TY - JOUR
T1 - Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model
AU - Takahashi, Keigo
AU - Eultgen, Elizabeth M.
AU - Wang, Sophie H.
AU - Rensing, Nicholas R.
AU - Nelvagal, Hemanth R.
AU - Dearborn, Joshua T.
AU - Danos, Olivier
AU - Buss, Nicholas
AU - Sands, Mark S.
AU - Wong, Michael
AU - Cooper, Jonathan D.
N1 - Funding Information:
We thank Jill M. Weimer and David A. Pearce (Sanford Research) for supplying the Cln2R207X mice that were used in this study. We also thank the Washington University Center for Cellular Imaging supported by Washington University School of Medicine, the Children’s Discovery Institute of Washington University in St. Louis and St. Louis Children’s Hospital, and the Foundation for Barnes-Jewish Hospital in St. Louis, for providing a Zeiss Axio Scan.Z1 fluorescence slide scanner; the Molecular Microbiology Imaging Facility at Washington University School of Medicine, for providing a Zeiss LSM880 confocal laser scanning microscope with Airyscan; Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, for the use of the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University in St. Louis, which provided the Luminex multiplex service; and the Washington University Metabolomics Facility at Washington University School of Medicine, for providing the LC-MS/MS service. We acknowledge Diane Bender, Washington University in St. Louis, for assistance with cytokine profile analysis and Xuntian Jiang, Washington University in St. Louis, for assistance with neurotransmitter analysis. We also acknowledge Alison Barnwell for constructive comments on the manuscript. This work was supported by Noah’s Hope/ Hope for Bridget; REGENXBIO Inc. to JDC; McDonnell Center for Systems Neuroscience Small Grant award, Washington University in St. Louis, to JDC; institutional support from the Department of Pediatrics, Washington University School of Medicine, to JDC; NIH P50 HD103525 to the Washington University in St. Louis Intellectual and Developmental Disabilities Research Center; McDonnell International Scholars Academy award, Washington University in St. Louis, to KT; and NIH National Institute of Neurological Disorders and Stroke grant R01 NS100779 to MSS.
Publisher Copyright:
© 2023, Takahashi et al.
PY - 2023/6/15
Y1 - 2023/6/15
N2 - 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 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, 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 Cln2R207X 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.
AB - 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 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, 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 Cln2R207X 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.
UR - http://www.scopus.com/inward/record.url?scp=85163904157&partnerID=8YFLogxK
U2 - 10.1172/JCI165908
DO - 10.1172/JCI165908
M3 - Article
C2 - 37104037
AN - SCOPUS:85163904157
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
M1 - e165908
ER -