SuperGAGs for Intravesicular Treatment of Interstitial Cystitis

用于间质性膀胱炎膀胱内治疗的 SuperGAG

• 批准号: 10205046
• 负责人: ROBERT Evan HURST
• 金额: $ 126.66万
• 依托单位: GLYCOLOGIX, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205046
• 关键词: Abdominal Pain; Adherence; Affinity; American; Animal Model; Binding; Biological Assay; Biopolymers; Bladder; Brain; CCL2 gene; Charge; Chelating Agents; Chemicals; Chemistry; Chondroitin Sulfates; Chronic; Chronic Disease; Clinical; Clinical Trials; Consultations; Cyclic GMP; Data; Development; Devices; Disease; Effectiveness; Etiology; Extravasation; FDA approved; Face; Family; Filtration; Fluorescent Dyes; Future; Generations; Glycosaminoglycans; Goals; Heparin; Human; Hydrophobicity; Increased frequency of micturition; Inflammation; Inflammatory; Interstitial Cystitis; Intravesical Administration; Investigation; Irritable Bowel Syndrome; Label; Lead; Lectin; Ligands; Magnetic Resonance Imaging; Measures; Mediating; Medical; Medical Device; Methods; Modality; Modeling; Molecular Weight; Morbidity - disease rate; Normal Range; Organ; Pain; Patients; Pelvic Pain; Performance; Permeability; Phase; Preparation; Process; Proteoglycan; Rattus; Research Contracts; Safety; Small Business Innovation Research Grant; Spinal; Structure; Surface; Symptoms; System; Testing; Therapeutic; Time; Tissue Banks; Tissues; Toxicology; Transgenic Mice; Treatment Efficacy; United States; Urge Incontinence; Urothelium; Visceral pain; Water; biomaterial compatibility; chronic pain; clinical candidate; clinical development; clinical material; comorbidity; compare effectiveness; contrast enhanced; design; effective therapy; hyaluronate; improved; innovation; meetings; micturition urgency; mouse model; novel; novel therapeutics; polysulfated glycosaminoglycan; pre-clinical; preclinical development; preclinical evaluation; preclinical study; programs; research clinical testing; residence; response; restoration; safety study; scale up; solute; success; therapeutic candidate; treatment strategy; urinary

PROJECT SUMMARY/ABSTRACT The goal of this Phase II SBIR project is to advance a new treatment for interstitial cystitis/bladder pain syndrome (IC/BPS) to clinical trials. IC/BPS is a chronic disease characterized by lower pelvic pain, urinary urgency and frequency, and urge incontinence. Chronic pain results from a disruption of the protective glycosaminoglycan (GAG) layer of the bladder wall, causing permeability and urinary leakage. There are few therapeutic options and approved treatments have met with limited success. Hence, the 4-12 million Americans suffering with IC/BPS face a lifetime of chronic debilitating abdominal pain and other symptoms. One promising treatment option to restore bladder impermeability is GAG replenishment therapy. However, the single chain, low molecular weight (MW) GAGs that are currently used do not properly mimic the proteoglycan- bound GAG layer of the normal urothelium, and response rates are low. Proteoglycans display multiple sulfated GAG chains in clusters, creating zones of high anionic charge and bound water. Glycologix has developed a novel and innovative family of high MW, branched biopolymers known as SuperGAGs that mimic the structure of proteoglycans. SuperGAGs have been designed to improve adherence to the urothelium due to their greater size, dendritic structure, and affinity for the bladder surface. In the Phase I project, synthesis and preclinical evaluation of first-generation SuperGAGs successfully demonstrated proof of concept for the preparation of large SuperGAG biopolymers (MW > 1MDa), and the ability of these biopolymers to restore bladder impermeability and reduce visceral pain in a well-characterized rat model of bladder permeability. This result was confirmed in a second model in which bladder permeability was induced through an inflammatory process and bladder permeability was quantified using magnetic resonance imaging (MRI). In this Phase II project, Aim 1 is to synthesize and characterize a small number of SuperGAG derivatives bearing targeting ligands and other groups known to enhance binding to the bladder wall using methods validated in Phase I. Aim 2 is to compare the effectiveness of these biopolymers in a well-established mouse model of induced IC/BPS in which bladder permeability is induced by inflammation. Quantitative contrast- enhanced MRI will be used to measure restoration of bladder impermeability. The SuperGAG with the longest adherence time, tightest binding and most effectiveness will be selected for clinical development. Aim 3 will initiate development of the SuperGAG clinical candidate by executing required GLP safety studies and GMP synthesis in concert with input from the FDA. At the conclusion of the Phase II project, Glycologix intends to submit an Investigational Device Exemption with the FDA to gain approval for initiation of human clinical trials of SuperGAG Bladder Instillate as a new medical device treatment option for patients suffering with IC/BPS.

