FrostBite-DMR - A new Drug-Free Approach for Treating Type 2 Diabetes Supplemental Request

FrostBite-DMR - 一种治疗 2 型糖尿病的新无药方法补充请求

• 批准号: 10748325
• 负责人: John M BAUST
• 金额: $ 1.21万
• 依托单位: CELL PRESERVATION SERVICES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10748325
• 关键词: Abbreviations; Ablation; Acute Renal Failure with Renal Papillary Necrosis; Address; Adverse event; Age; Agonist; Allergic Reaction; Applications Grants; Arrhythmia; Back; Biliary; Biological Products; Biomedical Engineering; Biotechnology; Body Weight decreased; Businesses; Cardiac; Cardiovascular system; Catheters; Cells; Clinical Research; Clinical Trials; Communities; Cryopreserved Cell; Cryosurgery; Development; Devices; Diabetic Retinopathy; Disease; Disease model; Dose; Drug Side Effects; Drug Storage; Duodenum; Endoscopes; Equipment; Esophagus; Failure; Freezing; Frostbite; Funding; GLP-I receptor; Gallbladder; Grant; Headache; Hemorrhage; Hepatic; Human Resources; Hyperglycemia; Hypoglycemia; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Knowledge; Licensing; Life; Liver; Malignant neoplasm of pancreas; Malignant neoplasm of thyroid; Marketing; Measures; Medical; Medical Device; Metformin; Methods; Modality; Molecular; Molecular Biology; Mucous Membrane; Muscle; National Institute of Diabetes and Digestive and Kidney Diseases; Necrosis; Nitrogen; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Pancreas; Pancreatitis; Parents; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Postoperative Period; Production; Prostate; Publishing; Radiofrequency Interstitial Ablation; Recording of previous events; Reporting; Risk; Safety; Serous Membrane; Small Intestines; Surface; System; Taste Perception; Technology; Temperature; Testing; Thermal Ablation Therapy; Time; Tissues; Water; alternative treatment; bariatric surgery; comparative efficacy; design; efficacy testing; first-in-human; flexibility; gastrointestinal; improved; in vivo Model; in vivo evaluation; indexing; infancy; inhibitor; instrument; interest; medical schools; microwave electromagnetic radiation; non-compliance; novel strategies; novel therapeutics; parent grant; preservation; pressure; repaired; response; safe patient; side effect; success; tumor; tumor ablation

Type 2 diabetes mellitus (T2D) is increasing in incidence throughout the world with nearly 552 million people who may be afflicted with this disease by 2030. There are now over 50 different drugs that can be used to treat T2D but about half of patients do not respond well to these agents and their hyperglycemic condition remains a life-threatening problem. Indeed, the first line drugs such as Metformin, GLP-1 receptor agonists (e.g. Semaglutide), DPP-4 inhibitors, SGLT2 inhibitors and others have documented side effects that include hypoglycemia, gastrointestinal side effects, pancreatitis, pancreatic cancer, thyroid cancer, gallbladder issues, cardiovascular changes, acute kidney injury, diabetic retinopathy, allergic reactions, increase in biliary disease, change in taste and headaches. As an alternative to these drugs, the first in human report was published in 2016 showing that duodenal mucosal resurfacing (DMR) of T2D patients could improve their hyperglycemic conditions as well as several hepatic indices without having to use these front line drugs. This study was initiated, in part, because of the well documented and surprising observation that bariatric surgery also resulted in a similar benefit to T2D patients that was independent of consequential weight loss. Since 2016 several clinical studies have been conducted on DMR and all showed benefit to patients with T2D who weren’t responding to traditional medical treatments or who were non- compliant with medications. While promising, DMR has been reported to have a high rate of technical failure due to catheter malfunctioning suggesting that improvements in the technical-functional aspects of current devices need to be addressed. Furthermore, one such DMR device that has shown benefit in several clinical trials uses hydrothermic ablation (hot water at 80 to 90°C) to achieve DMR. Like radiofrequency ablation, HiFU, microwave and other heat ablation technologies used to target and ablate tumors and treat cardiac arrhythmias, the passive spread of heat can’t be easily controlled and has shown to result in collateral tissue damage such as muscular segmental necrosis and serosa bleeding with postoperative adverse events from DMR hydrothermic ablation reported to be an issue with 64% of the cases. CPSI Biotech intends to capitalize on this emerging DMR market that is currently in its infancy and develop an improved DMR thermal ablation probe that uses freezing (cryoablation) rather than heat for duodenal resurfacing. The advantages of the proposed FrostBite- DMR cryoballoon include (a) freezing is self-limiting in contrast to heat and presents less opportunity for collateral damage to adjacent deeper duodenal tissue; (b) cryoablation has been shown to be more effective, safer and have fewer complications than heat based ablation in numerous tissues including cardiac, esophageal, renal, prostate and pancreatic among others; (c) CPSI’s PSN cryoablation systems can generate and deliver ablative temperatures faster and colder than any other known cryoablation systems currently on the market thus decreasing procedural time and, as such, will offer improved versatility and safety compared to current technologies. The Specific Aims of this project are the following: (SA1) Determine the thermal ablative dose of duodenum cells subjected to cryoablation; (SA2) Develop FrostBite-DMR™, a flexible endoscope compatible cryoballoon, and (SA3) Test the efficacy of FrostBite in ex vivo and in vivo models. The overall intent of the project is to capitalize on the documented success of DMR published in the last few years as well as CPSI’s expertise in developing improved cryoablation catheters so that an improved DMR ablation device can be developed that is safer, more efficient, and can be better operator controlled leading to more successful DMR for T2D patients who do not respond well to current T2D drug treatments. This is a supplemental equipment request under the parent grant, 1R43DK135117-01, to replace a -80o freezer that given its age is no longer repairable. CPSI currently has no -80o freezer and needs to acquire one to satisfy the specific aims detailed in the parent Phase I grant application.

