XHA-A Novel Tolerance Therapeutic for Allergic Rhinitis

描述（由申请人提供）：本项目的目标是扩展一种新型化合物的开发，该化合物可以重编程记忆T淋巴细胞以诱导过敏性鼻炎（AR）的耐受性。AR是美国（US）最常见的慢性疾病之一，估计影响超过5000万人[1，2]。因此，美国每年的AR经济负担超过120亿美元，其中一半的费用归因于处方药[3]。在全球范围内，超过4亿人患有AR，估计经济负担超过200亿美元[4]，并且患病率继续增加。 变应性鼻炎是一种上呼吸道慢性炎症性疾病。它发生在过敏原，如皮屑，灰尘或花粉被具有致敏免疫系统的个体吸入时。过敏性炎症可导致鼻塞、头痛、声音嘶哑、鼻后滴漏、扁桃体炎、喉咙痛、打喷嚏和鼻塞。由于鼻窦的复发性炎症，已知AR患者发展为慢性鼻窦炎。此外，与无AR的哮喘患者相比，患有AR的患者更有可能在以后的生活中发展为哮喘[5]，并且表现出对哮喘发作的控制较差[6，7]。最后，AR会影响睡眠质量，导致疲劳、易怒、记忆缺陷、白天嗜睡和抑郁。对于成年人来说，AR症状会影响成年人的情绪健康和工作效率[8]。对于儿童来说，它会影响在学校学习，社交和运动的能力[9]。 最近，我们发现，当记忆T细胞在多聚体形式的高分子量透明质酸（HMW-HA）（愈合组织中存在的天然多糖）的背景下遇到抗原时，它们发展出耐受性诱导的TR 1表型并产生大量的白细胞介素-10（IL-10）。我们的研究表明，多聚体HMW-HA通过CD 44依赖性MAP激酶信号传导促进IL-10的产生[10-13];相反，我们发现单体HMW-HA不会。因此，基于该研究，通过化学交联HMW-HA开发了一种称为XHA的新型多聚体治疗剂，以保持完整性和功效并延长体内半衰期。使用0.1%XHA溶液的鼻内递送，我们在体内产生了抗原特异性TR 1细胞，并在小鼠气道超敏反应模型中抑制疾病。总体目标是开发XHA作为一种治疗方法，诱导对周围空气过敏原的耐受性，逆转与AR相关的症状和炎症。拟定研究的目的是：1）建立GMP兼容的XHA规模化生产和QA/QC方案，2）确定XHA的最佳剂量以最大限度地抑制鼻过敏性鼻炎，3）证明在最佳剂量下XHA能够逆转已建立的过敏性鼻炎。

DESCRIPTION (provided by applicant): The goal of this project is to extend the development of a novel compound that can reprogram memory T lymphocytes to induce tolerance in allergic rhinitis (AR). AR is one of the most common chronic diseases in the United States (US) and is estimated to affect more than 50 million people [1,2]. As a result, the annual US economic burden of AR exceeds $12 billion, with half of these costs attributed to prescription medications [3]. Globally, over 400 million people suffer from AR, with an estimated economic burden of greater than $20B [4] and the prevalence continues to increase. Allergic rhinitis is a chronic inflammatory disease of the upper airway. It occurs when an allergen, such as dander, dust, or pollen is inhaled by an individual with a sensitized immune system. The allergic inflammation can result in nasal congestion, headaches, hoarseness, postnasal drip, tonsillitis, sore throat, sneezing and stuffy nose. Due to recurring inflammation o the sinuses, AR patients are known to develop chronic rhinosinusitis. Moreover, patients suffering from AR are more likely to develop asthma later in life [5] and to demonstrate less control of asthma attacks compared to asthma patients without AR [6,7]. Finally, AR can impact quality of sleep, contributing to fatigue, irritability, memory deficits, daytime sleepiness and depression. For adults, AR symptoms impact adult emotional well-being and work productivity [8]. For children, it can impact the ability to learn in school, socialize and play sports [9]. Recently, we discovered when memory T-cells encounter antigen in the context of a multimeric form of high- molecular weight hyaluronan (HMW-HA), a natural polysaccharide present in healing tissues, they develop a tolerance-inducing TR1 phenotype and produce high amounts of interleukin-10 (IL-10). Our studies have demonstrated that multimeric HMW-HA promotes IL-10 production via CD44 dependent MAP kinase signaling [10-13]; in contrast, we have found monomeric HMW-HA does not. Thus, based on this research, a novel multimeric therapeutic called XHA was developed by chemically cross-linking HMW-HA to maintain integrity and efficacy and to prolong in vivo half-life. Using intranasal delivery of a 0.1% XHA solution, we have generated antigen-specific TR1 cells in vivo and inhibited disease in a mouse model of airway hypersensitivity. The overall goal is to develop XHA as a therapeutic that induces tolerance against ambient aeroallergens, reversing symptoms and inflammation associated with AR. The aims of the proposed studies are to: 1) establish GMP-compatible XHA scale-up production and QA/QC protocols, 2) determine the optimal dosing of XHA to maximize inhibition of nasal allergic rhinitis, and 3) demonstrate that at optimal dosing XHA is able to reverse established allergic rhinitis.