项目总结/摘要 该二期SBIR项目的目标是推进间质性膀胱炎/膀胱疼痛的新治疗 综合征（IC/BPS）的临床试验。IC/BPS是一种慢性疾病，其特征是下骨盆疼痛、泌尿系统疾病、 尿急和尿频以及急迫性尿失禁。慢性疼痛是由于神经系统的保护功能被破坏， 膀胱壁的糖胺聚糖（GAG）层，导致渗透性和尿渗漏。很少 治疗选择和批准的治疗方法的成功有限。因此，400 - 1200万 患有IC/BPS的美国人一生都面临慢性衰弱性腹痛和其他症状。 恢复膀胱不通透性的一种有希望的治疗选择是GAG补充疗法。但 目前使用的单链、低分子量（MW）GAG不能正确地模拟蛋白聚糖， 结合正常尿路上皮的GAG层，应答率低。蛋白聚糖显示多种 硫酸化的GAG链成簇，产生高阴离子电荷和结合水的区域。 Glycologix开发了一种新型的高分子量、支链生物聚合物， 模拟蛋白聚糖结构的SuperGAG。SuperGAG的设计旨在改善 由于它们较大的尺寸、树枝状结构和对膀胱表面的亲和力，粘附于尿道。在 第一代SuperGAG的I期项目、合成和临床前评价成功 证明了制备大型SuperGAG生物聚合物（MW > 1 MDa）的概念验证， 这些生物聚合物恢复膀胱不渗透性和减少内脏疼痛的能力， 大鼠膀胱通透性模型。这一结果在第二个模型中得到了证实， 通过炎症过程诱导，并使用磁共振成像技术定量膀胱渗透性。 磁共振成像（MRI）。 在该第二阶段项目中，目标1是合成和表征少量SuperGAG衍生物 带有靶向配体和其它已知增强与膀胱壁结合的基团 在第一阶段得到验证。目的2是比较这些生物聚合物在良好建立的小鼠中的有效性 诱导IC/BPS模型，其中膀胱渗透性由炎症诱导。定量对比- 增强MRI将用于测量膀胱不渗透性的恢复。最长的SuperGAG 将选择粘附时间、最紧密结合和最有效性进行临床开发。目标3将 通过执行所需的GLP安全性研究和GMP，启动SuperGAG临床候选药物的开发 与FDA的输入一致的合成。在第二阶段项目结束时，Glycologix打算 向FDA提交研究器械豁免，以获得启动人体临床试验的批准 SuperGAG膀胱灌注液作为IC/BPS患者的新医疗器械治疗选择。

项目成果

SuperGAG biopolymers for treatment of excessive bladder permeability.

Supergag生物聚合物治疗过度膀胱渗透性。

• DOI: 10.1002/prp2.709
• 发表时间: 2021-03
• 期刊: Pharmacology research & perspectives
• 影响因子: 2.6
• 作者: Towner RA;Greenwood-Van Meerveld B;Mohammadi E;Saunders D;Smith N;Sant GR;Shain HC;Jozefiak TH;Hurst RE
• 通讯作者: Hurst RE