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ResearchIn-Press PreviewNeuroscienceTherapeutics Open Access | 10.1172/JCI165908

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

Keigo Takahashi,1 Elizabeth M. Eultgen,1 Sophie H. Wang,1 Nicholas R. Rensing,2 Hemanth R. Nelvagal,1 Joshua T. Dearborn,3 Olivier Danos,4 Nicholas Buss,4 Mark S. Sands,3 Michael Wong,2 and Jonathan D. Cooper1

1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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1Department of Pediatrics, Washington University in St Louis School of Medicine, St. Louis, United States of America

2Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, United States of America

3Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, United States of America

4Research and Development, REGENXBIO, Inc., Rockville, United States of America

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Published April 27, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI165908.
Copyright © 2023, Takahashi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 27, 2023 - Version history
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Abstract

Although a disease-modifying therapy for CLN2 disease now exists, a 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 Cln2R207X 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 and quantifiable disease-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 differs markedly from the staging seen in mouse models of other forms of NCL. Neonatal administration of adeno-associated virus 9 (AAV9)-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the lifespan of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging pre-clinical efficacy of therapeutic interventions for CLN2 disease.

Graphical Abstract
graphical abstract
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View Video 1: EEG and video of mouse seizure

Version history
  • Version 1 (April 27, 2023): In-Press Preview
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