Effects of Ozanimod on Immune-mediated Mechanisms of Neurodegeneration in Multiple Sclerosis - a Preclinical Study

NCT05245344 | Unknown

• 1 other identifier: MulticOZ-MS
• Study Type: observational
• Target: 154
• Locations: 1 country
• Sites: 3

Brief Summary

This is a prospective non interventional study including patients with Relapsing-Remitting Multiple Sclerosis (RRMS) or with Neuromyelitis Optica Spectrum Disorders (NMOSD) and healthy subjects, who are enrolled within the routinely programmed clinical examinations at the IRCCS Neuromed (Pozzilli, Italy), IRCCS Polyclinic Hospital San Martino (Genoa, Italy) and Sant'Andrea Hospital - University of Rome La Sapienza (Rome, Italy). Specifically, the study investigates how ozanimod may contrast neurodegenerative mechanisms triggered by both arms of the adaptive immune response (T and B cells) and by their suboptimal regulation in MS. Overall, the project aims at assessing by in vitro experiments (there will be no patients on treatment with ozanimod and the drug will be only used in vitro): AIM1: ozanimod ability to modulate the synaptotoxic effect of T-cells derived from patients with MS relapse in a MS-chimeric ex-vivo model and to identify possible mediators (IRCCS Neuromed-Pozzilli, in collaboration with Synaptic Immunopathology Laboratory Dep. Systems Medicine, Tor Vergata University of Rome); AIM2: ozanimod ability to reduce the cytokine-mediated breakdown of the BBB and the migration of the here studied immune cells through ex vivo models of BBB (IRCCS Polyclinic Hospital San Martino); AIM3: ozanimod ability to affect the migration properties of Epstein Barr virus (EBV) infected B cells in MS (Sant'Andrea Hospital); AIM4: ozanimod ability to modulate the number and/or function of regulatory T cells (Treg), a lymphocyte population playing a key role in the control of pathogenic adaptive immune responses (Treg Cell Laboratory, Università degli Studi di Napoli "Federico II", Naples, Italy, receiving blood samples from Neuromed Hospital and Sant'Andrea Hospital; not recruiting unit). The work of the four labs is conceptually and operationally integrated: the labs at IRCCS Neuromed-Pozzilli/Tor Vergata University (Aim1) and at Polyclinic Hospital San Martino (Aim2) will investigate the effects of ozanimod on well-known mechanisms of damage in MS, inflammatory synaptopathy and BBB damage and immune cell migration. The lab at Sant'Andrea Hospital (Aim3), will verify whether B cells infected by different EBV genotypes are involved in BBB migration, and how ozanimod may interfere with this mechanism. The Treg Cell Laboratory (Aim4) will investigate whether ozanimod can also act "upstream" of these mechanisms by regulating the adaptive immune response.

Conditions

Relapsing-Remitting Multiple Sclerosis (RRMS); Neuromyelitis Optica; Healthy

Keywords

in vitro ozanimod treatment; T cells; Treg cells; NK cells; B cells; T-cell-mediated synaptotoxicy; cytokine-mediated breakdown of the Blood Brain Barrier; Epstein-Barr virus (EBV) infected B cells

Outcome Measures

Primary Outcomes (9)

• To evaluate the potential anti-synaptotoxic effect of ozanimod on electrophysiological kinetics in the MS chimeric model

  1.1.1. T cells will be isolated from the peripheral blood of naïve active RRMS patients and will be reated in culture with ozanimod (1000 nM) or vehicle for 24 h. After treatment, T cells will be incubated on corticostriatal slices derived from healthy mice and electrophysiological recording will be performed to measure: • kinetics of the spontaneous synaptic transmission (half width, decay time and rise time, in ms); The same experiments will be performed by using cell treated with S1P1 and S1P5 selective agonists. The primary endpoint will be the comparison of electrophysiological parameters between ozanimod and vehicle conditions, to evaluate a potential beneficial effect of ozanimod on the synaptic alterations induced by MS lymphocytes.

  18 months

• To evaluate the potential anti-synaptotoxic effect of ozanimod on electrophysiological frequency in the MS chimeric model

  1.1.2. T cells will be isolated from the peripheral blood of naïve active RRMS patients and will be reated in culture with ozanimod (1000 nM) or vehicle for 24 h. After treatment, T cells will be incubated on corticostriatal slices derived from healthy mice and electrophysiological recording will be performed to measure: • frequency of the spontaneous synaptic transmission (in Hz); The same experiments will be performed by using cell treated with S1P1 and S1P5 selective agonists. The primary endpoint will be the comparison of electrophysiological parameters between ozanimod and vehicle conditions, to evaluate a potential beneficial effect of ozanimod on the synaptic alterations induced by MS lymphocytes.

