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

Takahashi, Keigo; Eultgen, Elizabeth M.; Wang, Sophie H.; Rensing, Nicholas; Nelvagal, Hemanth R.; Dearborn, Joshua T.; Danos, Olivier; Buss, Nicholas; Sands, Mark S.; Wong, Michael L.; Cooper, Jonathan D.

doi:10.1172/jci165908

Cited by 6 publications

(22 citation statements)

References 68 publications

(130 reference statements)

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“…Here, Takahashi and colleagues report a new mouse model carrying a common gene mutation found in patients with CLN2, Cln2 R207X . 4 First, to assess for behavioral phenotypes, Cln2 R207X mice and wildtype (WT) littermates were implanted with EEG electrodes and longitudinal EEG data collected. Nine of 10 Cln2 R207X mice displayed spontaneous seizures between 14 and 19 weeks.…”

Section: Commentarymentioning

confidence: 99%

Revoking the Seize Order: Preventing Spontaneous Seizures With AAV in a CLN2 Mouse Model

Buchanan

2023

Epilepsy Curr

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Section: Commentarymentioning

confidence: 99%

Revoking the Seize Order: Preventing Spontaneous Seizures With AAV in a CLN2 Mouse Model

Buchanan

2023

Epilepsy Curr

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“…Forty µm coronal forebrain sections were cut using a Microm HM430 freezing microtome (Microm International) equipped with a Physitemp BFS-40MPA freezing stage (Physitemp, Clifton, NJ). Sections were collected into 96 well plates containing cryoprotectant solution, as described 27,30,31 .…”

Section: Brain Processing and Immunostainingmentioning

confidence: 99%

“…A one-in-six series of coronal forebrain sections from each mouse were stained on slides using a modified immunofluorescence protocol 30,31 employing TrueBlack and stained with GFAP, CD68 and SCMAS antibodies (Table 1). To quantify AFSM accumulation and glial activation (GFAP+ astrocytes, CD68+ microglia), thresholding image analysis was performed as described 30,31 using slide-scanned images at 10x magnification (Zeiss Axio Scan Z1). Contours of appropriate anatomical regions were drawn and images analyzed using Image-Pro Premier (Media Cybernetics) and thresholds selected for foreground immunoreactivity above background.…”

Section: Brain Processing and Immunostainingmentioning

confidence: 99%

“…Symptoms appear in the first (CLN1 disease) or second year of life (CLN2 disease), progress rapidly, and cause premature death. Mice modeling CLN1 (Ppt1 -/-) or CLN2 disease (Tpp1 R207X/R207X ) display behavioral, pathological, and molecular phenotypes that recapitulate human disease manifestations [26][27][28][29][30] . Because CNS neurodegeneration is profound, prior treatment attempts mainly targeted the CNS disease manifestations via intracerebroventricular enzyme replacement 31 or CNS-directed gene therapy 27,30 .…”

Section: Introductionmentioning

confidence: 99%

“…Mice modeling CLN1 (Ppt1 -/-) or CLN2 disease (Tpp1 R207X/R207X ) display behavioral, pathological, and molecular phenotypes that recapitulate human disease manifestations [26][27][28][29][30] . Because CNS neurodegeneration is profound, prior treatment attempts mainly targeted the CNS disease manifestations via intracerebroventricular enzyme replacement 31 or CNS-directed gene therapy 27,30 . Because treated mice still die prematurely, we hypothesized that extra-CNS disease manifestations may also need treatment.…”

Section: Introductionmentioning

confidence: 99%

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Bowel dysmotility and enteric neuron degeneration in lysosomal storage disease mice is prevented by gene therapy

Jansen

Williams

Wang

et al. 2023

Preprint

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Background and aims: Children with neurodegenerative disease often have debilitating gastrointestinal (GI) symptoms that may be due at least in part to underappreciated involvement of neurons in the enteric nervous system (ENS), the master regulator of bowel function. Methods: We investigated bowel motility in mouse models of CLN1 and CLN2 disease, neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 (PPT1) and tripeptidyl peptidase-1 (TPP1), respectively. We then explored the integrity of ENS anatomy in immunostained bowel wholemount preparations from these mice. Lastly, we administered adeno-associated viral gene therapy to neonatal mice and determined if this would prevent these newly identified bowel phenotypes. Results: Mouse models of CLN1 and CLN2 disease both displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Neonatal administration of adeno-associated virus-mediated gene therapy prevented bowel transit defects and the loss of many ENS neurons. Conclusions: We show that two neurodegenerative lysosomal storage diseases cause profound and progressive damage to the mouse enteric nervous system and impair bowel motility. We also provide proof-of-principle evidence that gene therapy can prevent enteric nervous system disease. This study may have general therapeutic implications for many inherited neurodegenerative disorders.

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Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model

He,

Cao,

et al. 2024

Annals of Neurology

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ObjectiveThe aim of this study was to explore the pathogenesis of CLCN6‐related disease and to assess whether its Cl−/H+‐exchange activity is crucial for the biological role of ClC‐6.MethodsWe performed whole‐exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock‐in mouse model of a patient variant (p.E200A) and compared it with a Clcn6−/− mouse model. Additional functional tests were performed with heterologous expression of mutant ClC‐6.ResultsWe identified a de novo heterozygous p.E200A variant in the proband. Expression of disease‐causing ClC‐6E200A or ClC‐6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport‐deficient ClC‐6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC‐6E200A, but not loss of ClC‐6 in Clcn6−/− mice, increased lysosomal biogenesis by suppressing mTORC1‐TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6−/− brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss.InterpretationCLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl− transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. ANN NEUROL 2024

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

Cited by 6 publications

References 68 publications

Revoking the Seize Order: Preventing Spontaneous Seizures With AAV in a CLN2 Mouse Model

Revoking the Seize Order: Preventing Spontaneous Seizures With AAV in a CLN2 Mouse Model

Bowel dysmotility and enteric neuron degeneration in lysosomal storage disease mice is prevented by gene therapy

Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model

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