six months from 24 months to 48 months of age.…”

Section: Pcr Screen and Cellmentioning

confidence: 99%

“…Electroretinogram: Miniswine were tested for retinal function using a flash electroretinogram (ERG) every six months from 24 to 48 months of age as previously described 48 . Briefly, animals were anesthetized with 14 mg/kg ketamine (intramuscular) with anesthesia maintained with 1-2% isoflurane.…”

Section: Pcr Screen and Cellmentioning

confidence: 99%

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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: Pcr Screen and Cellmentioning

confidence: 99%

Section: Cln3 δEx7/8 Miniswine Present With Limited Cognitive Dysfunc...mentioning

confidence: 99%

Section: Pcr Screen and Cellmentioning

confidence: 99%

Section: Pcr Screen and Cellmentioning

confidence: 99%

Section: Pcr Screen and Cellmentioning

confidence: 99%

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A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

Swier

White

Johnson

et al. 2022

Preprint

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Magnetic resonance brain volumetry biomarkers of CLN2 Batten disease identified with miniswine model

Knoernschild

Johnson

Schroeder

et al. 2023

Sci Rep

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Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease (Batten disease) is a rare pediatric disease, with symptom development leading to clinical diagnosis. Early diagnosis and effective tracking of disease progression are required for treatment. We hypothesize that brain volumetry is valuable in identifying CLN2 disease at an early stage and tracking disease progression in a genetically modified miniswine model. CLN2R208X/R208X miniswine and wild type controls were evaluated at 12- and 17-months of age, correlating to early and late stages of disease progression. Magnetic resonance imaging (MRI) T1- and T2-weighted data were acquired. Total intercranial, gray matter, cerebrospinal fluid, white matter, caudate, putamen, and ventricle volumes were calculated and expressed as proportions of the intracranial volume. The brain regions were compared between timepoints and cohorts using Gardner-Altman plots, mean differences, and confidence intervals. At an early stage of disease, the total intracranial volume (− 9.06 cm3), gray matter (− 4.37% 95 CI − 7.41; − 1.83), caudate (− 0.16%, 95 CI − 0.24; − 0.08) and putamen (− 0.11% 95 CI − 0.23; − 0.02) were all notably smaller in CLN2R208X/R208X miniswines versus WT, while cerebrospinal fluid was larger (+ 3.42%, 95 CI 2.54; 6.18). As the disease progressed to a later stage, the difference between the gray matter (− 8.27%, 95 CI − 10.1; − 5.56) and cerebrospinal fluid (+ 6.88%, 95 CI 4.31; 8.51) continued to become more pronounced, while others remained stable. MRI brain volumetry in this miniswine model of CLN2 disease is sensitive to early disease detection and longitudinal change monitoring, providing a valuable tool for pre-clinical treatment development and evaluation.

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GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

Takahashi,

Rensing,

Eultgen

et al. 2024

Preprint

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GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given thatCln2R207X/R207Xmice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related. To address this hypothesis, we first generated an inducible transgenic mouse expressing lysosomal membrane-tethered TPP1 (TPP1LAMP1) on theCln2R207X/R207Xgenetic background to study the cell-autonomous effects of cell-type-specific TPP1 deficiency. We crossed the TPP1LAMP1 mice withVgat-Cremice to introduce interneuron-specific TPP1 deficiency.Vgat-Cre; TPP1LAMP1 mice displayed storage material accumulation in several interneuron populations both in cortex and striatum, and increased susceptibility to die after PTZ-induced seizures. Secondly, to test the role of GABAergic interneuron activity in seizure progression, we selectively activated these cells inCln2R207X/R207Xmice using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) inVgat-Cre: Cln2R207X/R207Xmice. EEG monitoring revealed that DREADD-mediated activation of interneurons via chronic deschloroclozapine administration accelerated the onset of spontaneous seizures and seizure-associated death inVgat-Cre: Cln2R207X/R207Xmice, suggesting that modulating interneuron activity can exert influence over epileptiform abnormalities in CLN2 disease. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.

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A Novel Porcine Model of CLN2 Batten Disease that Recapitulates Patient Phenotypes

Cited by 9 publications

References 66 publications

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

Magnetic resonance brain volumetry biomarkers of CLN2 Batten disease identified with miniswine model

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

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