Multiple sclerosis (MS) belongs to demyelinating diseases, which are progressive and highly debilitating pathologies that imply a high burden both on individual patients and on society. Currently, several treatment strategies differ in the route of administration, adverse events, and possible risks. Side effects associated with multiple sclerosis medications range from mild symptoms, such as flu-like or irritation at the injection site, to serious ones, such as progressive multifocal leukoencephalopathy and other life-threatening events. Moreover, the agents so far available have proved incapable of fully preventing disease progression, mostly during the phases that consist of continuous, accumulating disability. Thus, new treatment strategies, able to halt or even reverse disease progression and specific for targeting solely the pathways that contribute to the disease pathogenesis, are highly desirable. Here, we provide an overview of the recent literature about peptide-based systems tested on experimental autoimmune encephalitis (EAE) models. Since peptides are considered a unique therapeutic niche and important elements in the pharmaceutical landscape, they could open up new therapeutic opportunities for the treatment of MS.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that leads to progressive neurodegeneration. A crux of the disease is an autoimmune attack of the self-antigens, that is the proteins of the myelin sheath that wrap around the nerve fibers are mistaken for foreign agents by macrophages, CD4+T, CD8+T, and B cells infiltrating the blood-brain barrier (BBB). The role of the myelin sheath is crucial both to provide protection and nourishment to nerve fibers and to enable the efficient transmission of nerve impulses. Demyelination elicits axonal injury, plaques, or lesions’ formation in the brain and spinal cord, and causes a range of symptoms, depending on the neurons that are affected. MS is a very heterogeneous disease, with different pathological and clinical manifestations. It is estimated that worldwide, more than 2.3 million people between ages 20 to 50 are affected by MS, that is usually diagnosed with signs and symptoms that may differ from person to person and throughout the disease, such as loss of balance and coordination, visual and sensory deficiency, fatigue, weakness, vertigo, pain, and cognitive difficulties. Before being officially diagnosed with MS, patients can experience a first neurologic event indicative of potential MS, defined as Clinically Isolated Syndrome, that lasts for at least 24 h with symptoms and signs indicating either a single lesion (monofocal) or more than one lesion (multifocal) within the CNS. Multiple sclerosis is divided into four types, named according to the way the disease acts on the body over time: Progressive Relapsing MS (PRMS), characterized by a steady degeneration since onset with super-imposed attacks, Relapsing-Remitting MS (RRMS), the most common disease course diagnosed for 85% of people, characterized by defined attacks of new or even increasing neurological symptoms (relapses), followed by periods of partial or complete recovery (remissions), Primary Progressive MS (PPMS), consisting of progressive disability from the onset of symptoms, and Secondary Progressive MS (SPMS), marked by an initial relapsing-remitting course that suddenly begins to progressively decline over time.
The pathogenesis of MS is still unknown: immune-system cells and proteins that can have a crucial role in the initiation and progression of disease are not fully understood. A multitude of factors may cause the insurgence of this disease, ranging from genetic factors, such as class-II allele of the major histocompatibility complex (MHC), to environmental agents, such as pathogenic infections. Some correlations actually have been made between MS and different viruses, such as varicella zoster and the Epstein-Barr virus, or bacteria such as chlamydia pneumonia, as well as other environmental factors such as vitamin D deficiency, smoking, and obesity. Despite this, direct evidence of a correlation between pathogenic infections and MS is still lacking, with the most commonly accepted hypothesis being that MS is an autoimmune disease affecting genetically predisposed individuals already plagued by an environmental pathogen.
An intricate interplay of inflammatory cells (T cells, B cells, and macrophages) and CNS resident cells (microglia, astrocytes, oligodendrocytes, and neurons) is associated with the pathology. Among the different cells of the innate and adaptive immune systems that may arrange the inflammatory response within the CNS, a key role is played by autoreactive CD4+T cells that migrate into the CNS after the activation in the peripheral lymph nodes. Many findings indicate a central role of Th1, Th17, Th1–Th17-like, Th22, and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)-producing CD4+T cells, in beginning and prolonging the inflammatory reactions and in causing neurodegeneration in MS as well as dysfunction in regulatory T cell (T reg) subsets. In the CNS, these cells are reactivated and secrete cytokines and chemokines, thus contributing to the breakdown of the BBB, the activation of resident astrocytes and microglia, and finally, the mediation of inflammatory reaction responsible for the distinctive lesions of the disease.
