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.

项目概要 治疗性肽、蛋白质和寡核苷酸的口服递送受到高效层的阻止 胃肠道表面的上皮细胞。因此，几乎所有的生物疗法都是 通过注射或输注给药。这些方法成本高昂、痛苦、不方便，并且会导致费率较低 相对于口服给药的患者依从性。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，可促进整个身体的吸收 肠上皮，使生物制剂能够口服输送。先前的研究表明，鞘糖脂 由短酰基链神经酰胺组成的神经酰胺通过上皮细胞运输，过程称为 转胞吞作用。其他研究表明，鞘糖脂可以作为结合货物的载体， 实现跨肠道粘膜上皮的主动和内源性跨细胞转运。因为 鞘糖脂合成复杂，限制了临床应用，我们合成了 简化的平台。一种仅由 C6-D-赤型神经酰胺组成，足以实现体外转胞吞作用， 但在体内由于这些分子的溶解度和两亲性降低而受到阻碍。自从我们上次 应用中，我们合成了新的基于神经酰胺的载体，其显示出增强的溶解度和两亲性。 基于这些发现，我们将优化新的神经酰胺平台，以实现 GLP-1 的口服给药 用于治疗II型糖尿病和肥胖症。 在本文提出的研究中，神经酰胺将用不同的头基进行化学修饰，每个头基具有 不同的理化性质。我们将研究每个头组对渗透性的影响， 结合物的溶解度和活性。此外，我们将确定药代动力学和 GLP-1-神经酰胺缀合物在啮齿动物中的药效学。我们将直接将共轭物与 唯一市售的口服 GLP-1 疗法 Rybelsus，我们期望展示出卓越的生物利用度， 神经酰胺融合物的半衰期和功效。在完成这些研究后，我们希望能够确定 适合临床前开发的最佳口服生物利用度 GLP-1 缀合物。鉴于需要改进 II 型糖尿病和肥胖症的口服治疗方案，成功完成这些研究将导致 对数百万患有这些疾病的患者产生了重大影响。此外，验证 神经酰胺平台将为开发其他口服生物可利用的生物药物奠定基础。