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.
Public Health Relevance Statement: PROJECT NARRATIVE We are developing a ceramide-based platform to enable oral delivery of therapeutic peptides and proteins. Focusing on GLP-1 agonists for the treatment of type II diabetes and obesity, we will optimize the platform specifically around three parameters - permeability, solubility, and activity â and demonstrate its superiority to the only other oral GLP-1 agonist. Once optimized, we will harness these next-generation fusion molecules as therapeutics and begin preclinical studies.
Project Terms: absorption; Oral Drug Administration; intraoral drug delivery; Oral Administration; Biological Availability; Bioavailability; Physiologic Availability; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Biology; Biotechnology; Biotech; Blood Glucose; Blood Sugar; Body Weight; Boston; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Cells; Cell Body; Ceramides; Charge; Non-Insulin-Dependent Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Ketosis-Resistant Diabetes Mellitus; Maturity-Onset Diabetes Mellitus; NIDDM; Non-Insulin Dependent Diabetes; Noninsulin Dependent Diabetes; Noninsulin Dependent Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Stable Diabetes Mellitus; T2 DM; T2D; T2DM; Type 2 Diabetes Mellitus; Type 2 diabetes; Type II Diabetes Mellitus; Type II diabetes; adult onset diabetes; ketosis resistant diabetes; maturity onset diabetes; type 2 DM; type II DM; type two diabetes; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Eating; Food Intake; Engineering; Epithelial Cells; Exhibits; Foundations; Ganglioside GM1; G(A(2)) Ganglioside; G(M1) Ganglioside; GA(2) Ganglioside; Monosialosyl Tetraglycosyl Ceramide; Gastrointestinal tract structure; Alimentary Canal; Digestive Tract; GI Tract; Gastrointestinal Tract; alimentary tract; digestive canal; Glycosphingolipids; Asialogangliosides; Sphingoglycolipids; Half-Life; Pediatric Hospitals; Children's Hospital; Immunoglobulin G; 7S Gamma Globulin; IgG; In Vitro; Intravenous infusion procedures; IV Infusion; intravenous infusion; Subcutaneous Injections; subdermal injection; Intestines; Intestinal; bowel; Lead; Pb element; heavy metal Pb; heavy metal lead; Lipids; Marketing; Medicine; Methods; Obese Mice; ob/ob mouse; Mucous Membrane; Mucosa; Mucosal Tissue; Nucleic Acids; Obesity; adiposity; corpulence; Oligonucleotides; Oligo; oligos; Oligosaccharides; Pain; Painful; Legal patent; Patents; Patients; Peptides; Permeability; Drug Kinetics; Pharmacokinetics; Pharmacology; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma Proteins; Proteins; Rattus; Common Rat Strains; Rat; Rats Mammals; Endosomes; Receptosomes; Research; Resources; Research Resources; Respiratory System; Respiratory tract structure; Pulmonary Body System; Pulmonary Organ System; Respiratory Tracts; Rodent; Rodentia; Rodents Mammals; Role; social role; medical schools; medical college; school of medicine; Solubility; Sphingolipids; Miniature Swine; Minipigs; mini pig; mini-swine; miniswine; Technology; Toxicology; Translations; translation; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; glucagon-like peptide 1; GLP-1; Measures; Drug Delivery; Drug Delivery Systems; Injectable; Schedule; macromolecule; improved; Surface; Clinical; Phase; biologic; Biological; Chemicals; Epithelium; intestinal epithelium; diabetic; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Licensing; analog; Agonist; Letters; Therapeutic; Investigation; Hour; Complex; Oral; extracellular; N-caproylsphingosine; C(6)-ceramide; C6-ceramide; N-hexanoylsphingosine; Infusion procedures; Infusion; infusions; acyl group; glucose metabolism; Membrane; membrane structure; success; transcytosis; professor; trafficking; aqueous; Toxic effect; Toxicities; novel; Erythro; Sorting; Pharmacodynamics; Property; therapeutic protein; native protein drug; pharmaceutical protein; protein drug agent; protein-based drug; preventing; prevent; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; Control Animal; Preclinical Testing; pre-clinical testing; in vivo; Cellular Membrane; Conjugated Carrier; Validation; validations; Preparation; preparations; Process; preclinical study; pre-clinical study; cost; designing; design; next generation; Coupled; innovate; innovative; innovation; clinical applicability; clinical application; restore function; restore functionality; restore lost function; functional restoration; biophysical characteristics; biophysical characterization; biophysical measurement; biophysical parameters; biophysical properties; Peptide-based drug; therapeutic peptide; peptide drug; efficacy study; clinical development; pre-clinical development; preclinical development; Injections; adherence rate; PK/PD; pharmacokinetics and pharmacodynamics; pharmacologic; Circulation; comparison control; compare to control; technology platform; technology system