  18 months

• To evaluate the potential anti-synaptotoxic effect of ozanimod on electrophysiological amplitude in the MS chimeric model

  1.1.3. T cells will be isolated from the peripheral blood of naïve active RRMS patients and will be reated in culture with ozanimod (1000 nM) or vehicle for 24 h. After treatment, T cells will be incubated on corticostriatal slices derived from healthy mice and electrophysiological recording will be performed to measure: • amplitude of the spontaneous synaptic transmission (in pA). The same experiments will be performed by using cell treated with S1P1 and S1P5 selective agonists. The primary endpoint will be the comparison of electrophysiological parameters between ozanimod and vehicle conditions, to evaluate a potential beneficial effect of ozanimod on the synaptic alterations induced by MS lymphocytes.

  18 months

• To asses the ability of ozanimod to reduce the breakdown of the ex vivo model of BBB (BBB integrity).

  2.1. The impact on the integrity of BBB will be assessed for T and NK cells isolated from naive MS patients, and exposed or not ex-vivo to ozanimod. Differences in the expression of the tight junction proteins as Claudin-5, Occludin, Zonula Occludens-1 (fold change) upon exposure of BBB models to immune cells from MS patients, treated or not ex vivo with ozanimod, will be evaluated. The primary endpoint will be the comparison of BBB integrity, matching the results from ozanimod stimulated vs ozanimod unstimulated cells taken from each patient.

  18 months

• To asses the ability of ozanimod to reduce the cytokine-mediated permeability of the ex vivo model of BBB.

  2.2. The impact on the migration ability across the BBB will be assessed for T and NK cells isolated from naive MS patients, and exposed or not ex-vivo to ozanimod. Differences in the migration across ex vivo models of BBB of immune cells isolated from MS patients after incubation with ozanimod, will be evaluated (dye fluorescencent signal). The primary endpoint will be the comparison of BBB permeability to T and NK cells, matching the results from ozanimod stimulated vs ozanimod unstimulated cells taken from each patient.

  18 months

• To evaluate the migration properties of B cells, spLCLs (with 1.2 and with 1.3 viral alleles) and B95.8LCLs isolated from peripheral blood of (untreated) RRMS and HD.

  3\. B cells and LCLs will be cultured in the presence of different drug concentrations and transwell migration assays will be performed to evaluate their ability to migrate through a membrane. At least 5 LCLs and related B cells will be tested for each EBNA2 alleles. Specifically, this aim will investigate: The migration properties of B cells, spLCLs and B95.8LCLs from MS patients and age- and sex-matched HD, and if ozanimod is able to modulate the migration properties of the above cells from patients and HD. The primary endpoint will be the comparison of the migratory capacity (sphingosine- and chemokine-driven) of EBV-infected B cells compared to non-infected cells; whether different viral genotypes modify this capacity; whether and how the above properties differ between patients and controls; whether and how ozanimod affects the above properties.

  18 months

• To evaluate the effect of ozanimod on the proliferation of Treg cells

  4.1. It has been demonstrated that human CD4+CD25- Tconv cells isolated from PBMC of human subjects and activated in vitro in the presence of low-TCR engagement, acquire a suppressive phenotype and generate highly suppressive human iTreg cells. Therefore, in order to evaluate the effect of ozanimod on the induction of iTreg, Tconv cells will be isolated from healthy subjects and RRMS patients and after 36 h culture in the presence of ozanimod or vehicle, activated CD4+CD25- T cells will be FACS-sorted and will be analyzed for their proliferative potential (Ki67 fluorescence). The primary endpoint will be the comparison of iTreg cell proliferation between Tconv cell stimulated in the presence or not of ozanimod.

  18 months

• To evaluate the effect of ozanimod on metabolic asset of Treg cells.

  4.2. After Tconv cells isolation from healthy subjects and RRMS patients and 36 h culture in the presence of ozanimod or vehicle, activated CD4+CD25- T cells will be FACS-sorted and will be analyzed for metabolic asset. The effect of ozanimod on the metabolic asset of iTreg will be evaluated by assessing p-S6 fluorescence. The primary endpoint will be the comparison of iTreg cell metabolic asset between Tconv cell stimulated in the presence or not of ozanimod.

  18 months

• To evaluate the effect of ozanimod on the function of Treg cells.