At present, there is no definite cure for MS, but therapies based on immunosuppressive and immune-modulating agents can modify or slow the course of disease and manage symptoms. Several disease-modifying treatments (DMTs) to treat relapsing forms of MS have been developed and proved able to reduce the frequency and severity of relapses as well as the accumulation of lesions in the CNS. They cover injectable and orally administrated drugs, monoclonal antibodies, transplantation of autologous bone marrow, strategies to restore myelination, and targeting T cells, besides mesenchymal stem cells’ employment. So far, about 20 DMTs, approved by the FDA, are available in many countries for the different types of MS, but they can only minimize symptoms, preserving patients as relapse-free, with no new lesion visible on MRI. Moreover, the most current therapies are not specific but suppress the general immune response, leading to many negative side effects. For this, the development of therapeutic agents able to specifically control and modulate the immune response is an urgent need.
In this context, peptide molecules appear as appealing candidates for many reasons. In fact, some of them have a deep impact on important physiological mechanisms controlling many vital functions in humans, such as metabolism, respiration, reproduction, and immune defense. They possess many advantages over other classes of molecules, being small in size (up to 50 amino acids), easy to synthesize, and having the ability to penetrate the cell membranes, mainly when bearing specific modifications (N-methylation, stapling, etc.). They also have high activity, specificity, and affinity, good efficacy and tolerability, as well as biological and chemical diversity. As a result, an increasing number of peptides are both entering clinical trials and being approved as drugs.
In this review, attention is pointed to some peptides reported in the recent literature representing new potential candidates for MS therapy. Generally, for pre-clinical studies, the experimental autoimmune encephalitis is the most commonly used immune-driven demyelinating model that closely resembles RRMS. It is an animal model of brain inflammation induced by immunization with neural antigens, such as myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein (PLP). Additionally, the cuprizone model, that mimics the acute and chronic courses of MS and is thus suited for the study of the demyelination mechanism, represents a valid tool to develop novel therapies aimed at protecting oligodendrocytes and promoting remyelination.
Here, we describe peptide systems arbitrarily sorted into two groups: peptides modulating T cells’ functions and peptides modulating cells other than T lymphocytes.
Currently, MS therapies are unable to specifically regulate immune cells because they suppress the overall immune system, causing undesirable side effects from opportunistic infections. Thus, to preserve host capability provided by the general immune response to protect against extraneous pathogens, the development of therapeutic agents capable of specifically controlling the myelin-reactive immune response is required.
Antigen-specific treatments targeting key regulators in the failure of tolerance to self-antigens, such as myelin basic protein (MBP), were developed to silence or reprogram autoreactive T cells in the peripheral zone to a regulatory phenotype, thus creating a tolerogenic state to the targeted protein. Autoantigen T-cell responses to MBP are known to be involved in the pathogenesis of MS, and, in particular, five of the eight identified regions of MBP are the most recognized by T-cells. Based on this consideration, Streeter and coworkers in 2015 reported for the first time a study on ATX-MS-1467, a cocktail of four peptides derived from the MBP region (MBP 30–44 [ATX-MS1], MBP 130–144 [ATX-MS4], 140–154 [ATX-MS6], and MBP 83–99 [ATX-MS7], Table 1), which resulted acting as apitopes (antigen processing independent epitope) and to prevent the worsening of signs of disease in EAE in a humanized mouse, (DR2 9 Ob1)F1, in a dose-dependent fashion. A few years later, De Souza et al. demonstrated that subcutaneous treatment with an ATX-MS-1467 mixture, after established induction of EAE in the same mouse model, was able to reverse the clinical disability, to diminish the histological markers of inflammation and demyelination, and to reduce the T-cell and B-cell infiltration in the spinal cord and the disruption of BBB integrity, as shown in MRI analysis. All these effects were more e
