Phenotyping Interstitial Cystitis/Bladder Pain Syndrome by ICE-MRI Based Bladder Permeability Assay

基于 ICE-MRI 的膀胱通透性测定对间质性膀胱炎/膀胱疼痛综合征进行表型分析

• 批准号: 10545115
• 负责人: JONATHAN H KAUFMAN
• 金额: $ 67.3万
• 依托单位: LIPELLA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545115
• 关键词: Affect; Anti-Inflammatory Agents; Area; Biological Assay; Bladder; Bladder mucosa; Caring; Catheters; Chronic; Clinical; Clinical Trials; Complement; Cystoscopes; Cystoscopy; Data; Development; Diagnosis; Diagnostic tests; Diffuse; Diffusion; Ensure; Etiology; Exclusion; Exposure to; FDA approved; Female; Funding; Grant; Human; Hypersensitivity; Impairment; Individual; International; Interstitial Cystitis; Ionizing radiation; Lesion; Magnetic Resonance Imaging; Measures; Medical; Mucous Membrane; Mus; Pain; Pathology; Patients; Permeability; Pharmacologic Substance; Phase; Phenotype; Population; Prevalence; Prospective Studies; Radiation; Radiolabeled; Rattus; Relaxation; Signal Transduction; Societies; Sterility; Symptoms; Testing; Thinness; Time; Touch sensation; assay development; base; chronic pelvic pain; contrast enhanced; contrast imaging; dalton; ferumoxytol; gadobutrol; human subject; improved; intravesical; minimally invasive; new therapeutic target; pressure; urinary; working group

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic, debilitating condition that affects more than 2 million individuals within the US. Recently, the chronic pelvic pain working group of the ICS has classified IC/BPS into either hypersensitive bladder with no identifiable pathology explaining the symptoms of IC/BPS, IC/BPS with Hunner lesion (HIC) or IC/BPS with no lesions on cystoscopy (NHIC). Though the etiology of IC/BPS is multifactorial, a large body of evidence supports the impairment of bladder mucosal permeability as a major pathophysiological cause in HIC. Yet, there remains variability (5-57%) in the true identification of IC/BPS that is bladder-centric on the basis on cystoscopy. Therefore, a minimally invasive, assay that reliably measures bladder permeability without evoking pain or exposing ionizing radiation to subjects may be able to meet the FDA regulatory criteria for a diagnostic test. With the past funding support, we developed a radiation free, minimally invasive assay of bladder mucosal permeability, and we demonstrated the validity of intravesical contrast enhanced magnetic resonance imaging (ICE-MRI) to measure permeability of thin mouse and rat bladder at high field scanners of 7T and 9.4T (PMC7509285; PMC6028942; PMC8484474). A key feature of our ICE-MRI assay of bladder permeability is the transurethral catheter instillation of Gadobutrol and Ferumoxytol mixture and then MRI capitalizes on the linear relationship between the concentration of instilled Gadobutrol diffusing passively into the mucosa to cause concentration dependent changes in T1 relaxation rate (1/T1 relaxation time) of the mucosa. While Gadobutrol instilled into bladder lumen diffuses into mucosa down the concentration gradient, our preliminary data demonstrates that mucosa lesion accelerates the Gadobutrol diffusion relative to normal areas. We now seek funding support to generate clinical evidence for demonstrating that ICE-MRI can be a diagnostic test for bladder-centric phenotype in IC/BPS patients to complement conventional cystoscopy-based diagnosis. Following Specific Aims will test the hypothesis that bladder mucosal permeability of instilled Gadobutrol mixture descends quantitatively from HIC >NHIC >asymptomatic control subjects.: Aim 1: To calibrate the ICE-MRI based bladder mucosal permeability assay on HIC, NHIC patients and asymptomatic subjects who have normal cystoscopic findings. In a cross-sectional prospective study on previously cystoscoped 10 HIC patients, 10 NHIC patients, and 10 asymptomatic controls, we will calibrate the ICE-MRI based bladder mucosal permeability assay. Aim 2: To manufacture sterile clinical trial materials and complete the IND/IDE submission for the ICE-MRI based bladder permeability assay kit. A radiation-free, objective diagnostic test of bladder permeability can objectively phenotype IC/BPS IC/BPS that is bladder-centric, thereby identifying patients who would be most likely to benefit from anti- inflammatory therapies and avoid the delay in getting appropriate medical care. Our assay can also enable the objective selection of IC/BPS patients for clinical trials of newer therapies targeting bladder pathology.

间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种慢性、使人衰弱的疾病， 在美国境内的百万人。最近，ICS的慢性盆腔疼痛工作组将 IC/BPS进入过敏性膀胱，没有可识别的病理学解释IC/BPS的症状， IC/BPS伴Hunner病变（HIC）或IC/BPS膀胱镜检查无病变（NHIC）。虽然病因 IC/BPS是多因素的，大量证据支持膀胱粘膜通透性受损， 是HIC的主要病理生理原因。然而，在真正识别方面仍然存在差异（5-57%） 基于膀胱镜检查以膀胱为中心的IC/BPS。因此，一种微创的、可靠地 测量膀胱渗透性而不引起疼痛或使受试者暴露于电离辐射， 符合FDA诊断测试的监管标准。在过去的资金支持下，我们开发了一种辐射 自由，微创膀胱粘膜渗透性测定，我们证明了有效性， 膀胱内对比增强磁共振成像（ICE-MRI）测量瘦小鼠渗透性 在7 T和9.4T的高场扫描仪（PMC 7509285; PMC 6028942; PMC 8484474）下观察大鼠膀胱。一个关键 我们的膀胱渗透性ICE-MRI测定的特征是经尿道导管滴注钆布醇， Ferumoxytol混合物，然后MRI利用滴注浓度之间的线性关系， 钆布醇被动扩散到粘膜中，引起T1弛豫率的浓度依赖性变化 （1/T1弛豫时间）。当Gadobutrol滴入膀胱腔时， 浓度梯度，我们的初步数据表明，粘膜损伤加速钆布醇 相对于正常区域的扩散。我们现在寻求资金支持，以产生临床证据， 证明ICE-MRI可以作为IC/BPS患者膀胱中心表型的诊断测试， 补充传统的膀胱镜检查为基础的诊断。以下具体目标将检验假设， 膀胱粘膜渗透性从HIC >NHIC定量下降 >无症状对照受试者。目的1：校准基于ICE-MRI的膀胱粘膜渗透性测定 HIC、NHIC患者和膀胱镜检查结果正常的无症状受试者。以横截面 对10例既往接受过膀胱镜检查的HIC患者、10例NHIC患者和10例无症状患者进行的前瞻性研究 对照，我们将校准基于ICE-MRI的膀胱粘膜渗透性测定。目标2：制造 无菌临床试验材料，并完成基于ICE-MRI的膀胱渗透性的IND/IDE提交 检测试剂盒。一种无辐射的、客观的膀胱通透性诊断试验可以客观地表现为IC/BPS 以膀胱为中心的IC/BPS，从而确定最有可能从抗- 炎症治疗，避免延误获得适当的医疗护理。我们的试验还可以使 客观选择IC/BPS患者进行针对膀胱病理学的新疗法的临床试验。