The Role of the Coagulation Pathway at the Synapse in Prion Diseases

Creutzfeldt-Jakob Syndrome Clinical Trial

Official title:

The Role of the Coagulation Pathway at the Synapse in Prion Diseases

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02480725
• Other study ID #: 1702-14 SMC
• Status: Not yet recruiting
• Phase: N/A
• First received: June 22, 2015
• Last updated: June 23, 2015
• Start date: June 2015
• Est. completion date: July 2025

Study information

• Verified date: June 2015
• Source: Sheba Medical Center
• Contact: Oren Cohen, Dr. (MD)
• Phone: +972-52-6667584
• Email: coheno[@]asaf.health.gov.il
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Observational

Clinical Trial Summary

The study hypothesis is that that the deleterious effect of prions on the brain may be mediated (at least partially) by activation of serine proteases involved in the coagulation system. If this is true, then measurement of the activity of the coagulation system may be a marker of disease onset (in at higher risk individuals such as E200K* carriers) and for disease progression or activity in affected individuals. In addition, modulation of the coagulation system activity may be a potential tool for therapeutic intervention.

*E200K- E200K mutation (Glu to Lys substitution) in the prion protein gene

Description:

We plan to collect Cerebrospinal fluid (CSF) samples for thrombin activity assay in order to test whether there is a difference in thrombin activity in the CSF between CJD (Creutzfeldt-Jakob disease) and non-CJD patients. CSF samples will be obtained from two sources 1. Patients with familial or sporadic CJD and control patients with other neurodegenerative disorders (e.g. SDAT**, NPH) that will be evaluated in Sheba Medical Center 2. From our collaborating group of Prof. Zerr in the German Prion Referral Center at the University of Gottingen which has a collection of thousands of CSF samples from patients with familial and sporadic CJD as well as ideal controls with other degenerative brain disease.

The study has 2 sections:

1. Prospective part in which we plan to recruit 25 patients with CJD and 25 patients with other types of dementia from Sheba Medical Center (SMC). Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded).

Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales.

No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study.

2. Retrospective part in which CSF samples from CJD patients and patients with other type of dementia will be shipped to us from our collaborators in Germany ans will be assayed for Thrombin activity. We plan to recruit to this part of the study 100-200 CJD patient CSF samples and a same number of samples from age matched controls.

Thrombin activity (for samples from both parts of the study) will be assayed as follows: CSF sample will be placed in a black 96 well dish (10 per well). Thrombin activity will be measured by a fluorometric assay, quantifying the cleavage of the synthetic peptide substrate Boc-Asp(OBzl)-Pro-Arg-AMC*** (I-1560, Bachem, Switzerland, 13 molar final concentration). Measurements will be performed by the Infinite 2000 microplate reader (Tecan, infinite 200, Switzerland) with excitation and emission filters of 360±35 and 460±35 nm, respectively. CSF testing for thrombin activity will be conducted in Professor Chapman's laboratory in Sheba. This laboratory is actively engaged in research on the role of thrombin and PAR-1 in diseases of the nervous system and is fully equipped to perform the biochemical and protein levels experiments.

The assay has the potential for commercialization as a diagnostic test for CJD. In addition, there is the potential to develop therapeutic agents targeting excessive thrombin activation.

**SDAT=Senile Dementia of Alzheimer Type

***AMC= Amino Methyl Coumarin

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: July 2025
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 35 Years to 90 Years

Eligibility

Inclusion Criteria:

• Patient undergoing lumbar puncture test as part of the investigation of cognitive decline.

Exclusion Criteria:

• Patients on anticoagulation or those who have contraindication for undergoing lumbar puncture.

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Creutzfeldt-Jakob Syndrome
• Prion Diseases

Intervention

Procedure:
• collect CSF (Cerebrospinal fluid) sample
collecting CSF samples for thrombin activity assay

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Sheba Medical Center	Prof. Zerr , Prion Referral Center , University of Gottingen, Germany

References & Publications (29)

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Beilin O, Gurwitz D, Korczyn AD, Chapman J. Quantitative measurements of mouse brain thrombin-like and thrombin inhibition activities. Neuroreport. 2001 Aug 8;12(11):2347-51. — View Citation

Beilin O, Karussis DM, Korczyn AD, Gurwitz D, Aronovich R, Hantai D, Grigoriadis N, Mizrachi-Kol R, Chapman J. Increased thrombin inhibition in experimental autoimmune encephalomyelitis. J Neurosci Res. 2005 Feb 1;79(3):351-9. — View Citation

Beilin O, Karussis DM, Korczyn AD, Gurwitz D, Aronovich R, Mizrachi-Kol R, Chapman J. Increased KPI containing amyloid precursor protein in experimental autoimmune encephalomyelitis brains. Neuroreport. 2007 Apr 16;18(6):581-4. — View Citation

Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C. Mice devoid of PrP are resistant to scrapie. Cell. 1993 Jul 2;73(7):1339-47. — View Citation

Bushi D, Chapman J, Katzav A, Shavit-Stein E, Molshatzki N, Maggio N, Tanne D. Quantitative detection of thrombin activity in an ischemic stroke model. J Mol Neurosci. 2013 Nov;51(3):844-50. doi: 10.1007/s12031-013-0072-y. Epub 2013 Jul 31. — View Citation

Chapman J. Coagulation in inflammatory diseases of the central nervous system. Semin Thromb Hemost. 2013 Nov;39(8):876-80. doi: 10.1055/s-0033-1357482. Epub 2013 Oct 9. Review. — View Citation

