Hypoglycemia Vagal Nerve Stimulation Therapy (HVNS Therapy)

项目摘要/摘要 3030万美国人患有糖尿病，每年新增病例150万。低血糖对健康的负面影响 糖尿病患者。1型糖尿病患者平均每周有2次有症状的低血糖发作。严重者 低血糖(需要第三方帮助)导致每个患者每年1.0-1.7次发作。每年，73% 在胰岛素依赖型2型糖尿病患者中，有15%的人有低血糖发作，有严重的发作。 低血糖可导致意识丧失、中风、昏迷或死亡，反复发作与 心血管疾病。治疗通常需要摄入15克速效碳水化合物。 然而，这种治疗对于夜间低血糖并不理想，对于严重低血糖是禁忌。 剧集。采用葡萄糖传感器技术的胰岛素泵降低了低血糖风险，但它仍然是一种 有意义的问题。不到1%的胰岛素依赖型糖尿病患者使用胰岛素泵治疗 持续使用外部设备所需的维护和容错能力。因此，需要新的 低血糖的治疗方式。重塑生命科学公司正在开发一种创新的方法来 植入式脉冲低血糖迷走神经刺激(HVNS)的降糖控制 发电机与连续血糖监测仪(CGM)相互作用。HVNS系统由可植入的 脉冲发生器，刺激导联，可连接迷走神经后部、CGM和外部 程序员可以改变参数以定制治疗效果。该HVNS系统已通过以下方式显示出有效性 胰岛素对糖尿病大鼠和糖尿病猪模型血糖的升高作用。我们 假设下丘脑室旁核头侧至腹膜支的HVNS(可增加胰高血糖素释放)是一种 低血糖时提高血糖至安全水平的有效方法。这项NIH-SBIR第一阶段研究将 成功论证了HVNS系统的可行性，具体目标如下：具体目标1： 开发微创电极植入技术。具体目标2：确定 HVNS和非低血糖素鼻腔用药。特定目标3测定高血糖素和胰岛素的变化 W/HVNS。明确目标4通过健康示范确定刺激迷走神经的安全性 神经、胰腺、脑和肝脏组织病理学重塑生命科学公司组建了一支经验丰富的团队 完成这一项目，这是之前开发的HFAC技术，用于阻断膈下迷走神经 商业用途的勇气。NIH SBIR第一阶段研究的成功完成将允许申请 对于允许进一步开发HVNS硬件的第二阶段资金，更大规模的良好实验室 对猪的安全性和有效性研究以及监管策略的发展 启动人体试验。

Project Summary/Abstract 30.3 million Americans are diabetic w/ 1.5 million new cases per year. Hypoglycemia negatively affects diabetics. The average type 1 diabetic experiences 2 symptomatic hypoglycemia episodes/week. Severe hypoglycemia (need for 3rd party assistance) results in 1.0 – 1.7 episodes per patient per year. Annually, 73% of insulin dependent type 2 diabetics experience hypoglycemic episodes and 15% have severe episodes. Hypoglycemia can cause loss of consciousness, stroke, coma or death with repeated episodes linked to cardiovascular disease. Treatments typically involve consuming 15 grams of fast-acting carbohydrate. However, this treatment is not ideal for nocturnal hypoglycemia & contraindicated for severe hypoglycemic episodes. Insulin pumps w/ glucose sensor technology decreases hypoglycemia risk, but it still remains a meaningful problem. Less than 1% of insulin dependent diabetics use insulin pumps with issues of maintenance and tolerance required by continuous use of an external device. Thus, there is need for new treatment modalities for hypoglycemia. ReShape Lifesciences Inc. is developing an innovative approach to hypoglycemic control involving hypoglycemia vagal nerve stimulation (HVNS) using an implantable pulse generator interacting with a continuous glucose monitor (CGM). The HVNS System consists of an implantable pulse generator, stimulation leads attachable to posterior vagal nerve, a CGM and an external programmer to alter parameters to customize therapeutic effect. This HVNS system has shown efficacy by increasing plasma glucose (PG) in diabetic rat and diabetic pig models following insulin administration. We hypothesize that HVNS of PVN cranial to the celiac branch (shown to increase glucagon release) is an effective method to increase PG to a safe level during hypoglycemia. This NIH-SBIR Phase I study will successfully demonstrate feasibility of the HVNS system with the following specific aims: Specific Aim 1: Develop minimally invasive electrodes implantation technique. Specific Aim 2: Determine Effectiveness of HVNS and Non-Inferiority to Intranasal Glucagon. Specific Aim 3 Determine change in glucagon and insulin w/HVNS. Specific Aim 4 Determine the safety of stimulation on vagus nerve by demonstration of healthy nerve, pancreas, brain and liver histopathology ReShape Lifesciences has assembled an experienced team to complete this project which was previously developed HFAC technology to block sub-diaphragmatic vagus nerve for commercial use. The successful completion of this NIH SBIR Phase I study will allow an application for Phase II funding allowing the further development of HVNS hardware, larger scale Good Laboratory Practices (GLP) safety and efficacy studies in swine and development of regulatory strategies leading to the initiation of human trials.