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Principal Investigator: Vladimir R Muzykantov
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $792,842
Funding agency: National Heart Lung and Blood Institute
Clinical approval of Lipid Nano Particles (LNP) for RNA heralded the advent of nanotechnology-
based pharmacotherapy. Yet, RNA delivery to extra-hepatic sites remains a major unmet challenge.
Weissman pioneered modifications of mRNA providing effective translation in diverse cell types, while
Muzykantov introduced “vascular targeting”, nanomedicine strategy for drug delivery to desired areas
in the vasculature. Here we converge these advances to devise nanocarriers targeting RNA to
desired sites of transgene synthesis and therapeutic action. We found that ligands of Inter-Cellular
Adhesion Molecule-1 (ICAM) conjugated to nanocarriers, direct ICAM-LNP (ILNP) to accumulate in
lungs, especially, in the inflamed lungs, with trivial cerebral uptake. In opposite, LNP targeting to
Vascular Cell Adhesion Molecule-1 (VCAM) provides trivial pulmonary uptake of VCAM-LNP (VLNP),
and selective uptake in the inflamed brain, surpassing the benchmarks by orders of magnitude. VLNP
loaded with mRNA encoding endothelial multifunctional anti-thrombotic and anti-inflammatory protein
thrombomodulin (TM) provides transgene synthesis and protective effect in the inflamed CNS
unrivaled by other agents. We will characterize and if needed reiteratively re-engineer targeting
features of this powerful nanotechnology platform, by pursuing the following Specific Aims. Aim 1:
Multi-scale spatiotemporal mapping of vascular targeting of ILNP and VLNP. Using isotope tracing
and real time imaging, in vivo microscopy and flow cytometry, we will define PK/BD, dynamics of LNP
localization and reporter transgene activity in the sites of desirable therapeutic action. Aim 2:
Targeting therapeutic thrombomodulin RNA to lung and brain. We will characterize salient parameters
of TM transgene expression, beneficial and unintended effects of ILNP and VLNP in naive mice and
in mouse models of pulmonary and cerebral inflammation. Aim 3: Translational development of LNP.
We will upgrade LNP to clinically applicable format via site-specific conjugation of small recombinant
ligands. This study will define key specification parameters of a novel nanotechnology platform for
selective delivery of RNA to desirable cells and cellular compartments in brain, lungs and likely other
organs. It will establish proof of principle for a new nanomedicine approach for effective, specific and
safe biological pharmacotherapy of ALI and stroke, with future expansion to other diseases.
Terms: <Acute Lung Injury><Acute Pulmonary Injury><Adhesion Molecule><Affinity><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antigenic Determinants><Antiinflammatories><Antiinflammatory Agents><Apoplexy><Area><Benchmarking><Best Practice Analysis><Binding><Binding Determinants><Biologic Products><Biological><Biological Agent><Biological Products><Biological Response Modifier Therapy><Biological Therapy><Blood Vessels><Body Tissues><Brain><Brain Inflammation><Brain Nervous System><Brain Vascular Accident><CD106><CD106 Antigens><CD54 Antigens><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><Cell membrane><CellLine><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cerebrovascular system><Cerebrum><Clinical><Coupled><Cytoplasmic Membrane><Development><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Therapy><Dysfunction><Elements><Encephalitis><Encephalon><Endocytosis><Endothelial Cells><Endothelium><Engineering><Epitopes><Extrahepatic><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formulation><Functional disorder><Future><Gene Proteins><Goals><Human><ICAM-1><INCAM-110><Inducible Cell Adhesion Molecule 110><Inflammation><Intercellular adhesion molecule 1><Intracellular Communication and Signaling><Isotopes><Ligands><Liver><Lung><Lung Inflammation><Lung Respiratory System><Maps><Medical><Messenger RNA><Methods><Mice><Mice Mammals><Microscopy><Modeling><Modern Man><Modification><Molecular Interaction><Murine><Mus><Nanoplatform><Nanotechnological platform><Nanotechnology><Non-Polyadenylated RNA><Organ><Pharmacokinetics><Pharmacotherapy><Physiopathology><Pilot Projects><Plasma Membrane><Pneumonitis><Protein Gene Products><Proteins><Pulmonary Inflammation><RNA><RNA Gene Products><RNA delivery><Recombinants><Reporter><Ribonucleic Acid><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specific qualifier value><Specified><Spleen><Spleen Reticuloendothelial System><Strains Cell Lines><Stroke><Surface><Testing><Therapeutic><Thrombomodulin><Thrombosis><Time><Tissues><Transgenes><Translating><Translations><VCAM><VCAM-1><Vascular Cell Adhesion Molecule><Vascular Cell Adhesion Molecule-1><antiinflammatory><benchmark><biologic><biological signal transduction><biological therapeutic><biological treatment><biologically based therapeutics><biologics><biopharmaceutical><biotherapeutic agent><biotherapeutics><biotherapy><blood vessels in the brain><brain attack><brain blood vessels><brain vasculature><cell adhesion protein><cell type><cerebral><cerebral blood vessel><cerebral vascular accident><cerebral vasculature><cerebrovascular accident><cerebrovascular vessels><cerebrovasculature><clinical applicability><clinical application><cultured cell line><developmental><drug treatment><flow cytophotometry><gene synthesis><gene therapeutics><gene-based therapeutic><gene-based therapeutics><genes therapeutic><genes therapeutics><hepatic body system><hepatic organ system><in vivo><intravenous injection><lead candidate><lipid based nanoparticle><lipid nanoparticle><mRNA><mouse model><murine model><nano medicinal><nano medicine><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanobodies><nanobody><nanocarrier><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><nanotech><nanotechnological><nanotechnology platform><nanovessel><new approaches><novel><novel approaches><novel strategies><novel strategy><pathophysiology><pilot study><plasmalemma><prophylactic><protective effect><pulmonary><real-time images><realtime image><sdAb><single domain antibodies><spatiotemporal><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic gene><thrombotic><thrombotic disease><thrombotic disorder><transgene><transgene expression><translation><uptake><vascular>