Platform for practical delivery of oral autoantigens as co-therapies for neurolog

描述（由申请人提供）：已经提出超过30种不同的神经系统疾病具有与其病理生理学相关的假定自身免疫组分。虽然识别抗原有助于诊断某些疾病，但此类研究工作的最终目标是开发可以减少或消除疾病的自身免疫成分的疗法。一些研究者声称，系统性自身抗原治疗是未来的发展方向，而另一些人则声称，口服抗原特异性治疗不太可能永远 成功。 创建有效的口服自身抗原疗法的困难基本上是 双重性：实用性和有效性。实际上，大多数蛋白质自身抗原的制造、施用将是昂贵的，并且在通过胃肠道后可能不能保持完整。在治疗上，即使一些蛋白质自身抗原存活以与肠相关类淋巴组织（GALT）中的免疫细胞相互作用，它们显著降低患者中自身免疫T和B细胞应答的能力尚未得到有效证实。开发一个常规的，实用的口服自身抗原治疗策略肯定是一个困难和风险的命题。 证明常规和实用的口服自身抗原治疗技术的可行性将是独一无二的。作为该平台技术的原理证明，我们提出使用转基因大豆种子作为表达平台来制造大量由自身抗原和呼肠孤病毒sigma 1蛋白组成的新型融合蛋白。这种方法背后的逻辑在于呼肠孤病毒sigma 1蛋白结合覆盖粘膜淋巴组织的微折叠细胞的能力。与σ 1融合的自身抗原将免疫原靶向这些细胞，并在“耐受性环境”中递送自身抗原，以限制免疫原的表达。 持续的自身免疫反应此外，虽然这种自身抗原和融合蛋白难以制造，但表达大量相当大的蛋白质并将其作为可消耗的豆奶制剂施用的能力是该平台表达系统所独有的。我们将在这些研究中关注的自身抗原是大多数重症肌无力患者产生免疫应答的抗原：即烟碱乙酰胆碱受体α 1链的细胞外部分。 使用传统的资助机制阻止这样的提议获得资助的偏见包括以下概念：1）口服自身抗原疗法在人类中不起作用，即使技术进步; 2）尚不清楚使用任何蛋白质表达系统表达口服疗法所需的神经元自身抗原的种类和数量是否实际; 3）没有公司使用转基因大豆种子作为蛋白质表达平台，因此该技术不是行业标准;以及4）监管机构不太可能批准包含在豆奶制剂中而不是纯化蛋白质中的口服自身抗原疗法。如果我们能够克服这些障碍，我们便可以证明这个策略是否可行和切实可行。

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.