Carlson Taylor L, Colbert Kevin, Vieira Marcela, Guerina Florence V, Bryant Christine L N, Habegger Kirk, Pasricha Pankaj Jay, Petersen John, Polomoscanik Steven, Jozefiak Thomas H, Nimgaonkar Ashish
Glyscend Therapeutics Inc., Baltimore, MD, 21205, USA.
Gastroenterology Imaging, Clario (eResearch Technology) , Philadelphia, PA 19103, USA.
Sci Adv. 2025 May 30;11(22):eadu1326. doi: 10.1126/sciadv.adu1326.
Type 2 diabetes (T2D) and obesity are chronic metabolic diseases with global morbidity and mortality. Decades of evidence from surgical and endoscopic procedures bypassing the duodenum underscore the duodenum's critical role in regulating glycemia and body weight. Although metabolic surgeries and endoscopic procedures are effective, their invasiveness, cost, and scalability limit patient access. We developed an orally administered mucin complexing polymeric (MCP) drug, designed to replicate duodenal exclusion physiology. MCPs, intended to have electrostatic and covalent cross-linkages with mucin glycoproteins, form extended network structures with resulting alteration of mucus barrier properties. Selective targeting of the duodenum is achieved via pH-based activation chemistry. Following screening for physiochemical properties, pharmacokinetics, and efficacy, GLY-200 emerged as the lead drug candidate replicating duodenal exclusion physiology with improved glycemia, reduced body weight, and modulation of gut hormones in rodent models. This targeted oral therapy holds promise for treatment of T2D and obesity by mimicking duodenal exclusion without the invasiveness of surgery or endoscopic procedures.
2型糖尿病（T2D）和肥胖症是具有全球发病率和死亡率的慢性代谢性疾病。数十年来，来自绕过十二指肠的外科手术和内窥镜手术的证据强调了十二指肠在调节血糖和体重方面的关键作用。尽管代谢手术和内窥镜手术有效，但其侵入性、成本和可扩展性限制了患者的可及性。我们开发了一种口服粘蛋白复合聚合物（MCP）药物，旨在模拟十二指肠排除生理功能。MCP旨在与粘蛋白糖蛋白形成静电和共价交联，形成扩展的网络结构，从而改变粘液屏障特性。通过基于pH的活化化学实现对十二指肠的选择性靶向。在对理化性质、药代动力学和疗效进行筛选后，GLY-200成为主要候选药物，在啮齿动物模型中模拟十二指肠排除生理功能，改善血糖、减轻体重并调节肠道激素。这种靶向口服疗法有望通过模拟十二指肠排除来治疗T2D和肥胖症，而无需手术或内窥镜手术的侵入性。
