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Principal Investigator: Xiangfei Han
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2023
Award: $69,500
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
Protein replacement therapy has been a cornerstone in treating genetic diseases (e.g., hemophilia) with loss or
reduction of the function of a particular protein, by using recombinant proteins or recombinant engineered
proteins. However, most protein therapeutics have short circulation lives, and thus require frequent invasive
infusion to maintain their therapeutic efficacy. For example, the most common treatment for hemophilia A caused
by a deficiency of blood clotting factor VIII (FVIII) is factor concentrate replacement, which is associated with
burdensome frequent intravenous infusion. To address the unmet medical need of hemophilia, the major
objective of this project is to develop a non-invasive oral mRNA delivery nanoplatform for durable protein
replacement therapy requiring infrequent dosing. Synthetic mRNA has shown enormous potential for biomedical
applications, with mRNA vaccines already clinically approved for COVID-19. Various delivery strategies have
been developed to improve mRNA translation; however, an ongoing challenge of mRNA therapy is managing
the transient efficacy due to its relatively short half-life, and oral mRNA delivery remains elusive. In my previous
work, I have identified a unique poly(zwitterion)-lipid-based micelle platform that can cross the intestinal epithelial
barrier and lead to a very potent oral bioavailability of biomolecules such as insulin. Recently, I have also
discovered a new type of ionizable lipids that can extend the duration of mRNA-mediated protein expression. In
this F32 project, I propose to combine the epithelium-crossing poly(zwitterion)-lipids and the unique ionizable
lipids to develop an innovative mRNA delivery platform for oral, durable replacement therapy of bleeding
disorders. In Aim 1, I will synthesize new poly(zwitterion)-lipids and ionizable lipids and generate a series of new
mRNA lipid nanoparticles (LNPs), and systematically investigate their effects on oral transcytosis and the
durability of protein expression in vitro and in vivo. In Aim 2, we will select the top-performing LNPs for oral
delivery of FVIII mRNA and evaluate the FVIII mRNA nanotherapy in healthy and hemophilia mouse models.
With the successful completion of this project, we expect that the oral durable mRNA delivery strategy will provide
a more effective and robust therapy for hemophilia and other bleeding disorders.
Terms: <Address><Amino Acid Channel><Amino Acid Transport Systems><Amino Acid Transporter><Antihemophilic Factor><Bioavailability><Biodistribution><Biological Availability><Blood Chemical Analyses><Blood Chemical Analysis><Blood Clotting><Blood Coagulation Disorders><Blood Coagulation Factor><Blood Coagulation Factor VIII><Blood coagulation><COVID-19><COVID19><CV-19><CV19><Circulation><Clinic><Clinical><Clotting><Coagulation><Coagulation Disorder><Coagulation Factor VIII><Coagulation Factor VIIIc><Coagulation Factors><Coagulation Process><Coagulopathy><Development><Diffusion><Doctor of Philosophy><Dose><ECSF><Epithelium><Epoetin><Erythropoietin><Evaluation><Factor VIII><Factor VIII Deficiency><Factor VIII F8B><Formulation><Generations><Genetic Diseases><Goals><H+ element><Half-Life><Hct><Hematocrit><Hematocrit procedure><Hematology><Hemophilia><Hemophilia A><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Humulin R><Hydrogen Ions><IV Infusion><In Vitro><Infusion><Infusion procedures><Insulin><Intravenous infusion procedures><Laboratories><Lead><Light><Lipid Chemistry><Lipids><Liver><Liver Cells><Lytotoxicity><Measures><Mediating><Medical><Messenger RNA><Mice><Mice Mammals><Micelles><Modality><Modeling><Modern Man><Monitor><Mucous body substance><Mucus><Murine><Mus><Nanoplatform><Nanotechnological platform><Nanotechnology><Nature><Novolin R><Occluding Junctions><Oral><Oral Administration><Oral Drug Administration><Organ><Packed Erythrocyte Volume><Packed Red-Cell Volume><Patient Compliance><Patients><Pattern><Pb element><Permeability><Ph.D.><PhD><Photoradiation><Physiologic Availability><Procoagulant Component><Property><Protein Engineering><Protein Overexpression><Protein Replacement Therapy><Proteins><Protons><RNA delivery><RNA vaccine><RNA-based vaccine><Recombinant Proteins><Recombinants><Regular Insulin><Replacement Therapy><Reporting><Route><Safety><Series><Staining method><Stains><Testing><Therapeutic><Thromboplastinogen><Tight Junctions><Time><Training><Translations><Transportation><Treatment Efficacy><Work><Zonula Occludens><absorption><antihemophilic factor A><biocompatibility><biomaterial compatibility><bleeding disorder><blood chemistry><clotting disorder><clotting factor><common treatment><complex Blood-coagulation factor VIII><compliance behavior><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytotoxicity><developmental><diffused><diffuses><diffusing><diffusions><enzyme replacement therapy><erythrocyte colony stimulating factor><genetic condition><genetic disorder><genetic protein engineering><heavy metal Pb><heavy metal lead><hematopoietin><hepatic body system><hepatic organ system><improved><in vitro activity><in vivo><infusions><injection/infusion><innovate><innovation><innovative><intervention efficacy><intestinal epithelium><intraoral drug delivery><intravenous infusion><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA Translation><mRNA delivery><mRNA vaccine><mRNA-based vaccine><mouse model><mucous><murine model><nano particle delivery><nano tech><nano technology><nano therapy><nano-technological><nanoparticle delivered><nanoparticle delivery><nanotech><nanotechnological><nanotechnology platform><nanotherapy><native protein drug><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><patient adherence><patient cooperation><pharmaceutical protein><platelet cofactor I><protein design><protein drug agent><protein expression><protein-based drug><screening><screenings><side effect><therapeutic efficacy><therapeutic protein><therapy compliance><therapy cooperation><therapy efficacy><thromboplastinogen A><transcytosis><translation><treatment compliance>