Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus. Sadegh, C., Xu, H., Sutin, J., Fatou, B., Gupta, S., Pragana, A., Taylor, M., Kalugin, P. N., Zawadzki, M. E., Alturkistani, O., Shipley, F. B., Dani, N., Fame, R. M., Wurie, Z., Talati, P., Schleicher, R. L., Klein, E. M., Zhang, Y., Holtzman, M. J., Moore, C. I., Lin, P., Patel, A. B., Warf, B. C., Kimberly, W. T., Steen, H., Andermann, M. L., & Lehtinen, M. K. Neuron, 111(10):1591–1608.e4, May, 2023. Place: United Statesdoi abstract bibtex Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K(+)] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K(+)] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.
@article{sadegh_choroid_2023,
title = {Choroid plexus-targeted {NKCC1} overexpression to treat post-hemorrhagic hydrocephalus.},
volume = {111},
copyright = {Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.},
issn = {1097-4199 0896-6273},
doi = {10.1016/j.neuron.2023.02.020},
abstract = {Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K(+)] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K(+)] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.},
language = {eng},
number = {10},
journal = {Neuron},
author = {Sadegh, Cameron and Xu, Huixin and Sutin, Jason and Fatou, Benoit and Gupta, Suhasini and Pragana, Aja and Taylor, Milo and Kalugin, Peter N. and Zawadzki, Miriam E. and Alturkistani, Osama and Shipley, Frederick B. and Dani, Neil and Fame, Ryann M. and Wurie, Zainab and Talati, Pratik and Schleicher, Riana L. and Klein, Eric M. and Zhang, Yong and Holtzman, Michael J. and Moore, Christopher I. and Lin, Pei-Yi and Patel, Aman B. and Warf, Benjamin C. and Kimberly, W. Taylor and Steen, Hanno and Andermann, Mark L. and Lehtinen, Maria K.},
month = may,
year = {2023},
pmid = {36893755},
pmcid = {PMC10198810},
note = {Place: United States},
keywords = {*Choroid Plexus, *Hydrocephalus/therapy, adeno-associated virus, Cerebral Hemorrhage/complications/therapy, Cerebrospinal fluid, choroid plexus, epithelial cells, gene therapy, Humans, hydrocephalus, intraventricular hemorrhage, NKCC1, ventricles},
pages = {1591--1608.e4},
}
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All rights reserved.","issn":"1097-4199 0896-6273","doi":"10.1016/j.neuron.2023.02.020","abstract":"Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K(+)] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. 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