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Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.
Sadegh, Cameron; Xu, Huixin; Sutin, Jason; Fatou, Benoit; Gupta, Suhasini; Pragana, Aja; Taylor, Milo; Kalugin, Peter N; Zawadzki, Miriam E; Alturkistani, Osama; Shipley, Frederick B; Dani, Neil; Fame, Ryann M; Wurie, Zainab; Talati, Pratik; Schleicher, Riana L; Klein, Eric M; Zhang, Yong; Holtzman, Michael J; Moore, Christopher I; Lin, Pei-Yi; Patel, Aman B; Warf, Benjamin C; Kimberly, W Taylor; Steen, Hanno; Andermann, Mark L; Lehtinen, Maria K.
Affiliation
  • Sadegh C; 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.
  • Xu H; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Sutin J; Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Fatou B; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Gupta S; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Pragana A; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Taylor M; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard College, Harvard University, Cambridge, MA 02138, USA.
  • Kalugin PN; 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.
  • Zawadzki ME; 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.
  • Alturkistani O; Cellular Imaging Core, Boston Children's Hospital, Boston, MA 02115, USA.
  • Shipley FB; 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.
  • Dani N; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Fame RM; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Wurie Z; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Talati P; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Schleicher RL; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Klein EM; Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA.
  • Zhang Y; Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO, 63110, USA.
  • Holtzman MJ; Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO, 63110, USA.
  • Moore CI; Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA.
  • Lin PY; Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Patel AB; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Warf BC; Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA.
  • Kimberly WT; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Steen H; 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.
  • Andermann ML; 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.
  • Lehtinen MK; 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 Prog
Neuron ; 111(10): 1591-1608.e4, 2023 05 17.
Article in En | MEDLINE | ID: mdl-36893755
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Choroid Plexus / Hydrocephalus Limits: Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2023 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Choroid Plexus / Hydrocephalus Limits: Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2023 Type: Article Affiliation country: United States