Multiple Sclerosis

THE DISEASE

Multiple sclerosis (MS) is a chronic inflammatory disease that results in autoimmune demyelination of the human central nervous system (CNS).

This produces a devastating impact for those afflicted with no curative treatment. In total, MS affects over 2.5 million people worldwide, including up to 1,000,000 cases in the US. MS is typed according to different flare-up patterns, or exacerbations, seen in patients; these patterns are either remitting/recurring, progressive, or a combination of patterns. Regardless of the type, it is an expensive disease to treat. Direct and indirect health care costs range from $8,500 to $54,000 per patient/year in the United States.

CURRENT TREATMENTS

The traditional treatment for MS is to employ intravenous steroids during acute attacks.

Steroids have not been shown to decrease the risk of future attacks or change the natural progression of the disease; however, but they have been useful to hasten recovery from acute attacks. IFN-β, an anti-inflammatory cytokine, is another well-recognized treatment to provide relief from and reduce symptoms. There are many immunomodulation agents on the market today that are used on an on-going basis to modify the course of the disease, that is, to slow down progression of the disease and to relieve chronic and acute symptoms. Newer therapeutic agents have been developed to interfere with immune system function at some step along the way, but these agents, in addition to being expensive, are associated with adverse effects due to broad immunological compromise. It is important to note that current therapies do not cure the disease, they provide only palliative attempts to alleviate symptoms and/or slow down progression.

Current multiple sclerosis therapies often result in broad-spectrum immunosuppression and other difficult to manage side-effects; therefore, antigen specific vaccines may be an important alternative. Traditional immunogenic vaccination is based on the introduction of foreign microbes, or microbe-associated antigens, to the immune system in order to develop memory T and B cells. These approaches also have met with limited success.

The TregTherapeutics approach is built upon providing a tolerogenic vaccine, rather than the traditional immunogenic vaccine. The fundamental principle of a tolerogenic vaccine is to suppress the activity of self-reactive Teffector cells. The TregTherapeutics vaccine provides a unique microenvironment for antigen presenting cells that allows the neuroantigen to be processed under uniquely tolerogenic conditions, with profound results.

THE TregTHERAPEUTICS APPROACH

The objective of the TregTherapeutics tolerogenic vaccine is to reverse the inflammatory T cell immune attack in demyelinating lesions of an MS patient, and subsequently, to create an anti-inflammatory tolerogenic response within that patient.

The vaccine is comprised of a tolerogenic cytokine and neuro-antigenic peptides. These components are electrostatically linked in an alum gel base and the formulation is injected subcutaneously. The cytokine utilized in such a manner induces a tolerogenic phenotype within antigen presenting cells (APCs), such as dendritic cells (DC), located in the subcutaneous tissue. The cytokine binds to its receptor on DCs, thus initiating a toleragenic cascade that results in subsequent preferential polarization of its cognate T cell into the FOX3P phenotype.

Concurrent with the action of the cytokine, the peptides are internalized by those same dendritic cells; these are processed and then arranged for presentation on MHC II molecules upon the surface of the cell. These activated DCs then travel to the draining lymph nodes where they come into contact with naive Tcells. When a cognate T cell receptor (TCR) is located, that Tcell, because of the influence of the tolerogenic cytokine previously described, is induced to become a FOXP3 Treg. This cell line is then clonally selected and expanded.

Instead of propagating pro-inflammatory T helper cells, as is the normal response of successful antigen presentation to a cognate Tcell, Teffector cells now undergo anergy and apoptosis. As stated, CD4+ CD25+, FOXP3+ Treg cells are clonally selected and their population expanded. The dynamic between declining T1 and T17 helper cells and the propagation of antigen-specific immunosuppressive Treg cell population reestablishes normal homeostasis, thus alleviating the pathogenic immune response. Tolerogenic memory T cells, created as part of this process, provide long-term recognition of pathologic neuropeptides as “self,” in lieu of the inflammatory reactions associated with the typical immune response in MS patients. The goal of the therapy is to end demyelination and other destructive neuropathological processes by reeducating the immune system to discriminate between self and non-self; thus, homeostatis is reestablished and long-term maintenance is accommodated by a robust population of antigen-specific memory Tregs in the CNS dedicated to self-tolerance.

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STATE OF PROJECT

The work in which the company is currently engaged is centered on humanization of a tolerogenic vaccine for multiple sclerosis. Specifically, formulation, human cell line in-vitro studies, and manufacturing are the current focal points in preparation for preliminary meetings with the FDA to review the regulatory plan. In addition, the company has submitted its request for orphan drug designation of primary progressive multiple sclerosis and will structure its regulatory plan accordingly.

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HOPE AND OBJECTIVES

After completing Investigational New Drug (IND) studies a Phase 1 clinical trial will be initiated, followed by Phase II clinical trials. It is the intention that a suitable biotech partner will be identified to move the MS project through latter stages of clinical trials.

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POTENTIAL APPLICATIONS

The American Autoimmune Related Diseases Association (AARDA) is dedicated to the eradication of autoimmune diseases and the alleviation of suffering and the socioeconomic impact of autoimmunity through fostering and facilitating collaboration in the areas of education, public awareness, research, and patient services in an effective, ethical and efficient manner.

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