Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus

Cameron Sadegh, Huixin Xu, Jason Sutin, Benoit Fatou, Suhasini Gupta, Aja Pragana, Milo Taylor, Peter N. Kalugin, Miriam E. Zawadzki, Osama Alturkistani, Frederick B. Shipley, Neil Dani, Ryann M. Fame, Zainab Wurie, Pratik Talati, Riana L. Schleicher, Eric M. Klein, Yong Zhang, Michael J. Holtzman, Christopher I. MoorePei Yi Lin, Aman B. Patel, Benjamin C. Warf, W. Taylor Kimberly, Hanno Steen, Mark L. Andermann, Maria K. Lehtinen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)1591-1608.e4
JournalNeuron
Volume111
Issue number10
DOIs
StatePublished - 17 May 2023
Externally publishedYes

Keywords

  • Cerebrospinal fluid
  • NKCC1
  • adeno-associated virus
  • choroid plexus
  • epithelial cells
  • gene therapy
  • hydrocephalus
  • intraventricular hemorrhage
  • ventricles

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