Dataset Information

Choroid plexus targeted gene therapy for the treatment of post-hemorrhagic hydrocephalus

ABSTRACT: A subset of infants and adults with hemorrhagic stroke and intraventricular hemorrhage (IVH) ultimately develop a life-threatening accumulation of cerebrospinal fluid (CSF), termed post-hemorrhagic hydrocephalus (PHH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. We describe an adeno-associated viral (AAV) gene augmentation approach leveraging the Na-K-Cl cotransporter, NKCC1, to enhance a choroid plexus (ChP) mechanism of CSF surveillance, potassium homeostasis, and water movement to drive decreases in ventricle size in embryonic, neonatal, and adult mouse models of IVH. Intraventricular blood led to increased CSF [K+], triggered cytosolic calcium in ChP epithelial cells, and was followed by NKCC1 activation. ChP-targeted AAV-NKCC1 rapidly reversed blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity, validating the model and treating the most salient clinical features of PHH. NKCC1 is a bi-directional cotransporter, and these data demonstrate that NKCC1 activation triggered a trans-choroidal, NKCC1-dependent CSF ion/water clearance out of the ventricle. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly, indicating that the beneficial effects of NKCC1 augmentation required both elevated CSF [K+] and upstream activation via phosphorylation. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting potential therapeutic benefits. Collectively, these data highlight a novel role for the ChP in rapid compensation for alterations in CSF homeostasis following IVH and demonstrate the utility of targeted gene therapy to mitigate intracranial fluid accumulation following hemorrhage.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma

SUBMITTER: Patrick van Zalm

LAB HEAD: Dr. Hanno Steen

PROVIDER: PXD039738 | Pride | 2024-05-24

REPOSITORIES: Pride

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			Action	DRS
	20190508_MousePlasma_A1.raw	Raw
	20190508_MousePlasma_A2.raw	Raw
	20190508_MousePlasma_A3.raw	Raw
	20190508_MousePlasma_A4.raw	Raw
	20190508_MousePlasma_A5.raw	Raw

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Publications

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

Sadegh Cameron C Xu Huixin H Sutin Jason J Fatou Benoit B Gupta Suhasini S Pragana Aja A Taylor Milo M Kalugin Peter N PN Zawadzki Miriam E ME Alturkistani Osama O Shipley Frederick B FB Dani Neil N Fame Ryann M RM Wurie Zainab Z Talati Pratik P Schleicher Riana L RL Klein Eric M EM Zhang Yong Y Holtzman Michael J MJ Moore Christopher I CI Lin Pei-Yi PY Patel Aman B AB Warf Benjamin C BC Kimberly W Taylor WT Steen Hanno H Andermann Mark L ML Lehtinen Maria K MK

Neuron 20230308 10

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 increase ...[more]

PMID: 36893755

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