Research Project
8640510
DESCRIPTION (provided by applicant): It has been proposed that over 30 different neurological diseases have a presumptive autoimmune component associated with their pathophysiology. While identifying antigens has aided in the diagnosis of some diseases, the ultimate goal of such research efforts is to develop therapies which can reduce, or eliminate, the autoimmune component of the disease. Some investigators claim that systemic autoantigen therapy is the future, while others claim that oral antigen-specific therapies are unlikely to ever be successful. The difficulties for creating an efficacious oral autoantigen therapy are basically twofold: practicality and efficacy. Practically, most protein autoantigens will be expensive to manufacture, to administer, and may not remain intact following passage through the gastrointestinal tract. Therapeutically, even if some of the protein autoantigens survive to interact with immune cells in the Gut Associated Lymphoid Tissue (GALT), their ability to significantly reduce autoimmune T and B cells responses in patients has not been effectively demonstrated. Developing a routine, practical strategy for oral autoantigen therapy is certainly a difficult and risky proposition. Demonstrating the feasibility of a technology for routine and practical oral autoantigen therapy would be unique. As a proof of principle for this platform technology, we propose to manufacture large quantities of a novel fusion protein consisting of an autoantigen and the reovirus sigma1 protein using transgenic soybean seeds as an expression platform. The logic behind such an approach lies in the ability of the reovirus sigma1 protein to bind microfold cell covering mucosal lymphoid tissues. Autoantigens fused to sigma1 target the immunogen to these cells, and deliver the autoantigen in a tolerizing context to limit an ongoing autoimmune response. Further, while such autoantigens and fusion proteins are difficult to manufacture, the ability to express large quantities of a sizeable protein, and administer it as a consumable soymilk formulation is unique to this platform expression system. The autoantigen that we will focus on for these studies is one that most patients with myasthenia gravis mount an immune response against: i.e. the extracelluar portion of the nicotinic acetylcholine receptor alpha 1 chain. Biases which prevent such a proposal from being funding using conventional granting mechanisms, include the notions that: 1) Oral autoantigen therapies will not work in humans, even with advances in technology; 2) It is unclear if it will evr be practical to express the variety and quantity of neuronal autoantigens necessary for oral therapy using any protein expression system; 3) No companies use transgenic soybean seeds as a protein expression platform, therefore this technology is not an industry standard; and 4) It is unlikely that the regulatory agencies will ever approve an oral autoantigen therapy contained within a soymilk formulation instead of a purified protein. If these hurdles can be overcome, we will have demonstrated whether such a strategy is feasible and practicable.
