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.

项目摘要 通过高效的层，可以预防治疗肽，蛋白质和寡核苷酸的治疗肽，蛋白质和寡核苷酸 胃肠道表面的上皮细胞。结果，几乎所有的生物疗法都是 通过注射或输注给药。这些方法是昂贵，痛苦，不便的，并导致率较低 相对于口服的患者依从性。基于哈佛医学院教授的发现 马里兰州韦恩·林克（Wayne Lencer），我们正在开发一个基于脂质的技术平台 肠上皮，使生物制剂的口服递送。先前的研究表明糖磷脂脂 由短囊肿神经酰胺组成的 转胞病。其他研究表明，糖磷脂脂可以用作共轭货物的载体，即 在肠道中的粘膜上皮上有活性和内源性细胞运输。因为 糖磷脂在合成上很复杂，将转换为临床应用，我们已经合成了 简化平台。其中一种仅由C6-D-rerythro-Ceramide组成，足以在体外造细胞增多症， 但由于这些分子的溶解度和两倍性的降低而阻碍了体内。自上次 应用，我们合成了新的基于神经酰胺的车辆，这些车辆显示出增强的溶解度和两亲性。 在这些发现的基础上，我们将优化新的神经酰胺平台，以使GLP-1的口服交付 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组化学修饰 不同的理化特性。我们将研究每个头部组对渗透率的影响， 溶解度和共轭的活性。此外，我们将确定药代动力学和 啮齿动物中GLP-1-陶瓷结合物的药效学。我们将直接比较 只有市售的口服GLP-1疗法，Rybelsus，我们希望能够证明出色的生物利用度， 半衰期和神经酰胺融合的功效。这些研究完成时，我们希望已经确定 最佳口服生物利用的GLP-1结合物，适合临床前开发。鉴于需要改进 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的重大影响。此外，验证 神经酰胺平台将为开发额外的生物利用生物学药物提供基础。