Oral Delivery of Therapeutic Peptides for Type II Diabetes and Obesity by Harnessing Endogenous Sphingolipid Trafficking

利用内源性鞘脂运输口服治疗 II 型糖尿病和肥胖症的肽

• 批准号: 10698654
• 负责人: Justin Mahoney Wolfe
• 金额: $ 32.49万
• 依托单位: TRANSCERA, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10698654
• 关键词: Agonist; Binding Proteins; Biological; Biological Availability; Biological Products; Biological Response Modifier Therapy; Biology; Biotechnology; Blood Glucose; Body Weight; Body Weight decreased; Boston; Canis familiaris; Cell Line; Cell membrane; Cells; Cellular Membrane; Ceramides; Charge; Chemicals; Circulation; Clinical; Complex; Conjugated Carrier; Control Animal; Coupled; Disease; Drug Delivery Systems; Drug Kinetics; Eating; Endosomes; Engineering; Epithelial Cells; Epithelium; Erythro; Exhibits; Foundations; Ganglioside GM1; Gastrointestinal tract structure; Glycosphingolipids; Half-Life; Hour; Immunoglobulin G; In Vitro; Infusion procedures; Injectable; Injections; Intestines; Intravenous infusion procedures; Investigation; Lead; Legal patent; Letters; Licensing; Lipids; Marketing; Measures; Medicine; Membrane; Methods; Miniature Swine; Mucous Membrane; N-caproylsphingosine; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Obese Mice; Obesity; Oligonucleotides; Oligosaccharides; Oral; Oral Administration; Pain; Patients; Pediatric Hospitals; Peptides; Permeability; Pharmacodynamics; Pharmacology; Phase; Plasma; Plasma Proteins; Preclinical Testing; Preparation; Process; Property; Proteins; Rattus; Research; Resources; Respiratory System; Rodent; Role; Schedule; Solubility; Sorting; Sphingolipids; Subcutaneous Injections; Surface; Technology; Therapeutic; Toxic effect; Toxicology; Translations; Validation; absorption; acyl group; adherence rate; analog; aqueous; biophysical properties; clinical application; clinical development; comparison control; compliance behavior; cost; design; diabetic; efficacy study; extracellular; functional restoration; glucagon-like peptide 1; glucose metabolism; improved; in vivo; innovation; intestinal epithelium; macromolecule; medical schools; next generation; novel; peptide drug; pharmacokinetics and pharmacodynamics; pharmacologic; preclinical development; preclinical study; prevent; professor; success; technology platform; therapeutic protein; trafficking; transcytosis

PROJECT SUMMARY Oral delivery of therapeutic peptides, proteins, and oligonucleotides is prevented by a highly effective layer of epithelial cells lining the surface of the gastrointestinal tract. As a result, nearly all biologic therapies are administered via injection or infusion. These methods are costly, painful, inconvenient, and lead to lower rates of patient adherence relative to oral administration. Building on discoveries by Harvard Medical School professor Wayne Lencer, MD, we are developing a lipid-based technology platform that facilitates absorption across the intestinal epithelium, enabling oral delivery of biologics. Previous research demonstrated that glycosphingolipids comprised of a short-acyl chain ceramide are trafficked through epithelial cells in a process known as transcytosis. Additional studies showed that the glycosphingolipids can serve as carriers for conjugated cargo, enabling active and endogenous transcellular transport across the mucosal epithelium in the gut. Because glycosphingolipids are synthetically complex, limiting translation to clinical applications, we have synthesized simplified platforms. One, comprised of just C6-D-erythro-ceramide, is sufficient to enable transcytosis in vitro, but was hindered in vivo by the diminished solubility and amphipathicity of these molecules. Since our last application, we synthesized new ceramide-based vehicles that show enhanced solubility and amphipathicity. Building on these discoveries, we will optimize the new ceramide platform to enable the oral delivery of GLP-1 for the treatment of type II diabetes and obesity. In the studies proposed herein, the ceramide will be chemically modified with different headgroups, each with different physicochemical properties. We will investigate the effects of each headgroup on the permeability, solubility, and activity of the conjugate. Additionally, we will determine the pharmacokinetics and pharmacodynamics of the GLP-1-ceramide conjugates in rodents. We will compare conjugates directly to the only commercially available oral GLP-1 therapy, Rybelsus, and we expect to demonstrate superior bioavailability, half-life, and efficacy for the ceramide fusions. At the completion of these studies, we expect to have identified an optimal orally bioavailable GLP-1 conjugate suitable for preclinical development. Given the need for improved oral treatment options for type II diabetes and obesity, successful completion of these studies will lead to significant impact for the millions of patients suffering with these diseases. Furthermore, validation of the ceramide platform will provide the foundation for developing additional orally bioavailable biologic medicines.

项目总结 口服治疗性多肽、蛋白质和寡核苷酸可被一层高效的 排列在胃肠道表面的上皮细胞。因此，几乎所有的生物疗法都是 通过注射或输液给药。这些方法昂贵、痛苦、不便，并导致费率较低 相对于口服给药，患者的依从性。以哈佛医学院教授的发现为基础 Wayne Lencer，医学博士，我们正在开发一种基于脂质的技术平台，以促进跨 肠道上皮，能够口服生物制剂。先前的研究表明，鞘糖脂 神经酰胺由短酰基链组成，通过上皮细胞运输，这一过程称为 细胞穿透。其他研究表明，鞘糖脂可以作为结合货物的载体， 能够通过肠道的粘膜上皮进行主动的、内源性的跨细胞运输。因为 鞘糖脂是一种合成复杂的化合物，限制了翻译到临床应用，我们已经合成了 简化的平台。一种仅由C6-D-红血球神经酰胺组成，足以在体外进行细胞转运， 但在体内受到这些分子的溶解性和两亲性减弱的阻碍。自从我们上一次 应用方面，我们合成了基于神经酰胺的新型载体，表现出更好的溶解性和两亲性。 在这些发现的基础上，我们将优化新的神经酰胺平台，使其能够口服GLP-1 用于治疗II型糖尿病和肥胖症。 在这里提出的研究中，神经酰胺将用不同的头基进行化学修饰，每个头基 不同的物理化学性质。我们将研究每个头部基团对渗透性的影响， 溶解度和偶联物的活性。此外，我们将测定药物动力学和 GLP-1-神经酰胺结合物在啮齿动物体内的药效学。我们将把共轭函数直接与 只有商业上可用的口服GLP-1疗法，Rybelsus，我们希望展示出卓越的生物利用度， 神经酰胺融合的半衰期和疗效。在完成这些研究后，我们预期已确定 适用于临床前开发的最佳口服生物利用型GLP-1结合物。考虑到需要改进 对于II型糖尿病和肥胖症的口服治疗选择，这些研究的成功完成将导致 对数百万患有这些疾病的患者产生重大影响。此外，验证 神经酰胺平台将为开发更多的口服生物利用药奠定基础。