Stem Cell Therapies for Progressive Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal degeneration. MS patients typically present with a relapsing-remitting (RR) disease course, manifesting as sporadic attacks of neurological symptoms including ataxia, fatigue, and sensory impairment. While there are several effective disease-modifying therapies able to address the inflammatory relapses associated with RRMS, most patients will inevitably advance to a progressive disease course marked by a gradual and irreversible accrual of disabilities. Therapeutic intervention in progressive MS (PMS) suffers from a lack of well-characterized biological targets and, hence, a dearth of successful drugs. The few medications approved for the treatment of PMS are typically limited in their efficacy to active forms of the disease, have little impact on slowing degeneration, and fail to promote repair. In looking to address these unmet needs, the multifactorial therapeutic benefits of stem cell therapies are particularly compelling. Ostensibly providing neurotrophic support, immunomodulation and cell replacement, stem cell transplantation holds substantial promise in combatting the complex pathology of chronic neuroinflammation. Herein, we explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and we discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.

Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure

“…In the context of non-active PMS, antigen-independent and compartmentalized chronic inflammation, shielded from therapeutic efforts, is plausible. The corollary to this hypothesis would be that even outside of common DMT, other anti-proliferative therapies might fail to provide meaningful clinical benefit to PMS ( 103 ), a logic that should guide hematopoietic stem cell transplants as well ( 104 ). Furthermore, if myeloid cells drive PMS, they probably do so in a stage-specific fashion; (1) BMC likely enter the CNS throughout active and non-active MS and are retained within the CNS; and (2) altered CNS-intrinsic myeloid cells, respond to BMC presence, at sites similar to the border of smoldering lesions.…”

Promoting exogenous repair in multiple sclerosis: myelin regeneration

“…These effects have been associated with reduced encephalitogenic T cells migration and activation and enhanced tolerance against myelin proteins [22]. About thirty clinical trials based on MSCs transplantation have been conducted so far in patients with MS [23], demonstrating safety and tolerability of the procedure and short-term benefits by inhibiting disease progression, especially in patients with previously active disease [24,25 ▪ ]. However, the outcome of the MESEMS study, which evaluated the activity of MSCs on MRI (gadolinium-enhancing lesions) and clinical (annualized relapse rate) surrogate markers of efficacy, do not support their use in patients with multiple sclerosis with ongoing inflammation [26 ▪▪ ].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles and Their Therapeutic Use in Central Nervous System Demyelinating Disorders

“…Due to the safety profile of MSCs when used for the treatment of other diseases—such as hematological malignancy, breast cancer, ischemic heart disease, and graft-versus-host disease—MSC-based therapy has been evoked for curing neurodegenerative diseases, including MS [ 81 , 82 ]. Most of the phase 1 or 2 clinical trials have employed autologous BM-MSCs or AD-MSCs, but allogeneic UC-MSCs and PMSCs have been also trialed [ 83 ]. A number of studies have demonstrated the feasibility and safety of intravenous (IV) or intrathecal (IT) administration, with disease stabilization and mitigation of clinical symptoms.…”

“…However, a recent report on the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study—a placebo-controlled, crossover phase 1/2 study [ 84 ]—failed to meet the primary efficacy endpoint represented by the reduction in the number of contrast-enhancing lesions detected by MRI at 24 weeks [ 85 ]. Other phase 2 and 3 clinical trials are either completed or ongoing [ 83 ]; however, it may be possible to assert at this stage of trial completion that MSCs are the main stem cell type sourced for clinical trials on MS to date.…”