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.

项目概要/摘要 该 II 期 SBIR 项目的目标是推进间质性膀胱炎/膀胱疼痛的新治疗方法 综合征（IC/BPS）到临床试验。 IC/BPS 是一种慢性疾病，其特征是下盆腔疼痛、尿频 尿急、尿频和急迫性尿失禁。慢性疼痛是由于保护性功能障碍造成的 膀胱壁的糖胺聚糖 (GAG) 层，导致渗透性和漏尿。有几个 治疗选择和批准的治疗方法取得的成功有限。因此，4-1200万 患有 IC/BPS 的美国人将面临终生的慢性腹痛和其他症状。 恢复膀胱不通透性的一种有前景的治疗选择是 GAG 补充疗法。然而， 目前使用的单链、低分子量 (MW) GAG 不能正确模拟蛋白聚糖。 正常尿路上皮结合 GAG 层，反应率较低。蛋白多糖显示多种 硫酸化 GAG 链成簇，形成高阴离子电荷和结合水区域。 Glycologix 开发了一种新颖且创新的高分子量支化生物聚合物系列，称为 模仿蛋白聚糖结构的 SuperGAG。 SuperGAG 旨在改进 由于其较大的尺寸、树突结构和对膀胱表面的亲和力，因此能够粘附于尿路上皮。在 第一代SuperGAGs一期项目合成及临床前评价成功 展示了制备大型 SuperGAG 生物聚合物（MW > 1MDa）的概念证明，以及 这些生物聚合物能够以充分表征的方式恢复膀胱不通透性并减轻内脏疼痛 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，其中膀胱通透性 通过炎症过程诱导，并使用磁力对膀胱通透性进行量化 磁共振成像（MRI）。 在这个二期项目中，目标 1 是合成和表征少量 SuperGAG 衍生物 承载靶向配体和其他已知使用方法增强与膀胱壁结合的基团 在第一阶段得到验证。目标 2 是比较这些生物聚合物在成熟小鼠中的有效性 诱导 IC/BPS 模型，其中膀胱通透性是由炎症诱导的。定量对比- 增强型 MRI 将用于测量膀胱不通透性的恢复情况。最长的 SuperGAG 将选择依从时间、最紧密的结合和最有效的方式进行临床开发。目标3将 通过执行所需的 GLP 安全研究和 GMP 启动 SuperGAG 临床候选药物的开发 合成与 FDA 的输入一致。在第二阶段项目结束时，Glycologix 打算 向 FDA 提交研究设备豁免以获得启动人体临床试验的批准 SuperGAG Bladder Intilate 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.

• 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