FrostBite-DMR - A New Drug-Free Approach for Treating Type 2 Diabetes

2型糖尿病（T2 D）的发病率在全球范围内不断增加，近5.52亿人 到2030年，这些人可能会患上这种疾病。现在有超过50种不同的药物 但大约一半的患者对这些药物反应不佳， 高血糖状态仍然是威胁生命问题。事实上，一线药物，如 二甲双胍、GLP-1受体激动剂（例如Semantine）、DPP-4抑制剂、SGLT 2抑制剂和 其他人有记录的副作用包括低血糖，胃肠道副作用， 胰腺炎、胰腺癌、甲状腺癌、胆囊问题、心血管变化、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，2016年发表的第一份人体报告显示， T2 D患者的十二指肠粘膜表面置换术（DMR）可以改善其高血糖， 条件以及几个肝脏指数，而不必使用这些一线药物。本研究 开始，部分是因为有充分的记录和令人惊讶的观察， 手术也为T2 D患者带来了类似的益处， 减肥.自2016年以来，已对DMR进行了几项临床研究，所有研究均显示出获益 对传统药物治疗无效或无反应的T2 D患者， 与药物相容。虽然很有希望，但据报道，DMR的技术应用率很高。 导管故障导致的失效表明技术功能的改进 需要解决当前设备的一些方面。此外，一个这样的DMR设备已经示出 在一些临床试验中，使用水热消融（80至90°C的热水）来实现DMR。 如射频消融、HiFU、微波等热消融技术用于靶向 消融肿瘤和治疗心律失常，热量的被动传播不容易控制， 并已显示导致附带组织损伤，例如肌肉节段性坏死和浆膜 DMR水热消融术的出血和术后不良事件报告为一个问题 64%的病例。CPSI Biotech打算利用这一新兴的DMR市场， 目前处于起步阶段，并开发一种改进的DMR热消融探头， （冷冻消融）而不是加热进行十二指肠表面重建。提出的FrostBite的优点- DMR冷冻球囊包括：（a）与加热相比，冷冻具有自限性，且机会较少 对于邻近的更深的十二指肠组织的附带损伤;（B）冷冻消融已被证明是 在许多组织中，比基于热的消融更有效、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 冷冻消融系统可以比其他任何系统更快更冷地产生和输送消融温度， 目前市场上已知的冷冻消融系统减少了手术时间，因此， 与现有技术相比，将提供改进的多功能性和安全性。具体目标是 （SA 1）确定十二指肠细胞的热消融剂量， 冷冻消融;（SA 2）开发FrostBite-DMR™，一种柔性内窥镜兼容冷冻球囊，以及 (SA3)测试FrostBite在离体和体内模型中的功效。该项目的总体意图是 利用过去几年出版的DMR以及CPSI的成功记录， 在开发改进的冷冻消融导管方面的专业知识， 可以开发出更安全、更高效、更好的操作员控制系统， 对目前T2 D药物治疗反应不佳的T2 D患者的成功DMR。

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.