XHA-A Novel Tolerance Therapeutic for Allergic Rhinitis

XHA-A 过敏性鼻炎新型耐受疗法

• 批准号: 8645072
• 负责人: Neil A Fanger
• 金额: $ 41.73万
• 依托单位: VIRTICI, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645072
• 关键词: Adrenal Cortex Hormones; Adult; Adverse effects; Affect; Allergens; Allergic; Allergic inflammation; Allergic rhinitis; Animals; Antigens; Antihistamines; Asthma; Automobile Driving; Breathing; Budgets; CD44 gene; Capital; Cataract Extraction; Cells; Child; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Clinical Trials; Cosmetics; Data; Degenerative polyarthritis; Development; Disease; Dose; Dust; Economic Burden; Emotional; Ensure; Extrinsic asthma; FDA approved; Fatigue; Funding; Future; Goals; Grant; Half-Life; Headache; Healed; Healon; Health; Hoarseness; Human; Hyaluronan; Hypersensitivity; Immune; Immune Tolerance; Immune system; Individual; Industry; Inflammation; Inflammatory; Interleukin-10; Investments; Learning; Legal patent; Leukotrienes; Life; Loratadine; Marketing; Medical; Memory impairment; Mental Depression; Mitogen-Activated Protein Kinases; Modeling; Molecular Weight; Non-Prescription Drugs; Nose; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Play; Pollen; Polysaccharides; Positioning Attribute; Prevalence; Production; Productivity; Protocols documentation; Regimen; Research; Research Design; Rights; Risk; Schedule; Schools; Signal Transduction; Sinus; Sinusitis; Sleep; Small Business Innovation Research Grant; Sneezing; Solutions; Sore Throat; Sports; Staging; Symptoms; Synvisc; T memory cell; TNFRSF11B gene; Therapeutic; Time; Tissues; Tonsillitis; United States; Work; airborne allergen; base; burden of illness; chronic rhinosinusitis; cost; crosslink; desensitization; design; healing; in vivo; inhibitor/antagonist; innovation; interest; meetings; mouse model; novel; phase 1 study; pre-clinical; programs; public health relevance; scale up; success; therapeutic target

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.

描述（由申请人提供）：该项目的目标是扩展一种新型化合物的开发，该化合物可以重新编程记忆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，其中一半归因于处方药。在全球范围内，有超过4亿人患有急性呼吸道感染，造成的经济负担估计超过200亿美元，而且发病率还在继续增加。