miR-142-3p as Potential Biomarker of Synaptopathy in MS
Clinical Relevance of miR-142-3p as Potential Biomarker of Synaptopathy in Multiple Sclerosis
We could not find results for this trial
What it found
We found no results in the registry or in papers.
What was tested
Treatment tested
- lumbar puncture and blood withdrawal
- Intermittent theta burst stimulation (iTBS) therapeutic protocol for spasticity
What it measured
Main measures
CSF concentration of miR-142-3p
T0 (enrollment); MS patients vs Control subjects
Blood or spinal fluid markersCSF concentration of soluble molecules
T0 (enrollment); MS patients vs Control subjects
Blood or spinal fluid markersImmune responseClinical disability assessment by Progression Index calculation for correlation analysis with CSF-miR-142-3p levels
Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up
Disability progressionBlood or spinal fluid markersClinical disability assessment by MSFC calculation for correlation analysis with CSF-miR-142-3p levels
Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up
Disability progressionBlood or spinal fluid markersThinking and memoryWalking and mobilityNeuroradiological assessment for correlation analysis with CSF-miR-142-3p levels
Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up
MRI lesionsBlood or spinal fluid markersNeurophysiological assessments for correlation analysis with CSF-miR-142-3p levels
Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up
Blood or spinal fluid markersNerve conduction testsStatistical correlation of miR-142-3p levels in MS CSF with disease and neurophysiological parameters
T0 (enrollment), T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months).
Blood or spinal fluid markersNerve conduction testsImmune response
Other measures (5)
Statistical correlation of miR-142-3p levels in MS CSF with patient's responsiveness to disease modifying therapies (DMTs).
Time Frame: T0 (enrollment); Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up
Blood or spinal fluid markersGenotyping of SNPs in SLC1A3 and MIR-142 genes for correlation analysis with disease parameters
Time Frame: T0 (enrollment); Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up
Nerve conduction testsLower limb spasticity assessment by H/M amplitude ratio for the therapeutic TMS substudy
Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up; Changes from the starting day (W0) to the end of t
Nerve conduction testsSpasticityLower limb spasticity assessment by MAS score for the therapeutic TMS substudy
Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up; Changes from the starting day (W0) to the end of t
Nerve conduction testsSpasticityStatistical correlation of response to iTBS treatment with MS-significant SNPs of both SLC1A3 and MIR-142.
T0 (enrollment); Changes from the starting day (W0) to the end of the 2-week iTBS protocol (W2).
Spasticity
Who could take part
MS (type not specified) · 18 to 65 · EDSS 0 to 6
Show the full criteria
Inclusion criteria
* Ability to provide written informed consent to the study; * Diagnosis of MS definite according to 2010 revised McDonald's criteria (Polman et al., 2011); * Age range 18-65 (included); * EDSS range between 0 and 6 (included); * Ability to participate to the study protocol.
Exclusion criteria
* Inability to provide written informed consent to the study; * Altered blood count; * Female with positive pregnancy test at baseline or having active pregnancy plans in the following months after the beginning of the protocol; * Contraindications to gadolinium (MRI); * Contraindications to TMS; * Patients with comorbidities for neurological disease other than MS, included other neurodegenerative chronic diseases or chronic infections (i.e tubercolosis, infectious hepatitis, HIV/AIDS); * Unstable medical condition or infections; * Use of medications with increased risk of seizures (i.e. Fampridine, 4- Aminopyridine); * Concomitant use of drugs that may alter synaptic transmission and plasticity (cannabinoids, L-dopa, antiepiletics, nicotine, baclofen, SSRI, botulinum toxin).
As registered. Criteria can change, so ask the trial team or your neurologist.
