Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03492606 |
| Other study ID # |
LipidMediators |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2019 |
| Est. completion date |
January 9, 2021 |
Study information
| Verified date |
November 2022 |
| Source |
Neuromed IRCCS |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease associated with
uncontrolled inflammation and autoimmunity and for which there is still an unmet need for new
diagnostic and therapeutic options, especially for the progressive forms. Recent studies
suggest that chronic inflammation can be a consequence of failure to resolve inflammation,
the resolution of which is mediated by a newly discovered genus of highly potent
anti-inflammatory lipids derived metabolically from omega-3 essential fatty acids and termed
specialized pro-resolving lipid mediators (SPMs).
Herein, we propose to identify SPMs as leads for the control of MS pathology and progression
and to propose them as novel disease-modifying treatments by assessing their ex vivo/in vitro
and in vivo role in modulating the balance of effector and regulatory cells and/or the
mechanisms leading to chronicity as wells as in promoting activation of anti-inflammatory and
neuroprotective pathways.
Description:
Uncontrolled or unresolved inflammation is associated with several widely occurring diseases
such as multiple sclerosis (MS), which is the most common chronic inflammatory demyelinating
disease of the central nervous system and a major cause of disability, triggered by an
autoimmune response to myelin that eventually leads to progressive neurodegeneration.Although
knowledge on its underlying immunopathogenesis has considerably improved and is mostly
believed to be mediated by autoreactive T cells that cause oligodendrocyte death and axonal
damage, resulting in demyelination, synaptic alteration, and neuronal loss, there is still an
unmet need for new diagnostic and therapeutic options, especially for the progressive forms
of MS for which no drugs are still available. In recent years, previously unrecognized
metabolites, termed specialized pro-resolving lipid mediators (SPMs), temporally and
spatially synthesized from omega-3 polyunsaturated fatty acids, were identified and have
emerged as biomarkers and potent mediators that control the magnitude and extent of
inflammatory events by activating local resolution programs. Despite emerging data suggest
that SPMs might control chronic inflammation, research on these mediators on MS is still
absent. Thus, a detailed investigation is needed to identify SPMs as modulators of
inflammation and disease progression in MS, which might lead to the development of new
disease-modifying treatments.
Hypothesis and Significance:
Our hypothesis is that the underlying mechanism of chronic inflammation in MS could be the
failure of activating pro-resolving mechanisms, involving the newly discovered omega-3
essential fatty acids-derived mediators of resolution of inflammation: resolvins, maresins,
and protectins. Endogenous mechanisms that curtail excessive inflammation and promptits
timely resolution are of considerable interest; our findings that these SPMs (recently
identified also in human lymphoidorgans, where most naïve-to-effector T cell differentiation
occurs) exert a non-cytotoxic regulatory role on cells central inautoimmunity, acting on the
balance between pathogenic Th1/Th17 and tolerogenic Treg cells - typically altered in MS
-represents a promising beginning for a new avenue of research for MS. The elucidation of
these mechanisms operating invivo to keep acute inflammation within physiologic boundaries as
well as to stimulate resolution and prevent chronicinflammation is particularly significant
and offers a novel opportunity to manage MS.
Preliminary Data:
Thanks to an ongoing collaboration with Prof. Serhan from Harvard Medical School (the father
and inventor of SPMs) we have demonstrated for the first time that specific SPMs modulate
adaptive immune responses in human peripheral blood T cells. These SPMs strongly reduce
cytokine production from activated T cells, prevent naïve CD4 T-cell differentiation into Th1
and Th17 and enhance the de novo generation and function of Foxp3+ regulatory T (Tregs)
cells. These results are supported in vivo in a mouse model deficient elongase 2 (Elovl2-/-),
the key enzyme for DHA synthesis (the precursor of resolvins and maresins). These findings
suggest that SPMs might act on the balance between pathogenic Th1/Th17 and tolerogenic Treg
cells and provide a new evidence for SPM-based therapeutic approaches to modulate T-cell
mediated chronic inflammatory and autoimmune diseases.
Specific Aims:
Characterization of the resolution code of inflammation in MS patientsInvestigation of SPMs
potential in modulating ex vivo/in vitro T cells in MS patientsExploitation of the
therapeutic potential of SPMs in animal models of MS
