Document text
Principal Investigator: Jacob Brenner
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $694,692
Funding agency: National Heart Lung and Blood Institute
ABSTRACT / PROJECT SUMMARY
Despite 50+ years of dissecting the pathways of acute respiratory distress syndrome (ARDS), there are
still no drugs which improve its mortality. From a pharmacology perspective, this lack of clinical trial success
falls into 2 major buckets: poor drug delivery to the alveoli and no platform technology to easily design a drug
for a given target protein. Here, we aim to solve these problems with a single nanotechnology. We began by
developing nano-scale drug carriers (nanocarriers) that can massively concentrate drugs in the alveoli,
~300-fold, after IV injection. These nanocarriers are lipid nanoparticles (LNPs) that are conjugated to targeting
moieties that either direct the LNPs to alveolar endothelial cells (via an anti-PECAM antibody on the LNP
surface), or to alveolar marginated leukocytes (via our recently developed NAP-tag). While we have for years
used these nanocarriers to deliver small molecule drugs, that class of cargo drugs had few molecules that
impacted ARDS-related pathways, and the drugs were difficult to load into LNPs. Therefore, here we will for
the first time deliver inside our alveolar-targeted LNPs a new class of drugs that can target virtually any
pathway: modified mRNA. Modified mRNA-LNPs drive the expression of encoded proteins for ~48 hours per
dose. In this proposal, we will combine our alveolar-targeting & mRNA technologies to treat two of the biggest
pathological processes of early-mid ARDS: alveolar capillary leak (Aim 1, targeting endothelial cells) and
leukocyte infiltration (Aim 2, targeting alveolar marginated leukocytes). For each of these 2 ARDS-related
disease processes, we will deliver mRNAs that encode either a secreted molecule (Ang1 or IL-10) or an
intracellular molecule (VE-cadherin or IkB), to compare how these different protein classes function with this
technology. Finally, we will test these in two ARDS-like mouse models of ARDS (Aims 1 & 2), and in ex vivo
human lungs (Aim 3). The platform technology developed here may directly produce an ARDS therapeutic,
and may also be extended later to probe ARDS pathophysiology, and treat other alveolar diseases.
Terms: <2019-nCoV vaccine><7B4 Antigen><7B4 protein><ARDS><Acids><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adhesion Molecule><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Air Bladder><Air Sacs><Alveolar><Alveolus><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Automobile Driving><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood capillaries><Blood leukocyte><Blood monocyte><Body System><Bronchial Alveolus><CD144 Antigen><COVID-19><COVID-19 vaccine><CSIF><CSIF-10><CV-19><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Count><Cell Function><Cell Number><Cell Physiology><Cell Process><Cell-Cell Adhesion><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Clinical Trials><Complement><Complement Proteins><Coronavirus Infectious Disease 2019><Critical Care><Critical Illness><Critically Ill><Cytokine Synthesis Inhibitory Factor><Da Nang Lung><Data><Death><Deposit><Deposition><Disease><Disorder><Dose><Dropsy><Drug Carriers><Drug Delivery><Drug Delivery Systems><Drugs><Dysfunction><Edema><Encapsulated><Endothelial Cells><Endothelium><Engineering><FDA approved><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Generalized Growth><Growth><Home><Hour><Human><Hydrops><IL-10><IL10><IL10A><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infiltration><Inflammation><Inflammatory><Inhalation><Inhaling><Injections><Interleukin 10 Precursor><Interleukin-10><K pneumoniae><K. pneumoniae><Klebsiella pneumoniae><Lavage><Leucocytic infiltrate><Leukocytes><Leukocytes Reticuloendothelial System><Lipids><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Marrow Neutrophil><Marrow leukocyte><Marrow monocyte><Measures><Mediating><Medication><Messenger RNA><Mice><Mice Mammals><Modern Man><Murine><Mus><Nanotechnology><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Oral><Organ><Organ System><Organ failure><Pathologic Processes><Pathological Processes><Pathway interactions><Patients><Perfusion><Pharmaceutical Preparations><Pharmacology><Phenotype><Physicians><Physiologic><Physiological><Physiopathology><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Process><Protein Secretion><Proteins><Publishing><Pulmonary Inflammation><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Shock Lung><Stiff lung><Stimulus><Subcellular Process><Surface><Swimbladder><Technology><Testing><Therapeutic><Time><Tissue Growth><Transplantation><VE-Cadherin><Vascular Endothelial Cadherin><Vascular Endothelial Cadherin 1><White Blood Cells><White Cell><aspirate><cadherin 5><capillary><cell adhesion protein><cell type><complementation><coronavirus disease 2019><coronavirus disease 2019 vaccine><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus infectious disease-19><cost><cytokine><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><driving><drug/agent><falls><flow cytophotometry><homes><human tissue><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><lavage therapy><leukocyte activation><lipid based nanoparticle><lipid nanoparticle><lung artery blood pressure><lung injury><mRNA><mRNA delivery><messenger RNA delivery><model of animal><monocyte><mortality><mouse model><murine model><mutant><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nano medicinal><nano medicine><nano meter scale><nano meter sized><nano particle delivery><nano tech><nano technology><nano-technological><nanocarrier><nanomedicinal><nanomedicine><nanometer scale><nanometer sized><nanoparticle delivered><nanoparticle delivery><nanoscale><nanotech><nanotechnological><nanovessel><native protein drug><neutrophil><new drug class><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug class><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><pathophysiology><pathway><pharmaceutical protein><pressure in pulmonary arteries><protein drug agent><protein expression><protein-based drug><pulmonary><pulmonary arterial blood pressure><pulmonary arterial pressure><pulmonary artery pressure><pulmonary artery systolic pressure><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><side effect><small molecule><success><technology platform><technology system><therapeutic protein><tissue resource><tool><transplant><uptake><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID><virtual><wet lung><white blood cell><white blood corpuscle>