Document text
Principal Investigator: Jacob Brenner
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $679,571
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.
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Mammals><Modern Man><Murine><Mus><Nanotechnology><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nonvaginal irrigation><Nonvaginal lavage><Oral><Organ><Organ System><Organ failure><Pathologic Processes><Pathological Processes><Pathway interactions><Patients><Perfusion><Pharmaceutic Preparations><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-CoV2 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 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molecule><success><technology platform><technology system><therapeutic protein><tissue resource><tool><transplant><uptake><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine for novel coronavirus><virtual><wet lung><white blood cell><white blood corpuscle>