Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage

Summary

Hydrocephalus is a serious condition in which fluid builds up inside the brain, often requiring lifelong surgical placement of a shunt to drain excess cerebrospinal fluid (CSF). One of the most common causes of hydrocephalus is bleeding into the brain's fluid spaces after aneurysm rupture, prematurity, or infection. Currently, no medication exists to prevent hydrocephalus from developing after these injuries. The investigators' recent research suggests that hydrocephalus may result not only from blocked fluid pathways but also from harmful inflammation within the brain's ventricular system. The investigators discovered that inflammation activates the choroid plexus, the tissue that produces CSF, causing excessive CSF production and inflammatory injury to the ventricular lining and surrounding brain tissue. The investigators also identified inflammatory biomarkers and extracellular vesicles in human CSF that may enable real-time monitoring of these disease processes. In this project, the investigators will perform a first-in-human pilot study testing whether targeted "intraventricular mTOR inhibition" can reduce ventricular inflammation and prevent hydrocephalus after severe brain hemorrhage. The medication will be delivered via temporary ventricular drains already in place as part of routine clinical care. The investigators will study safety, inflammation, CSF production, brain imaging changes, and whether patients ultimately require permanent shunts. Although this initial study focuses on adults with hemorrhage-related hydrocephalus, our long-term goal is to develop non-surgical therapies that could help children with hydrocephalus caused by prematurity or infection, especially in regions where access to neurosurgical care and shunt surgery is limited.

Timeline

Start

2027-01-01

Primary completion

2027-12-31

Completion

2027-12-31

Publications

• Background Ziai WC, Parry-Jones AR, Thompson CB, Sansing LH, Mullen MT, Murthy SB, Mould A, Nekoovaght-Tak S, Hanley DF. Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage. Biomolecules. 2021 Jul 30;11(8):1123. doi: 10.3390/biom11081123.
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• Background Foerster P, Daclin M, Asm S, Faucourt M, Boletta A, Genovesio A, Spassky N. mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis. Development. 2017 Jan 15;144(2):201-210. doi: 10.1242/dev.138271. Epub 2016 Dec 19.
• Background Kuo LT, Huang AP. The Pathogenesis of Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage. Int J Mol Sci. 2021 May 10;22(9):5050. doi: 10.3390/ijms22095050.
• Background Holste KG, Xia F, Ye F, Keep RF, Xi G. Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review. Fluids Barriers CNS. 2022 Apr 1;19(1):28. doi: 10.1186/s12987-022-00324-0.
• Background Lolansen SD, Rostgaard N, Barbuskaite D, Capion T, Olsen MH, Norager NH, Vilhardt F, Andreassen SN, Toft-Bertelsen TL, Ye F, Juhler M, Keep RF, MacAulay N. Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters. Fluids Barriers CNS. 2022 Aug 10;19(1):62. doi: 10.1186/s12987-022-00360-w.
• Background Sadegh C, Xu H, Sutin J, Fatou B, Gupta S, Pragana A, Taylor M, Kalugin PN, Zawadzki ME, Alturkistani O, Shipley FB, Dani N, Fame RM, Wurie Z, Talati P, Schleicher RL, Klein EM, Zhang Y, Holtzman MJ, Moore CI, Lin PY, Patel AB, Warf BC, Kimberly WT, Steen H, Andermann ML, Lehtinen MK. 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.
• Background Strahle J, Garton HJ, Maher CO, Muraszko KM, Keep RF, Xi G. Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res. 2012 Jul;3(Suppl 1):25-38. doi: 10.1007/s12975-012-0182-9.
• Background Zhang J, Bhuiyan MIH, Zhang T, Karimy JK, Wu Z, Fiesler VM, Zhang J, Huang H, Hasan MN, Skrzypiec AE, Mucha M, Duran D, Huang W, Pawlak R, Foley LM, Hitchens TK, Minnigh MB, Poloyac SM, Alper SL, Molyneaux BJ, Trevelyan AJ, Kahle KT, Sun D, Deng X. Modulation of brain cation-Cl- cotransport via the SPAK kinase inhibitor ZT-1a. Nat Commun. 2020 Jan 7;11(1):78. doi: 10.1038/s41467-019-13851-6.
• Background Mukumbya B, Adeleye AO, Siddig AHE, Mbilinyi RH, Woo J, Agwu C, Min Htike WY, Mustapha MJ, Dada OE, Ramos S, Adereti C, Ssembatya JM, Petitt Z, Still MEH, Blackwood ER, von Isenburg M, Haglund MM, Ukachukwu AK. Outcomes of ventriculoperitoneal shunt surgery for hydrocephalus in children in low- and middle-income countries: a systematic review. J Neurosurg Pediatr. 2025 Aug 15;36(5):570-581. doi: 10.3171/2025.4.PEDS24598. Print 2025 Nov 1.
• Background Vinchon M, Rekate H, Kulkarni AV. Pediatric hydrocephalus outcomes: a review. Fluids Barriers CNS. 2012 Aug 27;9(1):18. doi: 10.1186/2045-8118-9-18.
• Background Karimy JK, Reeves BC, Damisah E, Duy PQ, Antwi P, David W, Wang K, Schiff SJ, Limbrick DD Jr, Alper SL, Warf BC, Nedergaard M, Simard JM, Kahle KT. Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets. Nat Rev Neurol. 2020 May;16(5):285-296. doi: 10.1038/s41582-020-0321-y. Epub 2020 Mar 9.
• Background Kahle KT, Klinge PM, Koschnitzky JE, Kulkarni AV, MacAulay N, Robinson S, Schiff SJ, Strahle JM. Paediatric hydrocephalus. Nat Rev Dis Primers. 2024 May 16;10(1):35. doi: 10.1038/s41572-024-00519-9.
• Background Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med. 2017 Aug;23(8):997-1003. doi: 10.1038/nm.4361. Epub 2017 Jul 10.
• Background Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS, Marlier A, Allington G, Greenberg ABW, DeSpenza T Jr, Singh AK, Zeng X, Mekbib KY, Kundishora AJ, Nelson-Williams C, Hao LT, Zhang J, Lam TT, Wilson R, Butler WE, Diluna ML, Feinberg P, Schafer DP, Movahedi K, Tannenbaum A, Koundal S, Chen X, Benveniste H, Limbrick DD Jr, Schiff SJ, Carter BS, Gunel M, Simard JM, Lifton RP, Alper SL, Delpire E, Kahle KT. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell. 2023 Feb 16;186(4):764-785.e21. doi: 10.1016/j.cell.2023.01.017.

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Indications