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 治疗性肽、蛋白质和寡核苷酸的口服递送被高效的抗肿瘤药物层阻止。 衬在胃肠道表面的上皮细胞。因此，几乎所有的生物疗法都是 通过注射或输注施用。这些方法都是昂贵的，痛苦的，不方便的，并导致较低的利率 患者的依从性相对于口服给药。基于哈佛医学院教授的发现 韦恩兰瑟，医学博士，我们正在开发一种基于脂质的技术平台，促进吸收整个 肠上皮，使得能够口服递送生物制剂。以前的研究表明，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， 转胞吞作用另外的研究表明，鞘糖脂可以作为缀合货物的载体， 使得能够在肠道中主动和内源性跨粘膜上皮细胞转运。因为 鞘糖脂是合成复杂的，限制了临床应用的翻译，我们合成了 简化平台。一种仅由C6-D-β-神经酰胺组成，足以在体外实现转胞吞作用， 但在体内由于这些分子溶解度和两亲性的降低而受阻。自我们上次 为了应用，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GLP-1的口服给药成为可能。 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部基团进行化学修饰，每个头部基团具有 不同的物理化学性质。我们将研究每个头基对渗透性的影响， 溶解度和缀合物的活性。此外，我们将确定药代动力学， GLP-1-神经酰胺缀合物在啮齿动物中的药效学。我们将直接比较共轭 只有市售的口服GLP-1治疗，Rybelsus，我们期望证明上级生物利用度， 半衰期和神经酰胺融合物的功效。在完成这些研究后，我们预计已确定 适合临床前开发的最佳口服生物可利用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， 神经酰胺平台将为开发其他口服生物可利用的生物药物提供基础。