About this trial
In the sponsor's words
Inflammatory synaptopathy is a prominent pathogenic mechanism in multiple sclerosis (MS) and in its mouse model, which can cause excitotoxic damage by long-lasting excessive synaptic excitation and, consequentially, drives disease progression by leading to motor and cognitive deficits. As synaptopathy occurs early during the disease course and is potentially reversible, it represents an appealing therapeutic target in MS. Although reliable biomarkers of MS synaptopathy are still missing, recent researches highlighted miR-142-3p as a possible candidate. Indeed, miR-142-3p has been described to promote the IL-1beta-dependent synaptopathy by downregulating GLAST/EAAT1, a crucial glial transporter involved in glutamate homeostasis. Furthermore, mir-142-3p has been suggested as a putative negative MS prognostic factor and a target of current MS disease modifying therapies. The hypothesis of this study is that miR-142-3p represents a good biomarker for excitotoxic synaptopathy to predict MS course, and, possibly, treatment efficacy at individual level, including both pharmacological strategies and non-pharmacological interventions, like therapeutic transcranial magnetic stimulation (TMS) to ameliorate MS spasticity. To this aim, the role of miR-142-3p in MS synaptopathy, its potential impact on the efficacy of disease-modifying treatments currently used in MS therapy as well as the influence of genetic variants (SNPs) of miR-142-3p and GLAST/EAAT1 coding genes on the responsiveness to therapeutic TMS, will be further investigated in the study. By validating miR-142-3p as potential biomarker of synaptopathy, it is expect to improve MS prognosis and personalized therapies. Patients with MS, who will undergo neurological assessment, conventional brain MRI scan, and CSF and blood withdrawal for diagnostic and clinical reasons at the Neurology Unit of IRCCS INM-Neuromed will be enrolled in the study. Neurophysiological, biochemical and genetic parameters together with lower limb spasticity will be evaluated. Subjects, who will undergo blood sampling and/or lumbar puncture for clinical suspicions, later on not confirmed, will be recruited as control group. A subgroup of MS patients showing lower limb spasticity will be included in a two-week repetitive TMS stimulation protocol (iTBS) to correlate the patient responsiveness to this non-pharmacological treatment with MS-significant SNPs of both miR-142-3p and GLAST/EAAT1 coding genes.
Papers
Background
Mandolesi G, De Vito F, Musella A, Gentile A, Bullitta S, Fresegna D, Sepman H, Di Sanza C, Haji N, Mori F, Buttari F, Perlas E, Ciotti MT, Hornstein E, Bozzoni I, Presutti C, Centonze D. miR-142-3p Is a Key Regulator of IL-1beta-Dependent Synaptopathy in Neuroinflammation. J Neurosci. 2017 Jan 18;37(3):546-561. doi: 10.1523/JNEUROSCI.0851-16.2016.Background
Mandolesi G, Gentile A, Musella A, Fresegna D, De Vito F, Bullitta S, Sepman H, Marfia GA, Centonze D. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol. 2015 Dec;11(12):711-24. doi: 10.1038/nrneurol.2015.222. Epub 2015 Nov 20.Background
Mori F, Codeca C, Kusayanagi H, Monteleone F, Boffa L, Rimano A, Bernardi G, Koch G, Centonze D. Effects of intermittent theta burst stimulation on spasticity in patients with multiple sclerosis. Eur J Neurol. 2010 Feb;17(2):295-300. doi: 10.1111/j.1468-1331.2009.02806.x. Epub 2009 Oct 23.Background
Centonze D, Koch G, Versace V, Mori F, Rossi S, Brusa L, Grossi K, Torelli F, Prosperetti C, Cervellino A, Marfia GA, Stanzione P, Marciani MG, Boffa L, Bernardi G. Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis. Neurology. 2007 Mar 27;68(13):1045-50. doi: 10.1212/01.wnl.0000257818.16952.62.Background
Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, D'Amelio M, Cavallucci V, Martorana A, Bergamaschi A, Cencioni MT, Diamantini A, Butti E, Comi G, Bernardi G, Cecconi F, Battistini L, Furlan R, Martino G. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci. 2009 Mar 18;29(11):3442-52. doi: 10.1523/JNEUROSCBackground
Gandhi R. miRNA in multiple sclerosis: search for novel biomarkers. Mult Scler. 2015 Aug;21(9):1095-103. doi: 10.1177/1352458515578771. Epub 2015 Apr 28.Background
International Multiple Sclerosis Genetics Consortium; Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007 Aug 30;357(9):851-62. doi: 10.10Background
Kiselev I, Bashinskaya V, Kulakova O, Baulina N, Popova E, Boyko A, Favorova O. Variants of MicroRNA Genes: Gender-Specific Associations with Multiple Sclerosis Risk and Severity. Int J Mol Sci. 2015 Aug 24;16(8):20067-81. doi: 10.3390/ijms160820067.Background
Bergman P, Piket E, Khademi M, James T, Brundin L, Olsson T, Piehl F, Jagodic M. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016 Apr 20;3(3):e219. doi: 10.1212/NXI.0000000000000219. eCollection 2016 Jun.Background
Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, Piras E, Gargano F, Borsellino G, Battistini L, Schubart A, Mandolesi G, Centonze D. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016 Aug 26;13(1):207. doi: 10.1186/s12974-016-0686-4.
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History
Started
Dec 2019
Main results due
Dec 2024
Finished
Dec 2025