Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage (VENTURE-PHH)
VENTURE-PHH: Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage
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.
Tutkimuksen yleiskatsaus
Tila
Interventio / Hoito
Yksityiskohtainen kuvaus
Hydrocephalus remains one of the most common neurosurgical disorders worldwide and is currently treated primarily with surgical diversion of CSF using implanted shunts. Although lifesaving, shunts frequently fail, require repeated surgeries, and do not directly address the underlying biological injury occurring within the brain and ventricular system. Many patients continue to experience lifelong neurological complications despite surgical treatment. This project has the potential to shift hydrocephalus treatment from surgical management toward mechanism-guided prevention. By targeting ventricular inflammation early after hemorrhage, the investigators aim to prevent the biological processes that drive excessive CSF accumulation, ventricular remodeling, ependymal injury, and chronic inflammatory scarring. Successful completion of this work could establish the first pharmacologic strategy designed to prevent hydrocephalus rather than simply treat its consequences after it develops.
The impact of this approach could extend far beyond adult hemorrhage-related hydrocephalus. Similar inflammatory mechanisms are believed to contribute to hydrocephalus caused by prematurity, infection, and traumatic brain injury. In particular, post-infectious and neonatal hydrocephalus remain major causes of childhood disability and death in many low-resource regions where access to shunt surgery and specialized neurosurgical care is limited. A scalable medical therapy capable of reducing hydrocephalus progression could therefore have a substantial global health impact. In addition, this project establishes a new translational framework for studying the ventricular neuroimmune microenvironment through real-time analyses of CSF biomarkers and extracellular vesicles. These tools may ultimately enable personalized monitoring and targeted treatment approaches for multiple forms of hydrocephalus and related neuroinflammatory disorders.
Opintotyyppi
Ilmoittautuminen (Arvioitu)
Vaihe
- Vaihe 2
- Vaihe 1
Yhteystiedot ja paikat
Opiskeluyhteys
- Nimi: Kristopher Kahle, M.D., Ph.D.
- Puhelinnumero: 14143057506
- Sähköposti: kahle.kristopher@mgh.harvard.edu
Tutki yhteystietojen varmuuskopiointi
- Nimi: Carla Fortes, BA
- Puhelinnumero: 16175489679
- Sähköposti: CFORTES@MGH.HARVARD.EDU
Opiskelupaikat
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Massachusetts
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Boston, Massachusetts, Yhdysvallat, 02114
- Massachusetts General Hospital Lunder 4 OR for adult surgeries
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Ottaa yhteyttä:
- Carla Fortes, BA
- Puhelinnumero: 16175489679
- Sähköposti: CFORTES@MGH.HARVARD.EDU
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Päätutkija:
- Kristopher Kahle, MD, PhD
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Osallistumiskriteerit
Kelpoisuusvaatimukset
Opintokelpoiset iät
- Aikuinen
- Vanhempi Aikuinen
Hyväksyy terveitä vapaaehtoisia
Kuvaus
Inclusion Criteria:
- Age ≥18 years
- Diagnosis of aneurysmal subarachnoid hemorrhage (aSAH)
- Hunt Hess grade IV to V
- Radiographic evidence of intraventricular hemorrhage (IVH)
- Clinically indicated EVD placement as part of standard neurocritical care
- Ability to enroll during the acute post-hemorrhagic inflammatory period, ideally within 24 hours of EVD placement
Exclusion Criteria:
- Pre-existing ventriculoperitoneal shunt dependence
- Severe baseline immunosuppression
- Uncontrolled systemic infection unrelated to hemorrhage
- Pregnancy
- Anticipated withdrawal of life-sustaining therapy within 24 hours
- Inability to safely receive investigational ventricular therapy
Opintosuunnitelma
Miten tutkimus on suunniteltu?
Suunnittelun yksityiskohdat
- Ensisijainen käyttötarkoitus: Hoito
- Jako: Ei käytössä
- Inventiomalli: Peräkkäinen tehtävä
- Naamiointi: Ei mitään (avoin tarra)
Aseet ja interventiot
Osallistujaryhmä / Arm |
Interventio / Hoito |
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Kokeellinen: Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage
The investigators will conduct a prospective, single-center, phase Ib/IIa, biomarker-rich translational pilot study evaluating intraventricular mTOR inhibition in adults with severe aneurysmal subarachnoid hemorrhage (aSAH) who require external ventricular drain (EVD) placement as part of routine neurocritical care management.
The central objective of the study is to determine whether early modulation of ventricular immune-secretory signaling is feasible, biologically active, and capable of altering inflammatory CSF physiology and ventricular remodeling following hemorrhage.
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Ventricular delivery
Muut nimet:
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Mitä tutkimuksessa mitataan?
Ensisijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
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CSF rapamycin concentration
Aikaikkuna: Baseline, 7 days, and 14 days after rapamycin treatment.
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The concentration of rapamycin will be measured in serial CSF samples collected longitudinally through EVDs.
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Baseline, 7 days, and 14 days after rapamycin treatment.
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Toissijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
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Change in Evans Index
Aikaikkuna: Baseline, 7 days, and 14 days after rapamycin treatment.
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Longitudinal change in the Evans index measured on serial brain MRI to assess ventricular enlargement and progression toward hydrocephalus.
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Baseline, 7 days, and 14 days after rapamycin treatment.
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Change in Frontal-Occipital Horn Ratio (FOHR)
Aikaikkuna: Baseline, 7 days, and 14 days after rapamycin treatment.
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Longitudinal change in the frontal-occipital horn ratio measured on serial brain MRI as a marker of ventricular size.
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Baseline, 7 days, and 14 days after rapamycin treatment.
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Change in Third Ventricular Width
Aikaikkuna: Baseline, 7 days, and 14 days after rapamycin treatment.
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Longitudinal change in third ventricular width measured on serial brain MRI to evaluate ventricular remodeling.
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Baseline, 7 days, and 14 days after rapamycin treatment.
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Change in Ventricular Volume
Aikaikkuna: Baseline, 7 days, and 14 days after rapamycin treatment.
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Change in total ventricular volume quantified by MRI-based volumetric segmentation, when imaging quality permits, to explore treatment effects on ventricular remodeling.
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Baseline, 7 days, and 14 days after rapamycin treatment.
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Yhteistyökumppanit ja tutkijat
Sponsori
Tutkijat
- Päätutkija: Kristopher Kahle, MD, PhD, Massachusetts General Hospital
Julkaisuja ja hyödyllisiä linkkejä
Yleiset julkaisut
- 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.
- 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.
- Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet. 2001;40(8):573-85. doi: 10.2165/00003088-200140080-00002.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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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Opintojen valmistuminen (Arvioitu)
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Muut tutkimustunnusnumerot
- 2026P001357
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