  4.3. After Tconv cells isolation from healthy subjects and RRMS patients and 36 h culture in the presence of ozanimod or vehicle, activated CD4+CD25- T cells will be FACS-sorted and will be analyzed for their function. The effect of ozanimod on the induction of iTreg will be evaluated by assessing the expression levels of the two major FoxP3 splicing forms, one containing (FoxP3E2) and the other lacking (FoxP3∆2) the exon 2. The primary endpoint will be the comparison of iTreg cell function between Tconv cell stimulated in the presence or not of ozanimod.

  18 months

Study Arms (3)

Patients with RRMS (untreated)

* Relapsing-remitting MS, as diagnosed by the revised 2010 McDonald Criteria; * EDSS score ≤ 5.5; * Age between 18 and 55 years (exclusive); * no disease modifying therapies for at least 3 months or treatment naïve; * no corticosteroid administration in the previous month; * disease duration \<10 years; * Ability to provide written informed consent.

Procedure: Peripheral blood withdrawal

Patients with Neuromyelitis Optica Spectrum Disorders (NMOSD)

Main inclusion criteria of NMOSD patients (Wingerchuk et al., 2015): * Positive test for Aquaporin 4 IgG; * Age between 18 and 55 years (exclusive); * no immunosuppressive therapies for at least 3 months or treatment naïve. * no corticosteroid administration in the previous month * disease duration \<10 years * Ability to provide written informed consent

Procedure: Peripheral blood withdrawal

Healthy subjects (HD)

* Age between 18 and 55 years (exclusive), matched by gender, age and ethnicity towards the MS groups. * Ability to provide written informed consent.

Procedure: Peripheral blood withdrawal

Interventions

Peripheral blood withdrawal PROCEDURE

25 ml of blood for T cell isolation or 40 ml of blood for B cell isolation will be obtained following informed consent as approved by the ethical committees of the MS centers.

Healthy subjects (HD); Patients with Neuromyelitis Optica Spectrum Disorders (NMOSD); Patients with RRMS (untreated)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

This is a prospective non interventional study with MS patients enrolled within the routinely programmed clinical examinations at the IRCCS NeuromedPozzilli, IRCCS polyclinic hospital San Martino (Genoa, Italy), Sant'Andrea Hospital - University of Rome La Sapienza (Rome, Italy). Study population: Approximately 72 Relapsing-Remitting Multiple Sclerosis (RRMS - naïve or after 3 months wash out from DMT patients; 10 Neuromyelitis Optica Spectrum Disorders patients (NMOSD); 72 healthy subjects (HD) will be recruited from the hospitals involved in the study.

You may qualify if:

• Relapsing-remitting MS, as diagnosed by the revised 2010 McDonald Criteria
• EDSS score ≤ 5.5;
• Age between 18 and 55 years (exclusive);
• No disease modifying therapies for at least 3 months or treatment naïve;
• No corticosteroid administration in the previous month;
• Disease duration \<10 years;
• Ability to provide written informed consent.
• For the estimation of radiological variables, brain and spinal cord MRI will be performed according to clinical practice and lesions will be classified as symptomatic or asymptomatic if they were associated with clinical relapse or not.
• Patient groups will be matched by gender, age, ethnicity and MS duration.
• Positive test for Aquaporin 4 IgG;
• Age between 18 and 55 years (exclusive);
• no immunosuppressive therapies for at least 3 months or treatment naïve
• no corticosteroid administration in the previous month
• disease duration \<10 years
• Ability to provide written informed consent

You may not qualify if:

• Adverse effects to MRI imaging with i.v. gadolinium;
• Blood count basal alteration;
• Clinically significant medical condition other than MS, including latent infections (e.g. tuberculosis, viral hepatitis, HIV/AIDS) that might confound the results of the study.

Sponsors & Collaborators

• Neuromed IRCCS: lead
• University of Rome Tor Vergata: collaborator

Study Sites (3)

IRCCS INM-Neuromed

Pozzilli, Isernia, 86077, Italy

Location

IRCCS Ospedale Policlinico San Martino

Genova, Italy

Location

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome

Roma, Italy

Location

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MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Neuromyelitis Optica; Epstein-Barr Virus Infections

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Myelitis, Transverse; Optic Neuritis; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Study Officials

• Fabio Buttari, PhD

  IRCCS Neuromed, Pozzilli, Isernia Italy

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Fabio Buttari, PhD

CONTACT

+393384999878; fabio.buttari@gmail.com

Mario Stampanoni Bassi, PhD

CONTACT

+39 2460181370; mario_sb@hotmail.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 30, 2021
• First Posted: February 17, 2022
• Study Start: April 1, 2022
• Primary Completion: June 30, 2023
• Study Completion: October 31, 2023
• Last Updated: February 17, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3)