Expression Profile of ERK5 and PKM2 Kinases in Neuroinflammatory Diseases.

NCT04674163 | Withdrawn

• 1 other identifier: CHRO-2018-07
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Demyelinating diseases represent a broad spectrum of disorders and are induced by excessive inflammation most often triggered by an autoimmune mechanism. Some of these pathologies are chronic and affect the central nervous system such as multiple sclerosis (MS), others are monophasic and target the peripheral nervous system such as Guillain Barré syndrome (GBS). In neuroinflammatory pathologies, the excessive response of the pro-inflammatory Th1 and Th17 lymphocyte lines and the insufficient response of regulatory T lymphocytes (Treg) cause excessive inflammation which is deleterious to the nervous tissue. The regulation of these signaling pathways involves key proteins such as kinases. Modulation of these kinases which could allow the development of new pharmacological targets for neuroinflammation. Recent work (unpublished data) has shown an association between the expression of ERK5 and PMK2 kinases, and the clinical severity of experimental allergic encephalomyelitis, a mouse model that mimics multiple sclerosis. In order to search for new biomarkers and improve our knowledge of the actors of the initial inflammatory phase of neuroinflammatory pathologies, we propose to study the differences in expression of ERK5 and PKM2 kinases in the blood and cerebral spinal fluid (CSF) of patients followed for relapsing-remitting MS and GBS by both RT-qPCR and protein quantification. We also want to study other biological parameters which include characterization of the pro / anti-inflammatory balance by cytokine assay and lymphocyte phenotyping, metabolome study, and mild form neurofilament (NfL) assay.

Conditions

Sclerosis, Multiple; Guillain-Barre Syndrome; Inflammation

Keywords

ERK5 kinase; M2 Type Pyruvate Kinase; cytokines

Outcome Measures

Primary Outcomes (1)

• Expression of genes encoding ERK5 and PKM2 kinases by RT-qPCR

  The expression of ERK5 and PKM2 by RT-qPCR will be analyze to investigate the transcriptome on RNA level. RT-qPCR require RNA extraction, reverse transcription into cDNA and then amplification of the genes encoding ERK5 and PKM2 using specific primers designed beforehand. The results will be compared with those obtained with primers of the HPRT gene. These analyzes are carried out using lymphocytes and neutrophils isolated from the blood sample.

  Day 0

Secondary Outcomes (4)

• Lymphocyte phenotyping

  Day 0

• Cytokine levels

  Day 0

• Metabolome analysis

  Day 0

• Measure of the neurofilament light chain (NfL)

  Day 0

Study Arms (1)

Patients with clinical signs that suggest Multiple Sclerosis (MS) or Guillain Barré Syndrome (GBS)

EXPERIMENTAL

Biological: Blood sample and Cerebrospinal fluid (CSF) collection.

Interventions

Blood sample and Cerebrospinal fluid (CSF) collection. BIOLOGICAL

An additional blood sample (25 ml) and a cerebrospinal fluid (CSF) sample (2 ml) will be taken.

Patients with clinical signs that suggest Multiple Sclerosis (MS) or Guillain Barré Syndrome (GBS)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Man and Woman
• to 80 years old
• Clinical signs that suggest MS or GBS within a month of onset symptom

You may not qualify if:

• Patient treated with immunosuppressive therapy, immunomodulator, or corticosteroids in chronic treatment
• Patient treated with corticosteroids in the past month
• without social security
• HIV positive serology
• dementia
• pregnant or breastfeeding woman
• previous participation in the study
• under judicial protection
• non-cooperating patient

Sponsors & Collaborators

• Centre Hospitalier Régional d'Orléans: lead
• Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM): collaborator

Related Publications (8)

• Gaetani L, Salvadori N, Lisetti V, Eusebi P, Mancini A, Gentili L, Borrelli A, Portaccio E, Sarchielli P, Blennow K, Zetterberg H, Parnetti L, Calabresi P, Di Filippo M. Cerebrospinal fluid neurofilament light chain tracks cognitive impairment in multiple sclerosis. J Neurol. 2019 Sep;266(9):2157-2163. doi: 10.1007/s00415-019-09398-7. Epub 2019 May 25.

  PMID: 31129709 BACKGROUND

• Kamil K, Yazid MD, Idrus RBH, Das S, Kumar J. Peripheral Demyelinating Diseases: From Biology to Translational Medicine. Front Neurol. 2019 Mar 19;10:87. doi: 10.3389/fneur.2019.00087. eCollection 2019.

  PMID: 30941082 BACKGROUND

• Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, Barro C, Kappos L, Comabella M, Fazekas F, Petzold A, Blennow K, Zetterberg H, Kuhle J. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018 Oct;14(10):577-589. doi: 10.1038/s41582-018-0058-z.

  PMID: 30171200 BACKGROUND

• Kuhle J, Plattner K, Bestwick JP, Lindberg RL, Ramagopalan SV, Norgren N, Nissim A, Malaspina A, Leppert D, Giovannoni G, Kappos L. A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult Scler. 2013 Oct;19(12):1597-603. doi: 10.1177/1352458513482374. Epub 2013 Mar 25.

  PMID: 23529999 BACKGROUND

• Rostami A, Ciric B. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J Neurol Sci. 2013 Oct 15;333(1-2):76-87. doi: 10.1016/j.jns.2013.03.002. Epub 2013 Apr 8.

  PMID: 23578791 BACKGROUND

• Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintore M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2. Epub 2017 Dec 21.

  PMID: 29275977 BACKGROUND

• Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens JL, Medaer R, Hupperts R, Stinissen P. Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology. 2008 Jan;123(1):79-89. doi: 10.1111/j.1365-2567.2007.02690.x. Epub 2007 Sep 25.

  PMID: 17897326 BACKGROUND

• Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments and Neurofilament Proteins in Health and Disease. Cold Spring Harb Perspect Biol. 2017 Apr 3;9(4):a018309. doi: 10.1101/cshperspect.a018309.

  PMID: 28373358 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis; Guillain-Barre Syndrome; Inflammation

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Polyradiculoneuropathy; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Pascal AUZOU, Dr

  CHR Orléans

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2020
• First Posted: December 19, 2020
• Study Start: January 1, 2023
• Primary Completion: January 1, 2023
• Study Completion: January 1, 2023
• Last Updated: January 23, 2023

Record last verified: 2023-01