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Principal Investigator: Michael J Sailor
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $684,136
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
New strategies to combat pneumonia caused by different pathogens are urgently needed. Inflammatory
macrophages play an essential role in clearing bacteria, fungi, and viruses during infections; however,
hyperinflammatory responses mediated by these cells can cause severe side effects, including death.
Immunotherapy that modulates macrophage polarization has shown promise in suppressing hyperinflammatory
responses while retaining the capability of macrophages to clear pathogens. To achieve successful
immunotherapy with RNA therapeutics, the following obstacles must be overcome: (1) rapid clearance of RNA
therapeutics by RNase in tissues; (2) poor cellular uptake of free RNA therapeutics; and (3) loss of RNA
therapeutics to non-infected tissues and potential off-target side effects. We previously discovered and
successfully transitioned to industry two nanotherapeutic systems that addressed these limitations for bacterial
infections. The elements of the nanosystems relevant to the present proposal are: high loading capacity for RNA
therapeutics; an ability to protect the RNA payload from degradation in vivo; and highly selective targeting of the
macrophages via pendant peptides. The proposed project hypothesizes that this approach may be generally
applicable across a spectrum of pathogens, and it aims to investigate treatment of viral and fungal pulmonary
infections. To address these goals, a deeper understanding of macrophage function and nanoparticle
interactions is needed, particularly in the context of pathogenic infections. Through three Specific Aims, we
propose to optimize and then evaluate three major nanoplatform-based systems that have shown promise for
nucleic acid delivery, and investigate the in vivo biological interactions of the targeted nanoplatforms to obtain
deeper understanding of macrophage polarization in combating pulmonary infections:
(1) Develop a targeting strategy for macrophage homing in infected lungs. We hypothesize designs that will allow
the nanoparticle to reach the infected regions of the lungs while preserving the potency of the RNAi therapeutic,
either by i.v. or by direct pulmonary delivery of nanoplatforms. This Aim will focus on screening for new peptides
that target macrophages in lung infection models, using the existing macrophage-targeting peptide CRV as a
benchmark. We will focus on well-established mouse models of pneumonia induced by carbapenem-resistant
K. pneumoniae, A. fumigatus, and influenza A.
(2) Develop, evaluate, and then downselect from three broad classes of nanoplatforms (i.e., lipid nanoparticles,
tandem peptide nanoparticles, and fusogenic porous silicon nanoparticles) to load RNA therapeutics. These
nanoplatforms will be targeted to macrophages in the infected lungs using peptides from Aim 1. Cytotoxicity,
gene knockdown efficiency, and macrophage polarization will be evaluated in vitro. Pharmacokinetics including
macrophage targeting and tissue distribution will be studied in vivo.
(3) Evaluate leading candidate(s) from Aim 2 for therapeutic performance in vivo through intranasal or nebulizing
administration. The goal of this Aim is to evaluate biosafety and therapeutic efficacy (i.e., pathogen burden
clearance, tissue recovery, and improved survival).
The significance of this project is that it will yield tools to actively target macrophages at infected lungs and it will
identify the essential design rules for nanoplatforms that can provide immunotherapy to combat a wide range of
pulmonary infections.
Terms: <A fumigatus><A. fumigatus><Address><Affinity Chromatography><Anti-viral Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Aspergillus fumigatus><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial Infections><Bacterial Pneumonia><Bacterial resistant><Benchmarking><Best Practice Analysis><Biological><Blood Plasma><Body Tissues><Bronchoalveolar Lavage Fluid><Cell Body><Cells><Cessation of life><Death><Drug Kinetics><Drug or chemical Tissue Distribution><Elements><Genes><Goals><Grippe><Hepatic><Histopathology><Homing><Immune mediated therapy><Immune response><Immunological response><Immunologically Directed Therapy><Immunotherapy><In Vitro><Industry><Infection><Inflammatory><Inflammatory Response><Influenza><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Innate Immune System><Innate Immunity><Intravenous><K pneumoniae><K. pneumoniae><Kidney><Kidney Urinary System><Klebsiella pneumoniae><Lead><Libraries><Life><Ligands><Lipids><Lung><Lung Respiratory System><Lung infections><Lytotoxicity><Macrophage><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Metabolic><Mice><Mice Mammals><Miscellaneous Antibiotic><Modality><Modeling><Murine><Mus><Mφ><NIH><Nanoplatform><Nanotechnological platform><National Institutes of Health><Native Immunity><Natural Immunity><Nebulizer><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Organ><Orthomyxovirus Type A><Pathogenicity><Pb element><Peptides><Performance><Phage Display><Pharmacokinetics><Plasma><Plasma Serum><Play><Pneumonia><Porosity><RNA><RNA Gene Products><RNA Interference Therapy><RNA Nucleases><RNA based therapeutics><RNA based therapy><RNA delivery><RNA interference therapeutics><RNA interference-based therapy><RNA therapy><RNAi therapeutics><RNAi therapy><RNAi-based therapeutics><RNAi-based therapy><RNase><Receptor Protein><Recovery><Reticuloendothelial System, Serum, Plasma><Ribonuclease Family Protein><Ribonucleases><Ribonucleic Acid><Role><Route><Sampling><Si element><Silicon><Surface><System><Therapeutic><Tissue Distribution><Tissues><Treatment Efficacy><Type A Influenza><United States National Institutes of Health><Update><Vaccines><Viral><Viral Pneumonia><Virus><affinity purification><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><bacteria infection><bacteria pathogen><bacteria pneumonia><bacterial disease><bacterial pathogen><bacterial resistance><benchmark><biologic><carbapenem resistance><carbapenem resistant><combat><cytotoxicity><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><design><designing><determine efficacy><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><fighting><fungal pathogen><fungal pneumonia><fungi pathogen><fungus><heavy metal Pb><heavy metal lead><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><improved><in vivo><influenza A pneumonia><intervention efficacy><intravenous administration><knock-down><knockdown><lead candidate><lipid based nanoparticle><lipid nanoparticle><mouse model><murine model><nano medicinal><nano medicine><nano particle><nano toxicity><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><nanosystems><nanotechnology platform><nanotherapeutic><nanotoxicity><nebulization><nebulize><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nucleic acid delivery><nucleic acid therapy><nucleic acid-based therapeutics><pathogen><pathogenic bacteria><pathogenic fungus><pathogenic virus><pneumonia model><pneumonia models><pneumonia therapy><pneumonia treatment><preservation><prevent><preventing><programs><pulmonary><pulmonary infections><receptor><renal><resistance in K pneumoniae><resistance in K. pneumoniae><resistance in Klebsiella pneumoniae><resistance to Bacteria><resistance to Bacterial><resistance to carbapenem><resistant K pneumoniae><resistant K. pneumoniae><resistant Klebsiella pneumoniae><resistant to Bacteria><resistant to Bacterial><resistant to carbapenem><response><screening><screenings><short interfering RNA delivery><siRNA delivery><side effect><site targeted delivery><small interfering RNA delivery><social role><targeted delivery><therapeutic RNA><therapeutic efficacy><therapeutic nucleic acids><therapy efficacy><tool><treat pneumonia><uptake><viral pathogen><virus pathogen>