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Principal Investigator: Michael J Mitchell
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $349,375
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY
Pre-eclampsia is an obstetric condition that affects 5–8% of all pregnancies and is a leading cause of maternal
mortality worldwide. Pre-eclampsia is characterized by the onset of maternal hypertension after 20 weeks of
gestation, stemming from insufficient remodeling of the uterine spiral arteries that supply blood flow to the
placenta and fetus. Clinical treatments for pre-eclampsia, such as antihypertensive drugs to manage blood
pressure and anticonvulsants to prevent seizures, address the associated symptoms, yet no drug or therapeutic
has been developed to slow the progression of pre-eclampsia. The only curative treatment option for pre-
eclampsia is the early delivery of the placenta and fetus, which often resolves maternal hypertension within a
few days, but can cause fetal morbidity and mortality, especially in cases where fetal growth restriction occurs
concurrently with pre-eclampsia. Therefore, a significant unmet need exists for novel therapeutic strategies that
can facilitate vasodilation in the placenta during pre-eclampsia to resolve maternal hypertension and improve
fetal health. With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs)
for extrahepatic mRNA delivery to the placenta is an attractive therapeutic platform to treat pre-eclampsia. The
goal of the proposed work is to develop a targeted, placenta-tropic LNP platform for the delivery of mRNA cargo
to the placenta to treat pre-eclampsia during pregnancy. First, high-throughput in vivo screening will be utilized
to evaluate a large library of LNPs with novel ionizable lipid structures and excipient compositions for extrahepatic
tropism to the placenta. Lead candidates from this high-throughput screen will be functionalized with active
targeting motifs, namely placenta-specific antibodies, for selective delivery to trophoblasts and endothelial cells
in vivo. Following enrichment analysis using next generation sequencing, LNPs demonstrating placental tropism
will be functionalized with placental-specific antibodies to promote active targeting to key cell types in the
placenta — trophoblasts and endothelial cells. In vitro, ex vivo, and in vivo expression of therapeutic mRNA
cargos (VEGF, PlGF, and eNOS) encapsulated in LNPs will then be evaluated in primary human and mouse
placentas. The lead mRNA LNP candidates will then be utilized to rescue maternal hypertension, fetal health,
and immunophenotype in an induced model of severe, early onset pre-eclampsia in mice. The work proposed
here is the first to evaluate the therapeutic efficacy of a pro-angiogenic mRNA LNPs for treating pre-eclampsia,
a placental disorder during pregnancy for which currently no curative treatment options exist. Due to the modular
nature of LNPs and the ability to readily swap mRNA cargoes, the platform developed through the completion of
these studies can be used for treating not only pre-eclampsia, but also a wide range of placental disorders
occurring during pregnancy.
Terms: <Address><Affect><Amyloidosis><Angiogenesis Factor><Angiogenic Factor><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Antibodies><Anticonvulsant Agent><Anticonvulsant Drugs><Anticonvulsants><Anticonvulsive Agents><Anticonvulsive Drugs><BP control><BP management><Bar Codes><Blood Pressure><Blood Serum><Blood flow><COVID-19><CV-19><Cell Body><Cell Line><CellLine><Cells><Cells Placenta-Tissue><Clinical><Clinical Treatment><Coronavirus Infectious Disease 2019><Culturing, in vitro Vertebrate, Primary><DNA><Decidua Basalis><Deoxyribonucleic Acid><Diffusion><Discipline of obstetrics><Disease><Disease Progression><Disorder><Drug Delivery><Drug Delivery Systems><Drugs><Dysfunction><ELISA><ENOS><EPH Gestosis><Encapsulated><Endothelial Cells><Endothelial Nitric Oxide Synthase><Engineering><Ensure><Enzyme-Linked Immunosorbent Assay><Excipients><Extrahepatic><Fetal Growth Restriction><Fetal Growth Retardation><Fetal health><Fetus><Formulation><Functional disorder><Gestation><Goals><Health><High Throughput Assay><Histology><Human><Hypotensive Agent><Hypotensive Drugs><IUGR><Immunoblotting><Immunologic Subtyping><Immunophenotyping><In Vitro><Intrauterine Growth Retardation><Isoforms><Lead><Libraries><Lipids><Lipopolysaccharides><Liver><Lung><Lung Respiratory System><Maternal Mortality><Maternal placenta><Mediating><Medication><Messenger RNA><Mice><Mice Mammals><Microscopy><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><NGS Method><NGS system><NOS3><NOS3 gene><Nature><Nitric Oxide Synthase 3><Normal Placentoma><Obstetrics><Organ><PGF gene><PLGF-2><Pb element><Pharmaceutical Preparations><Phase><Physiopathology><PlGF><PlGF protein><Placenta><Placenta Diseases><Placenta Disorders><Placenta Embryonic Tissue><Placental Diseases><Placental Growth Factor><Placentome><Pre-Eclampsia><Prealbumin><Preeclampsia><Pregnancy><Pregnancy Toxemias><Primary Cell Cultures><Proalbumin><Protein Isoforms><Proteins><Proteinuria-Edema-Hypertension Gestosis><RNA vaccine><RNA-based vaccine><Seizures><Serum><Spiral Artery><Spiral Artery of the Endometrium><Spleen><Spleen Reticuloendothelial System><Strains Cell Lines><Structure><Therapeutic><Transthyretin><Treatment Efficacy><Tropism><Type III nitric oxide synthase><Uterus><VEGF><VEGFs><Vascular Endothelial Growth Factors><Vascular blood supply><Vasodilatation><Vasodilation><Vasorelaxation><Western Blotting><Western Immunoblotting><Work><amyloid disease><angiogenesis><anti-hypertension><associated symptom><barcode><blood pressure control><blood pressure management><blood supply><blood vessel development><blood vessel formation><cell type><clinical applicability><clinical application><co-morbid symptom><co-occuring symptom><comorbid symptom><concurrent symptom><cooccuring symptom><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cultured cell line><curative intervention><curative therapeutic><curative therapy><curative treatments><cytokine><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><diffused><diffuses><diffusing><diffusions><drug/agent><early onset><enzyme linked immunoassay><fetal><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><high throughput screening><immunophenotype><impaired fetal growth><improved><in vivo><intervention efficacy><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth restriction><intravenous administration><lead candidate><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA Expression><mRNA delivery><mRNA vaccine><mRNA-based vaccine><maternal death><maternal hypertension><messenger RNA delivery><mortality><mouse model><multidisciplinary><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><native protein drug><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next gen sequencing><next generation sequencing><next generation therapeutics><nextgen sequencing><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><nucleic acid delivery><pathophysiology><pharmaceutical protein><placenta growth factor><placental disorders><placental trophoblasts><pre-clinical study><pre-eclamptic><preclinical study><pregnancy toxemia/hypertension><pregnant><prenatal growth disorder><prevent><preventing><product placenta growth factor><protein blotting><protein drug agent><protein-based drug><pulmonary><pup><screening><screenings><seizure drug><seizure medication><siRNA therapy><siRNA-based therapeutic><siRNA-based therapy><stem><success><symptom association><symptom comorbidity><systemic inflammation><systemic inflammatory response><therapeutic efficacy><therapeutic protein><therapeutic siRNA><therapeutic small interfering RNA><therapy efficacy><trial regimen><trial treatment><trophoblast><vascular supply><womb>