Multiple Sclerosis affects millions of people worldwide and while the past decade hasseen a wave of disease-modifying drugs and immunomodulating therapies approved by theFDA, these drugs are expensive and there is still no cure for the disease. Furthermore, thechance of disability is fairly certain for many diagnosed patients. For several decades, antigen-specific treatments have been used in experimentalautoimmune encephalomyelitis (EAE) animal models to demonstrate their potential forsuppressing autoimmune responses. Successes with preventing (prophylaxis) and limitingongoing disease (therapeutic) have been documented using a wide variety of myelin proteins,peptides, autoantigen-conjugates, and mimics when administered in a variety of ways (systemicinjections, intranasal, transdermal). While those successes were not translatable in the clinic,we have learned a great deal about the roadblocks and hurdles that must be addressed if suchtherapies are to eventually be realized. These include the use of autoantigens containingmultiple epitopes, the presentation of antigens in a tolerizing context, and a practical platformthat can generate the large amounts of autoantigens needed for therapy without extreme cost. The experimental approach in the accompanying SBIR Phase I application directlyaddresses current limitations with oral tolerance therapy. We propose to manufacture twoautoantigens involved with multiple sclerosis - myelin oligodendrocyte protein (MOG) andproteolipid protein (PLP) - as fusion proteins with reovirus sigma1 protein, using soybean as apractical expression system for production and formulation. We also propose to make achimeric protein containing domains from myelin basic protein (MBP), MOG and PLP, alsofused to sigma1 protein. The logic behind our approach lies in the ability of the reovirus sigma1protein to bind microfold cells covering mucosal lymphoid tissues. Autoantigens fused tosigma1 protein target the immunogen to these cells and deliver the autoantigen in a "tolerizingcontext" to limit an ongoing autoimmune response. In previous studies we demonstratedefficacy of a soy-derived sigma1 fusion protein containing the myelin basic protein (MBP)autoantigen. In the current study will expand our R&D to include expression and efficacy testingof MOG-sigma1 and PLP-sigma1 autoantigens expressed in soybean. Our long term goal is todevelop a practical cocktail of MBP, MOG and PLP autoantigens that can be formulated for themajority of patients that present with autoantibodies against any of these three proteins.
Public Health Relevance Statement: NARRATIVE
The overall objective of this proposal is to translate two recent discoveries into a
practical platform technology for development of an oral therapy for autoimmune multiple
sclerosis. Specifically, we propose to test the feasibility of producing low cost, consumable
formulations which can dramatically attenuate the host response against autoantigens by
targeting these specific proteins to mucosal lymphoid organs. At the conclusion of these
studies, we will have demonstrated our ability to express functional, and potentially therapeutic,
soy formulations which have unique advantages.
Project Terms: |