Cohen OS, Prohovnik I, Korczyn AD, Ephraty L, Nitsan Z, Tsabari R, Appel S, Rosenmann H, Kahana E, Chapman J. The Creutzfeldt-Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression. Acta Neurol Scand. 2011 Dec;124(6):368-74. doi: 10.1111/j.1600-0404.2011.01489.x. Epub 2011 Feb 8. — View Citation

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Deininger MH, Trautmann K, Magdolen V, Luther T, Schluesener HJ, Meyermann R. Cortical neurons of Creutzfeldt-Jakob disease patients express the urokinase-type plasminogen activator receptor. Neurosci Lett. 2002 May 10;324(1):80-2. — View Citation

Ellis V, Daniels M, Misra R, Brown DR. Plasminogen activation is stimulated by prion protein and regulated in a copper-dependent manner. Biochemistry. 2002 Jun 4;41(22):6891-6. — View Citation

Epple G, Schleuning WD, Kettelgerdes G, Kottgen E, Gessner R, Praus M. Prion protein stimulates tissue-type plasminogen activator-mediated plasmin generation via a lysine-binding site on kringle 2. J Thromb Haemost. 2004 Jun;2(6):962-8. — View Citation

Fischer MB, Roeckl C, Parizek P, Schwarz HP, Aguzzi A. Binding of disease-associated prion protein to plasminogen. Nature. 2000 Nov 23;408(6811):479-83. — View Citation

Harris DA, Lele P, Snider WD. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4309-13. — View Citation

Itzekson Z, Maggio N, Milman A, Shavit E, Pick CG, Chapman J. Reversal of trauma-induced amnesia in mice by a thrombin receptor antagonist. J Mol Neurosci. 2014 May;53(1):87-95. doi: 10.1007/s12031-013-0200-8. Epub 2013 Dec 19. — View Citation

Llorens F, Zafar S, Ansoleaga B, Shafiq M, Blanco R, Carmona M, Grau-Rivera O, Nos C, Gelpí E, Del Río JA, Zerr I, Ferrer I. Subtype and regional regulation of prion biomarkers in sporadic Creutzfeldt-Jakob disease. Neuropathol Appl Neurobiol. 2015 Aug;41(5):631-45. doi: 10.1111/nan.12175. Epub 2015 Apr 30. — View Citation

Maggio N, Cavaliere C, Papa M, Blatt I, Chapman J, Segal M. Thrombin regulation of synaptic transmission: implications for seizure onset. Neurobiol Dis. 2013 Feb;50:171-8. doi: 10.1016/j.nbd.2012.10.017. Epub 2012 Oct 25. — View Citation

Maggio N, Itsekson Z, Dominissini D, Blatt I, Amariglio N, Rechavi G, Tanne D, Chapman J. Thrombin regulation of synaptic plasticity: implications for physiology and pathology. Exp Neurol. 2013 Sep;247:595-604. doi: 10.1016/j.expneurol.2013.02.011. Epub 2013 Feb 27. — View Citation

Maggio N, Shavit E, Chapman J, Segal M. Thrombin induces long-term potentiation of reactivity to afferent stimulation and facilitates epileptic seizures in rat hippocampal slices: toward understanding the functional consequences of cerebrovascular insults. J Neurosci. 2008 Jan 16;28(3):732-6. doi: 10.1523/JNEUROSCI.3665-07.2008. — View Citation

Padilla D, Béringue V, Espinosa JC, Andreoletti O, Jaumain E, Reine F, Herzog L, Gutierrez-Adan A, Pintado B, Laude H, Torres JM. Sheep and goat BSE propagate more efficiently than cattle BSE in human PrP transgenic mice. PLoS Pathog. 2011 Mar;7(3):e1001319. doi: 10.1371/journal.ppat.1001319. Epub 2011 Mar 17. — View Citation

Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962-6. — View Citation

Praus M, Kettelgerdes G, Baier M, Holzhütter HG, Jungblut PR, Maissen M, Epple G, Schleuning WD, Köttgen E, Aguzzi A, Gessner R. Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110. Thromb Haemost. 2003 May;89(5):812-9. — View Citation

Prusiner SB. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515-22. Review. — View Citation

Shavit E, Beilin O, Korczyn AD, Sylantiev C, Aronovich R, Drory VE, Gurwitz D, Horresh I, Bar-Shavit R, Peles E, Chapman J. Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block. Brain. 2008 Apr;131(Pt 4):1113-22. doi: 10.1093/brain/awn005. Epub 2008 Feb 25. — View Citation

Shavit E, Michaelson DM, Chapman J. Anatomical localization of protease-activated receptor-1 and protease-mediated neuroglial crosstalk on peri-synaptic astrocytic endfeet. J Neurochem. 2011 Nov;119(3):460-73. doi: 10.1111/j.1471-4159.2011.07436.x. Epub 2011 Sep 23. — View Citation

Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M, Rülicke T, Moser M, Oesch B, McBride PA, Manson JC. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature. 1996 Apr 18;380(6575):639-42. — View Citation

Windl O, Dempster M, Estibeiro P, Lathe R. A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene. 1995 Jul 4;159(2):181-6. — View Citation

Zerr I, Bodemer M, Kaboth U, Kretzschmar H, Oellerich M, Armstrong VW. Plasminogen activities and concentrations in patients with sporadic Creutzfeldt-Jakob disease. Neurosci Lett. 2004 Nov 23;371(2-3):163-6. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Thrombin activity assay		10 years	No