Multiple sclerosis (MS) witnessed relevant therapeutic progress in the last decade. This
notwithstanding, safety, quality of life and overtreatment remain elements of strong
concern for the subjects. Safe and manageable therapies that can be used since the
(biological) onset of the disease, without risk of overtreatment, are important unmet
needs in MS.
Following the extraordinary progress in the treatment of relapsing-remitting (RR)
multiple sclerosis (MS), two major unmet needs remain to be addressed by translational
research in this field: progressive MS and the "dream" of a world free of MS. As far as
the latter is concerned, the investigators can hope to make the dream come true by
understanding the etiology of the disease and hence design definitive cures.
Unfortunately this perspective is neither at hand, nor it can be taken for granted that
the etiologic targets, once discovered, will be readily treatable.
A more realistic and pragmatic perspective may be the prevention of the clinical onset of
the disease, a research field that promises to become increasingly important as the
integration of genetic data with endophenotypes, magnetic resonance imaging and other
biomarkers ameliorates the ability to predict the development of the disease under
clinical circumstance.
Epidemiological data supporting vitamin D supplementation and smoking avoidance are
candidate approaches for primary and secondary prevention of the disease. Among other
interventions that may have characteristics compatible with those of a preventive
treatment, Bacille Calmette-Guerin (BCG) vaccine has been tested with encouraging results
in early MS and clinically isolated syndrome (CIS). The knowledge that disease-modifying
therapies work best when used early in the demyelinating process raises the question
about whether to try this approach - which is safe, cheap and handy - in individuals with
radiologically isolated syndrome (RIS).
Radiologically isolated syndrome is a new entity, diagnosed when the unanticipated
magnetic resonance imaging (MRI) finding of brain spatial dissemination of focal white
matter (WM) lesions highly suggestive of MS occurs in subjects without symptoms of MS,
and with normal neurological examinations. Approximately one-third and two-thirds of
individuals experience respectively clinical onset and/or radiological progression over a
mean follow-up of five years. However, predictors (male sex, age < 37, spinal cord
involvement) of higher risk of progression have been identified and conversion to
clinically isolated syndromes (CIS) were described in 84% of RIS individuals with spinal
cord lesions over a median time of 1.6 years from the date of the first MRI; the same
predictors have recently been shown to precede evolution toward primary progressive MS.
Whether or not to treat this condition remains currently a clinical conundrum.
Bacille Calmette-Guérin (BCG) vaccine may have these characteristics since it resulted
beneficial in early MS and first demyelinating episodes. Being safe, cheap and handy, the
investigators propose to explore its use to prevent progression of the demyelinating
process in radiologically isolated syndrome.
An approach such as BCG vaccine seems appropriate as a front-line immunomodulatory
approach for RIS people. This project is proposed in the context of the activity of the
Center for Experimental Neurological Therapies (CENTERS - a special project by the
Fondazione Italiana Sclerosi Multipla - FISM). CENTERS is especially dedicated to phase
II trials of this nature (independent, repurposing studies, that may be only funded by
not-for-profit institutions).
1.2 Preliminary Results
Experimental and epidemiological evidences suggested benefit of exposure to microbial
products (in the absence of infection, as is the case of vaccinations) in autoimmunity,
including MS. In a pilot study BCG vaccine was safe and effective in reducing disease
activity at MRI, and the risk of developing persistent T1-hypointense lesions ('black
holes' -BH- expression of tissue damage) in subjects with MS. A placebo-controlled trial
in people with clinically isolated syndrome supported the findings of the pilot study.
The researchers observed benefit on disease activity at MRI, reduced development of BH,
benefit on conversion to clinically definite MS over 5 years, during which the subjects
took interferon beta beginning from six months after BCG or placebo.
The investigators consider timely an extension of the adjuvant approach to subjects with
RIS, also considering recent achievements in 'metrics' suitable to analyze this
condition: neuroimaging has recently allowed to improve the characterization of RIS
(including the identification of individuals at higher risk of progression to MS; and to
disclose cortical lesions and axonal damage in RIS brain; immune-metabolic profiling
provides a complex correlation between immunometabolic cellular variables, that seems
especially apt to analyze preclinical phase of neuroinflammation and to study an approach
whose underlying mechanisms of actions remain largely unknown, in spite of encouraging
clinical results.
1.3 Scientific rationale and main objectives
BCG vaccine showed beneficial effects on disease activity and possibly on tissue damage
in relapsing-remitting MS and clinically isolated syndrome. The investigators now propose
to evaluate whether and how BCG vaccine exerts favorable biological effects in
individuals with RIS.
At present it is unclear whether the neuroprotective/neurorepair potential of BCG is a
consequence of its ability to reduce central nervous system (CNS) inflammation or it
depends on additional and specific mechanisms. Notably, neuroprotection after BCG
vaccination was reported in models of Parkinson disease, suggesting a neuroprotective
vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery
can limit potentially deleterious microglial responses to a neuronal insult. Accordingly,
convergent evidences suggest a role of BCG, as tumor necrosis factor (TNF)-inducer, in
another immune-mediated disease, type I diabetes: TNF receptor 2 may mediate, at least in
part, beneficial effects of BCG in neuroinflammation and type 1 diabetes by favoring
apoptosis of autoreactive T cells, counteracting T cell regulatory deficit and last, but
not least, fostering tissue repair.
Metabolic abnormalities suggestive of axonal damage were reported in a substantial
proportion of RIS subjects and cortical lesions of fronto-temporal lobes were associated
with predictors of evolution to multiple sclerosis (MS), such as spinal cord involvement,
presence of oligoclonal bands on cerebrospinal fluid and dissemination in time on brain
MRI. The researchers aim at verifying potential beneficial effects of BCG vaccination in
people with RIS, evaluating MRI metrics of macroscopic brain damage, as well as subtle
tissue damage as assessed by both conventional and non conventional MRI techniques. On
the immunological side the investigators will assess the immune-metabolic status of RIS
people as well as their regulatory T cell potential: a multiple parameter analysis will
provide a meta-immunologic profiling that has been recently shown to be impaired in MS.
This will be aimed at creating a follow-up scheme which should allow to monitor RIS
people over time, before and after BCG vaccine.
To reach the above purposes the investigators propose a 3 years longitudinal study
project, considered appropriate taking into account the relative rarity of RIS condition
as well as the need of an adequate follow-up to obtain informative outcome measures (see
methods).
The groups that engendered the above achievements are collaborators of this project, thus
warranting the experience and competence to pursue the proposed research.