mRNA-LNPs for ARDS

ARDS 的 mRNA-LNP

• 批准号: 10659792
• 负责人: Jacob Brenner
• 金额: $ 67.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659792
• 关键词: Acids; Acute; Acute Respiratory Distress Syndrome; Affect; Air Sacs; Alveolar; Alveolus; Animal Model; Anti-Inflammatory Agents; Antibodies; Automobile Driving; Blood capillaries; COVID-19; COVID-19 vaccine; Cell Adhesion Molecules; Cell Count; Cell physiology; Cell-Cell Adhesion; Cessation of life; Clinical Trials; Complement; Critical Care; Critical Illness; Data; Deposition; Disease; Dose; Drug Carriers; Drug Delivery Systems; Edema; Encapsulated; Endothelial Cells; Endothelium; Engineering; FDA approved; Flow Cytometry; Functional disorder; Growth; Home; Hour; Human; Immunosuppression; Infiltration; Inflammation; Inflammatory; Inhalation; Injections; Interleukin-10; Irrigation; Klebsiella pneumoniae; Leucocytic infiltrate; Leukocytes; Lipids; Lung; Measures; Mediating; Messenger RNA; Mus; Nanotechnology; Oral; Organ; Organ failure; Pathologic Processes; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacology; Phenotype; Physicians; Physiological; Process; Protein Secretion; Proteins; Publishing; Pulmonary Inflammation; Stimulus; Surface; Technology; Testing; Therapeutic; Time; Transplantation; aspirate; body system; cadherin 5; cell type; cost; cytokine; design; falls; human tissue; improved; in vivo; leukocyte activation; lipid nanoparticle; lung injury; monocyte; mortality; mouse model; mutant; nanocarrier; nanomedicine; nanoparticle delivery; nanoscale; neutrophil; novel drug class; novel therapeutics; protein expression; pulmonary arterial pressure; side effect; small molecule; success; technology platform; therapeutic protein; tissue resource; tool; uptake; virtual

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.

摘要/项目总结