A New Lipid Nanoparticle Technology Enabling Long-acting mRNA Therapy

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Principal Investigator: Jinjun  Shi
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2023
Award: $542,677
Funding agency: National Heart Lung and Blood Institute

ABSTRACT
Recent clinical success of mRNA vaccines for COVID-19 has sparked enormous interest in mRNA therapy for a
wide range of biomedical applications including protein replacement therapy. However, one unique challenge
associated with mRNA therapy is dealing with the transient efficacy due to its relatively short half-life. Current
nanoparticles including FDA-approved lipid nanoparticles (LNPs) could significantly improve mRNA translation
efficiency, but the duration of in vivo protein expression by these mRNA NPs is generally short (limited to a few
days), thus requiring frequent re-dosing. The main objective of this project is to advance a new transformative
LNP technology enabling long-acting mRNA replacement therapy of genetic disorders associated with loss of
function of a particular protein. In our recent studies, we developed a new generation of LNPs and performed
the head-to-head comparison in vitro and in vivo to the benchmark LNP formulations composed of FDA-approved
ionizable lipids. We observed a dramatic increase of the duration of model protein expression in vitro and in vivo
by our new mRNA LNPs. Preliminary safety studies showed that our mRNA LNPs were well tolerated without
observable adverse events in vivo. With the proof-of-concept demonstration of our long-acting mRNA LNPs, this
project aims to i) further optimize the mRNA LNP technology for longer-term, high level protein expression, and
ii) rigorously validate this transformative mRNA delivery platform using hemophilia A as a model disease. We
expect that with successful validation in normal and hemophilia A mice, this long-acting mRNA LNP platform
could be readily moved into clinical testing for hemophilia and expanded to other genetic diseases that require
restoration of normal protein functions.

Terms: <2019-nCoV vaccine><Address><Adeno-Associated Viruses><Adverse Experience><Adverse event><Antibodies><Antihemophilic Factor><Apoptosis><Apoptosis Pathway><Autoprothrombin II><Benchmarking><Best Practice Analysis><Blood><Blood Chemical Analyses><Blood Chemical Analysis><Blood Clotting><Blood Coagulation Disorders><Blood Coagulation Factor><Blood Coagulation Factor IX><Blood Coagulation Factor VIII><Blood Reticuloendothelial System><Blood coagulation><COVID-19 vaccine><COVID19 vaccine><Cholesterol><Christmas Disease><Christmas Factor><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Clotting><Coagulation><Coagulation Disorder><Coagulation Factor IX><Coagulation Factor VIII><Coagulation Factor VIII, Procoagulant Component><Coagulation Factor VIIIc><Coagulation Factors><Coagulation Process><Coagulopathy><D-Galactose><DNA Therapy><DXS1253E><Dependoparvovirus><Dependovirus><Disease><Disease model><Disorder><Dose><EC 3.4.21.22><ECSF><Eligibility><Eligibility Determination><Epoetin><Erythropoietin><F8 gene><F8 protein><F8B><F8C><FDA approved><FVIII><Factor IX><Factor IX Complex><Factor IX Deficiency><Factor IX Fraction><Factor VIII><Factor VIII Deficiency><Factor VIII F8B><Factor VIIIF8B><Formulation><Galactopyranose><Galactopyranoside><Galactose><Gene Transfer Clinical><Generations><Genes><Genetic><Genetic Diseases><Genetic Intervention><HEMA gene><Half-Life><Hct><Heart><Hematocrit><Hematocrit procedure><Hematology><Hemophilia><Hemophilia A><Hemophilia B><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><IV Infusion><In Vitro><Injections><Intravenous infusion procedures><Ligands><Lipids><Liver Cells><Lung><Lung Respiratory System><Measures><Mediating><Medical><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Murine><Mus><Organ><Other Genetics><Packed Erythrocyte Volume><Packed Red-Cell Volume><Patients><Plasma Thromboplastin Component><Play><Population><Procoagulant Component><Production><Programmed Cell Death><Protein Engineering><Protein Replacement Therapy><Proteins><Protocol Screening><RNA vaccine><RNA-based vaccine><Recombinant Proteins><Recombinants><Replacement Therapy><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><Safety><Secondary to><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Staining method><Stains><Surface><Technology><Testing><Therapeutic><Thromboplastinogen><Time><Toxic effect><Toxicities><Validation><Work><adeno associated virus group><antihemophilic factor A><antihemophilic factor B><benchmark><biocompatibility><biomaterial compatibility><bleeding disorder><blood chemistry><clinical test><clotting disorder><clotting factor><complex Blood-coagulation factor VIII><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><disorder model><enzyme replacement therapy><erythrocyte colony stimulating factor><gene repair therapy><gene therapy><gene-based therapy><genetic condition><genetic disorder><genetic protein engineering><genetic therapy><genomic therapy><head-to-head analysis><head-to-head comparison><hematopoietin><improved><in vivo><inter-patient variability><interest><interpatient variability><intravenous infusion><lipid based nanoparticle><lipid nanoparticle><loss of function><mRNA><mRNA Expression><mRNA Translation><mRNA delivery><mRNA vaccine><mRNA-based vaccine><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nano particle><nano-sized particle><nanoparticle><nanosized particle><platelet cofactor I><protein design><protein expression><protein function><pulmonary><research clinical testing><restoration><safety study><success><thromboplastinogen A><thromboplastinogen B><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><validations>