2型糖尿病(T2D)在全世界的发病率正在增加，有近5.52亿人 到2030年，可能会感染这种疾病的人。现在有超过50种不同的药物可以 用于治疗T2D，但约有一半的患者对这些药物和他们的 高血糖状况仍然是一个威胁生命的问题。事实上，一线药物，如 二甲双胍、GLP-1受体激动剂(如赛马鲁肽)、DPP-4抑制剂、SGLT2抑制剂和 其他人已经记录了副作用，包括低血糖，胃肠道副作用， 胰腺炎、胰腺癌、甲状腺癌、胆囊炎、心血管改变、急性 肾损伤、糖尿病视网膜病变、过敏反应、胆道疾病增加、味觉改变和 头痛。作为这些药物的替代品，第一份人类报告于2016年发表，显示 T2D患者十二指肠黏膜表面重建术可改善高血糖 在不使用这些一线药物的情况下，还可以检测多种肝功能指标。本研究 之所以被发起，部分原因是有很好的证据和令人惊讶的观察表明，减肥 手术也导致了与T2D患者类似的好处，这是独立于结果的 减肥。自2016年以来，已经对DMR进行了几项临床研究，所有研究都显示出好处 对于对传统药物治疗没有反应的T2D患者或非 服药依从性。虽然DMR前景看好，但据报道，DMR具有很高的技术效率 导管故障导致的故障表明技术功能的改善 当前设备的各个方面都需要解决。此外，一个这样的DMR设备已经显示出 Benefit在几个临床试验中使用水热消融(80至90°C热水)来实现DMR。 如射频消融、HIFU、微波和其他用于靶向的热消融技术 以及消融肿瘤和治疗心律失常，被动的热量传播不容易控制 并被证明会导致侧支组织损伤，如肌肉节段性坏死和浆膜 据报道，DMR水热消融术后出血和不良事件是一个问题 与有关的案件占比为%。CPSI Biotech打算利用这一新兴的DMR市场，即 目前还处于起步阶段，并开发了一种改进的DMR热消融探头，它使用冷冻 (冷冻消融)而不是加热用于十二指肠表面重建术。拟议中的冻伤的好处是- DMR冷冻包括：(A)与加热相比，冷冻是自我限制的，机会较少 对于邻近较深的十二指肠组织的附带损害；(B)冷冻消融术已被证明是 在许多组织中比热基消融更有效、更安全、并发症更少 包括心脏、食道、肾脏、前列腺和胰腺等；(C)CPSI的PSN 冷冻消融系统可以产生和提供比任何其他系统更快和更低的消融温度。 目前市场上已知的冷冻消融系统因此减少了程序时间，因此， 与目前的技术相比，它将提供更好的通用性和安全性。这样做的具体目的是 项目内容如下：(SA1)确定十二指肠细胞受热消融剂量 冷冻消融；(Sa2)开发冻伤-dmr™，一种与冷冻内窥镜兼容的柔性内窥镜，以及 (SA3)在体外和体内模型上测试冻伤的疗效。该项目的总体意图是 利用过去几年出版的DMR和CPSI的有据可查的成功 开发改进的冷冻消融导管的专业知识，以便改进的DMR消融设备 可以开发出更安全、更高效、可以更好地控制操作员的产品，从而实现更多 对于对当前的T2D药物治疗反应不佳的T2D患者，成功地进行DMR。这是一个 根据母公司拨款1R43DK135117-01提出的补充设备申请，以更换a-80o 冰柜由于年代久远不能再修理了。CPSI目前没有零下800度的冰柜，需要 获得一个，以满足家长第一阶段拨款申请中详细说明的具体目标。