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 Moore; Pei-Yi Lin; Aman B Patel; Benjamin C Warf; W Taylor Kimberly; Hanno Steen; Mark L Andermann; Maria K Lehtinen

doi:10.1016/j.neuron.2023.02.020

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

Neuron. 2023 May 17;111(10):1591-1608.e4. doi: 10.1016/j.neuron.2023.02.020. Epub 2023 Mar 8.

Authors

Cameron Sadegh¹, Huixin Xu², Jason Sutin³, Benoit Fatou², Suhasini Gupta², Aja Pragana², Milo Taylor⁴, Peter N Kalugin⁵, Miriam E Zawadzki⁶, Osama Alturkistani⁷, Frederick B Shipley⁸, Neil Dani², Ryann M Fame², Zainab Wurie², Pratik Talati⁹, Riana L Schleicher¹⁰, Eric M Klein¹¹, Yong Zhang¹², Michael J Holtzman¹², Christopher I Moore¹¹, Pei-Yi Lin³, Aman B Patel⁹, Benjamin C Warf¹³, W Taylor Kimberly¹⁰, Hanno Steen¹⁴, Mark L Andermann¹⁵, Maria K Lehtinen¹⁶

Affiliations

¹ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
² Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³ Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard College, Harvard University, Cambridge, MA 02138, USA.
⁵ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
⁷ Cellular Imaging Core, Boston Children's Hospital, Boston, MA 02115, USA.
⁸ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA.
⁹ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹¹ Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA.
¹² Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO, 63110, USA.
¹³ Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁴ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Precision Vaccines Program, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁵ Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹⁶ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA. Electronic address: maria.lehtinen@childrens.harvard.edu.

PMID: 36893755
PMCID: PMC10198810 (available on 2024-05-17)
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.

Keywords: Cerebrospinal fluid; NKCC1; adeno-associated virus; choroid plexus; epithelial cells; gene therapy; hydrocephalus; intraventricular hemorrhage; ventricles.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cerebral Hemorrhage / complications
Cerebral Hemorrhage / therapy
Choroid Plexus*
Humans
Hydrocephalus* / therapy

Abstract

Publication types

MeSH terms

Grants and funding