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Principal Investigator: HENRY DANIELL
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2019
Award: $726,730
Funding agency: National Heart Lung and Blood Institute
DESCRIPTION: Injectable biopharmaceuticals produced in current systems are prohibitively expensive and are not affordable for a large majority of the global population. Recent studies have shown that bioencapsulation of protein drugs in plant cells are protected in the stomach. Commensal microbes play a critical role in their release into the gut lumen. Rapid delivery of drugs bioencapsulated plant cells into circulation, histological evidence and studies with antibiotics show the critical role played by small intestinal microbes in this process. We have also identified unique tags that could deliver therapeutic proteins to the circulation, non-immune or immune modulatory cells after crossing the gut epithelium. This proposal addresses some of the remaining challenges in oral delivery of human blood proteins so that this novel concept could be advanced to the clinic. Protein drugs should be expressed in edible plant cells instead of tobacco and their expression level should be enhanced (especially for large proteins) to facilitate dose escalation studies. In order to achieve this, cutting edge modern tools will be utilized. Ribosome profiling of native human genes expressed in chloroplasts will identify ribosome pause sites. Codon optimization will substitute rare codons with optimal codons. Level of expression of GLP-1 like short peptides (exendin) or angiotensin 1-7 will be enhanced with tandem repeats and cleavage sites with ubiquitous proteases like furin. Different delivery tags will be tested to target proteins to non-immune or immune modulatory cells and their functionality will be evaluated for treatment of hypertension/diabetes or induction of oral tolerance in hemophilia using suitable animal models. The role of gut microbes will be studied by functional characterization and identification of human small intestinal bacterial species capable of releasing protein drugs bio encapsulated in plant cells and host absorption. Production successful candidates in cGMP facility (Fraunhofer USA, Delaware), evaluation of stability upon prolonged storage at ambient temperature, efficacy and dosage are proposed. These novel approaches should improve patient compliance in addition to significantly lowering the cost of healthcare by elimination of prohibitively expensive fermenters, purification, cold storage/ transportation, sterile delivery of currently used methods and extending shelf life of protein drugs. Clinical advancement of this concept would revolutionize protein drug production and delivery for most metabolic and genetic disorders. In contrast to the well-studied fecal/colonic system, functional characterization of the human small intestinal microbiota has not been previously explored and this study would facilitate further mechanistic understanding of the human gut and the role of intestinal microbes in processing of plant cells and delivery of protein drugs utilizing the largest absorption surface in the human body.
Terms: <Abscission><Acids><Address><Ailmentary System><Alimentary System><Angiotensins><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Antigen-Presenting Cells><Autoimmune Diseases><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Proteins><Biologic Products><Biological Agent><Biological Products><Blood Circulation><Blood Glucose><Blood Proteins><Blood Sugar><Bloodstream><Body Tissues><Carbohydrates><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Wall><Cells><Chloroplasts><Cholera Enterotoxin CT><Cholera Exotoxin><Cholera Toxin><Choleragen><Circulation><Cleaved cell><Clinic><Clinical><Codon><Codon Nucleotides><Country><Cryofixation><Cryopreservation><Cyclic GMP><Data><Delaware><Dendritic Cells><Diabetes Mellitus><Digestive System><Dose><Drug Delivery><Drug Delivery Systems><Drug Utilization><Drugs><Edible Plants><Encapsulated><Engineering><Enzyme Gene><Enzymes><Epithelial><Esteroproteases><Evaluation><Excision><Extirpation><Factor VIII Deficiency><Fermentation><Food Plants><Freeze Drying><Freeze Dryings><GI microbiota><GLP-1><Gastrointestinal Body System><Gastrointestinal Organ System><Gastrointestinal microbiota><Genes><Genetic Diseases><Glycans><Glycosides><Guanosine Cyclic Monophosphate><Gut Epithelium><Health Care Costs><Health Costs><Healthcare Costs><Heart Vascular><Hemophilia><Hemophilia A><Histologic><Histologically><Human><Human Figure><Human body><Humulin R><Hypertension><Immune><Immune Tolerance><Immune system><Immunes><Immunologic Tolerance><Injectable><Insulin><Intestinal><Intestines><Large Intestine><Lettuce><Lettuce - dietary><Life><Ligand Binding Protein><Ligand Binding Protein Gene><Lyophilization><Medication><Metabolic><Metabolic Diseases><Metabolic Disorder><Methods><Miscellaneous Antibiotic><Modern Man><Modernization><Molecular Interaction><Myelogenous><Myeloid><Novolin R><Oral><Patient Care><Patient Care Delivery><Patient Compliance><Peptidases><Peptide Hydrolases><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Plants><Play><Polysaccharides><Population><Process><Production><Property><Protease Gene><Proteases><Protein Binding><Proteinases><Proteins><Proteolytic Enzymes><Publications><Receptor Protein><Regular Insulin><Removal><Reporting><Reproducibility><Ribo-seq><Ribosomes><Role><Sampling><Scientific Publication><Site><Sterility><Stomach><Surface><Surgical Removal><System><T-Cells><T-Lymphocyte><Tandem Repeat Sequences><Tandem Repeats><Temperature><Testing><Therapeutic><Thesaurismosis><Tissues><Tobacco><Toxic effect><Toxicities><Transportation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Veiled Cells><Villus><absorption><accessory cell><allergic/immunologic body system><allergic/immunologic organ system><autoimmune disorder><bacterial disease treatment><bacterial infectious disease treatment><base><biopharmaceutical><biotherapeutic agent><bound protein><bowel><cGMP><cell type><circulatory system><cleaved><clinical translation><cold preservation><cold storage><commensal bacteria><commensal bacterial species><commensal flora><commensal microbes><commensal microbiota><commensal microflora><compliance behavior><cost><diabetes><dosage><drug production><drug/agent><enteric microbial community><enteric microbiota><gastric><gastrointestinal epithelium><gastrointestinal microbial flora><gastrointestinal system><genetic condition><genetic disorder><glucagon-like peptide 1><gut commensal><gut community><gut flora><gut microbe community><gut microbes><gut microbial community><gut microbial composition><gut microbial consortia><gut microbial species><gut microbiota><gut microbiotic><gut microflora><high blood pressure><histologic studies><histological studies><hyperpiesia><hyperpiesis><hypertension treatment><hypertensive disease><ileum><immune system tolerance><immune unresponsiveness><immunological paralysis><improved><intestinal epithelium><intestinal flora><intestinal microbes><intestinal microbiota><intestinal microflora><intestinal tract microflora><large bowel><metabolism disorder><microbial consortia><microbial flora><microbiota><microflora><model of animal><model organism><multispecies consortia><native protein drug><new approaches><novel><novel approaches><novel strategies><novel strategy><oral tolerance><patient adherence><patient cooperation><pharmaceutical protein><protein drug agent><public health relevance><receptor><receptor binding><receptor bound><resection><ribosome footprint profiling><ribosome profiling><scale up><site targeted delivery><social role><sterile><targeted delivery><therapeutic protein><therapy compliance><therapy cooperation><thymus derived lymphocyte><tool><treatment compliance><vector>