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

描述(由申请人提供)：已经提出了30多种不同的神经疾病有与其病理生理相关的推定的自身免疫成分。虽然识别抗原有助于某些疾病的诊断，但这种研究的最终目标是开发能够减少或消除疾病的自身免疫成分的治疗方法。一些研究人员声称全身性自身抗原治疗是未来，而另一些人则声称口服抗原特异性治疗永远不太可能。 一定要成功。创造一种有效的口服自身抗原疗法的困难基本上是 双重：实用性和有效性。实际上，大多数蛋白质自身抗原的制造和使用都很昂贵，而且在通过胃肠道后可能不会保持完好。在治疗方面，即使一些蛋白自身抗原存活下来与肠道相关淋巴组织(GALT)中的免疫细胞相互作用，它们显著降低患者自身免疫T和B细胞反应的能力尚未得到有效证明。开发一种常规的、实用的口服自身抗原治疗策略肯定是一个困难和危险的命题。证明一种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。为了验证这一平台技术的原理，我们建议以转基因大豆种子为表达平台，大量生产由自身抗原和呼肠孤病毒Sigma1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Sigma1蛋白结合覆盖粘膜淋巴组织的微折叠细胞的能力。融合为Sigma1的自身抗原将免疫原靶向这些细胞，并将自身抗原在“耐受环境”中递送以限制 一种持续的自身免疫反应。此外，虽然这种自身抗原和融合蛋白很难制造，但表达大量大小蛋白并将其作为消耗性豆奶配方给药的能力是该平台表达系统所独有的。在这些研究中，我们将重点关注的自身抗原是大多数重症肌无力患者对其产生免疫反应的抗原：即烟碱型乙酰胆碱受体α1链的细胞外部分。阻碍这样一项建议使用传统授予机制获得资金的偏见包括：1)即使技术进步，口服自身抗原疗法也不会在人类身上起作用；2)目前尚不清楚使用任何蛋白质表达系统来表达口服疗法所需的各种神经元自身抗原是否可行；3)没有公司使用转基因大豆种子作为蛋白质表达平台，因此这项技术不是行业标准；以及4)监管机构永远不太可能批准包含在豆浆制剂中的口服自身抗原疗法，而不是纯化的蛋白质。如果这些障碍能够克服，我们就已经证明了这种战略是否可行和可行。

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.