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Principal Investigator: HENRY DANIELL
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2022
Award: $739,713
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <ACE Inhibitors><ACE2><AD dementia><Ab response><Abscission><Acids><Address><Adjuvant><Affect><Alimentary Canal><Allergens><Allergic to food><Allergy><Allergy to food><Allergy to peanuts><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin Receptor><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Angiotensins><Animal Disease Models><Animal Model><Animal Models and Related Studies><Animals><Antibiotic Resistance><Antibody Formation><Antibody Production><Antigens><Biologic Products><Biological Agent><Biological Markers><Biological Products><Blood Plasma><Blood Proteins><Body Tissues><CSIF><CSIF-10><Canine Species><Canis familiaris><Cardiac Diseases><Cardiac Disorders><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Wall><Cells><Cessation of life><Chemicals><Chloroplasts><Cholera Toxin B Subunit><Cholera Toxin Protomer B><Choleragenoid><Clinic><Clinical><Clinical Evaluation><Clinical Markers><Clinical Testing><Codon><Codon Nucleotides><Cold Chains><Common Rat Strains><Communicable Diseases><Cytokine Synthesis Inhibitory Factor><Death><Developed Countries><Diabetes Mellitus><Digestive Tract><Disease><Disease Progression><Disorder><Dogs><Dogs Mammals><Dose><Drug Delivery><Drug Delivery Systems><Drugs><Enzyme Gene><Enzymes><Evaluation><Excision><Experimental Animal Model><Exposure to><Extirpation><Factor VIII Deficiency><Food Allergy><Food Hypersensitivity><Freeze Drying><Freeze Dryings><Funding><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Groundnut Hypersensitivity><Heart Diseases><Heart Vascular><Heart failure><Hemophilia><Hemophilia A><High Prevalence><Human><Humulin R><Hypersensitivity><Hypertension><IL-10><IL10><IL10A><Immune Modulation Therapy><Immune Tolerance><Immune system><Immunologic Tolerance><Implant><Industrialized Countries><Industrialized Nations><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Insulin><Intake><Interleukin 10 Precursor><Interleukin-10><Kininase II Antagonists><Kininase II Inhibitors><Laboratories><Lettuce><Lettuce - dietary><Life><Lyophilization><Measures><Medical><Medication><Methods><Mice><Mice Mammals><Modeling><Modern Man><Mouse Strains><Murine><Mus><Mutation><Novolin R><Operative Procedures><Operative Surgical Procedures><Oral><Oral Administration><Oral Drug Administration><Outcome><Pathway interactions><Patient Care><Patient Care Delivery><Patient Compliance><Patients><Peanut Hypersensitivity><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Plants><Plasma><Plasma Serum><Population><Position><Positioning Attribute><Primary Senile Degenerative Dementia><Production><Protein Replacement Therapy><Proteins><Rat><Rats Mammals><Rattus><Regular Insulin><Removal><Renin-Angiotensin-Aldosterone System><Resistance to antibiotics><Resistant to antibiotics><Reticuloendothelial System, Serum, Plasma><Skin><Sterility><Stomach><Stratum corneum basic protein><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><Tail><Temperature><Time><Tissues><Transportation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Work><alimentary tract><allergic to peanuts><allergic/immunologic body system><allergic/immunologic organ system><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibiotic drug resistance><antibiotic resistant><antibody biosynthesis><bio-markers><biologic marker><biologics><biomarker><biopharmaceutical><biotherapeutic agent><canine><cardiac failure><circulatory system><clinical relevance><clinical test><clinically relevant><commensal flora><commensal microbes><commensal microbiota><commensal microflora><compliance behavior><cost><dementia of the Alzheimer type><developed country><developed nation><developed nations><diabetes><digestive canal><domestic dog><dosage><drug production><drug/agent><enzyme replacement therapy><exosome><experience><extracellular vesicles><filaggrin><filagrin><food allergen><food antigen><gastric><genome mutation><heart disorder><high blood pressure><human disease><human subject><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><immune modulating therapies><immune modulatory therapies><immune system tolerance><immune unresponsiveness><immune-modulation treatment><immunogen><immunoglobulin biosynthesis><immunological paralysis><immunomodulation therapy><immunomodulation treatment><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><innovate><innovation><innovative><intestinal epithelium><intraoral drug delivery><model of animal><model organism><mouse model><murine model><native protein drug><novel><oral tolerance><pathway><patient adherence><patient cooperation><peanut allergy><pharmaceutical protein><pre-clinical><preclinical><prevent><preventing><primary degenerative dementia><protein drug agent><protein-based drug><research clinical testing><resection><resistance gene><resistance locus><resistant gene><senile dementia of the Alzheimer type><sterile><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic protein><therapy compliance><therapy cooperation><treatment compliance>