权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Affordable Oral Delivery of Human Therapeutic Proteins Bioencapsulated in Plant Cells

经济实惠地口服生物封装在植物细胞中的人类治疗蛋白

基本信息

批准号：
10471840
负责人：
HENRY DANIELL
金额：
$ 73.97万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471840
关键词：
ACE2 Acids Address Adjuvant Affect Allergens Allergy to peanuts Alzheimer&apos s Disease Anaphylaxis Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensins Animal Disease Models Animal Model Animals Antibiotic Resistance Antibody Formation Antigens Biological Markers Biological Products Blood Proteins Canis familiaris Cardiovascular system Cell Wall Cells Cessation of life Chemicals Chloroplasts Cholera Toxin Protomer B Clinic Clinical Clinical Markers Codon Nucleotides Cold Chains Communicable Diseases Developed Countries Diabetes Mellitus Disease Disease Progression Dose Drug Delivery Systems Enzymes Evaluation Excision Experimental Animal Model Exposure to Food Hypersensitivity Freeze Drying Funding Gastrointestinal tract structure Generations Genes Goals Heart Diseases Heart failure Hemophilia A High Prevalence Human Hypersensitivity Hypertension Immune Tolerance Immune system Implant Insulin Intake Interleukin-10 Laboratories Lettuce - dietary Life Measures Medical Methods Modeling Mouse Strains Mus Mutation Operative Surgical Procedures Oral Oral Administration Outcome Pathway interactions Patient Care Patients Peptides Pharmaceutical Preparations Plants Plasma Population Positioning Attribute Production Proteins Rattus Renin-Angiotensin-Aldosterone System Skin Sterility Stomach System Tail Temperature Time Tissues Transportation Work clinically relevant commensal microbes compliance behavior cost dosage drug production enzyme replacement therapy exosome experience extracellular vesicles filaggrin food allergen food antigen human disease human subject immunomodulatory therapies innovation intestinal epithelium mouse model novel oral tolerance pre-clinical prevent research clinical testing resistance gene targeted treatment therapeutic protein

项目摘要

PROJECT SUMMARY/ABSTRACT Current Protein Drugs (PD) are prohibitively expensive ($140 billion in top ten PDs, >75% of global GDP). One third of global population earning <$2 per day can’t afford any PD. Insulin, a five-decade old drug, is still unaffordable, even in developed countries, as illustrated by several recent deaths of diabetes patients in the US. Such high costs are due to PD production in prohibitively expensive fermenters, purification, cold transportation/storage, short shelf-life and sterile delivery methods. Patient compliance is less for repetitively injected or surgically implanted PDs. Therefore, affordable PDs with ease of delivery is an urgent unmet need. The Daniell laboratory has addressed these challenges by pioneering a novel concept to express PDs in plant chloroplasts (up to 10,000 gene copies per cell), leading to high levels of PD expression. Upon oral delivery, plant cell wall protects PDs from acids/enzymes in the stomach via bio-encapsulation. However, commensal microbes digest plant cell walls and release PDs in the gut. When tags are fused to protein drugs, they efficiently cross the intestinal epithelium and are delivered to the circulatory or immune system. PDs are stable for many years in lyophilized plant cells when stored at ambient temperature, maintaining their folding/ functionality, thereby totally eliminating the cold chain needed for storage/transportation. Through prior R01 funding (2011-2020), challenging mechanistic questions on oral drug delivery have been evaluated through several thousand oral doses of PDs in mice, rat, dog animal disease models. In this second renewal application, we propose to optimize expression of human blood proteins (Ace2/Ang1-7/IL10) and food allergens (Ara h 1, Ara h 2, Ara h 3, Ara h 6) in lettuce chloroplasts through codon optimization, removal of antibiotic resistance genes, GLP production, in planta drug dose determination and enhancement of PD oral delivery. In both dogs and humans, activation of the renin-angiotensin- aldosterone system (RAAS) represents a key neurohormonal aspect of heart failure (HF) and target of therapy. The effect of oral angiotensin converting enzyme-2 (ACE2) and angiotensin 1-7 (Ang 1-7) bioencapsulated in plant cells, on RAAS will be studied in a spontaneous model of HF in domestic dogs, in conjunction with ACE- inhibitor (ACEI) or angiotensin receptor blocker (ARB), evaluation of plasma and exosomal RAAS angiotensin peptides (APs) and echocardiographic and clinical measures of dogs with spontaneous HF. Further, we will extend our unique immune tolerance platform, developed in prior R01s to suppress antibody formation/ anaphylaxis in protein replacement therapy, to treat life-threatening food allergies. Therefore, we will develop oral immune modulatory therapy using peanut antigens fused to CTB expressed in chloroplasts using oral sensitization or skin sensitization mouse models of peanut allergy. The overarching goal of this proposal is to address the urgent unmet medical need of affordable PDs, harnessing work from prior two R01s to launch transformative solutions and develop specific treatments for heart disease or food allergies.

项目总结/文摘