Multiple sclerosis (MS) is a demyelinating disease of the CNS. In a vast majority of
patients, its clinical course is characterized by transient attacks of acute neurological
compromise, followed by variable degree of recovery. Each relapse leaves a patient with some
degree of residual disability. Higher number and longer duration of relapses are associated
with greater loss of function. Hence, it is imperative that these relapses are optimally
treated and curtailed in duration to allow for maximal recovery and repair.
ACTH (ACTHAR or IV formulation) has long been used for the treatment of MS relapses. ACTH has
equivalent efficacy to high-dose IV methylprednisolone in curtailing the duration of MS
relapses. ACTH has an advantage over steroids in that it has a short half-life and much less
deleterious steroid effect on bone and fat metabolism. Importantly, ACTH has a unique
mechanism of action on immune and brain cells through melanocortin receptors (MCRs), which
promote production of regulatory and anti-inflammatory cytokines and support oligodendrocyte
precursors and neuronal function, all of which could lead to better repair of MS lesions and
favorable clinical outcome.
The studies proposed herein will provide a better understanding of the effects of ACTHAR in
improving MRI lesion characteristics over time. The complementary immune and genetic studies
will further provide evidence for the mechanism of action (MOA) of ACTHAR in improving immune
dysfunction related to MS relapse. This is a one of a kind study, involving both
advanced/state-of-the art MRI techniques and immune studies to assess the beneficial effects
of ACTHAR in MS relapses in the same patients over time.
The primary outcome of all MRI techniques is to determine whether there is an improvement and
subsequent stabilization/repair over time of tissue damage caused by inflammatory MS disease
activity. Multiple conventional and nonconventional MR imaging modalities are examined here
to determine which of these are the most sensitive and reliable in detecting microstructural
damage and repair over time. The results of this study will also greatly impact the design of
future MS trials by providing a guide for selecting the most appropriate MRI and immune
methods to assess treatment efficacy in MS.
In terms of laboratory analysis, the following will be examined:
1. Determine immune subset expression in CD4+FOXP3 Tregs and CD8+CD28- T suppressor cells
by flow cytometry at each visit.
2. Global gene expression profiling in MNC with 913,000 probes at each visit.
Bioinformatics will include pathway analysis and ACTHAR-induced RNA signature.
3. Serum protein profiling for immune-regulated cytokines (Th1, Th2, Th17, monokines…) and
neuroprotective proteins (NGF, BDNF, ACTH, HGF, CNTF, IL-10…) at each visit.
4. All data from protein and gene expression, as well as immune subset expression will be
compared to our database generated from therapy-naïve stable and exacerbating MS. ACTHAR
signature will analyzed based on these comparisons.