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Principal Investigator: Saigopalakrishna Yerneni
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $142,452
Funding agency: National Institute of Neurological Disorders and Stroke
Diffuse midline glioma (DMG) is a lethal pediatric brain tumor without a cure and with a poor prognosis. The H3K27M mutation is present in 80% of DMG patients and is the primary driver of the disease. Therefore, targeting this oncohistone using mRNA-based gene therapies may represent a promising treatment option. However, mRNA as a drug needs to overcome the blood-brain and blood-tumor barriers to reach the tumor site, which is difficult due to the location of DMG in the brain stem. During my postdoctoral fellowship, I have developed non- toxic lipid nanoparticles (LNPs) that can effectively deliver mRNA to DMG tumors in vivo. This proposal aims to further optimize and evaluate the efficacy of these LNPs in delivering mRNA, explore the mechanism behind their delivery, and develop a new therapeutic approach targeting the H3K27M gene in DMG. In Aim 1, I will test the delivery of mRNA with different bases modifications and LNP chemistries to maximize LNP transfection and protein translation in DMG mouse models. In Aim 2, I will test the hypothesis that microglia take up LNPs and repackage them in extracellular vesicles that are subsequently delivered to DMG cells ‘in relay’. In the independent phase (Aim 3), I will explore LNP-mRNA-based gene therapy approach to target oncohistone H3K27M in DMG. Altogether this proposal aims to advance our understanding of DMG and establish a reliable and effective nucleic acid delivery approach for DMG. Completing the proposed project will allow me to build a strong scientific foundation under the mentorship of Profs. Kathryn A. Whitehead (lipid nanoparticle expert), Ian F. Pollack (pediatric brain tumor expert) and Drew Weissman (mRNA expert). An interdisciplinary advisory team has carefully been assembled, consisting of Prof. Robert S. Langer for translational drug delivery expertise, Profs. Maria G. Castro, Carl Koschmann and Sameer Agnihotri for DMG biology and mouse model expertise, Prof. Xiaoming Hu for microglia expertise and Prof. Samira Kiani for gene therapy expertise. Together, this research proposal, mentorship team, advisory committee and institutional support from Carnegie Mellon University will lay the scientific groundwork and provide the necessary training to reach my ultimate goal of successfully starting my independent academic career.
Terms: <0-11 years old><2019-nCoV vaccine><Address><Advisory Committees><Aggressive course><Antibodies><Antigens><Biodistribution><Biology><Blood><Blood Reticuloendothelial System><Brain><Brain Cancer><Brain Diseases><Brain Disorders><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Stem><Brain Tumors><Brainstem><CNS Nervous System><COVID-19 vaccine><Cancer Treatment><Cancers><Cell Body><Cell Membrane Permeability><Cells><Central Nervous System><Cessation of life><Chemistry><Child><Child Youth><Childhood Brain Neoplasm><Childhood Brain Tumor><Childhood Glioma><Children (0-21)><Clinic><Clinical><Committee Members><DNA Therapy><Data><Death><Development><Disease><Disease Progression><Disorder><Drug Delivery><Drug Delivery Systems><Drugs><Encephalon><Encephalon Diseases><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Fellowship><Foundations><Gene Transcription><Gene Transfer Clinical><Genes><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic Transcription><Genetic defect><Goals><H3 K27M mutant><H3 K27M mutation><H3K27M mutant><H3K27M mutation><Histone H3.3><Hortega cell><Immunocompetent><Institution><Intrabody><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Knowledge><Lipid Chemistry><Location><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mediating><Medication><Medicine><Mentors><Mentorship><Messenger RNA><Microglia><Modification><Mutation><Neuraxis><Patients><Pediatric Glioma><Pediatric high-grade glioma><Penetration><Pharmaceutical Preparations><Phase><Pons><Pons Cerebelli><Pons Varolii><Pontine><Pontine structure><Postdoc><Postdoctoral Fellow><Prognosis><Proteins><RNA Expression><RNA based therapeutics><RNA based therapy><RNA therapy><Radiation Sensitivity><Radiation Tolerance><Radiation therapy><Radiosensitivity><Radiotherapeutics><Radiotherapy><Reporter><Research Associate><Research Proposals><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Safety><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Site><Sphingolipids><Survival Rate><System><Task Forces><Technology><Testing><Therapeutic><Therapeutic Uses><Time><Training><Transcription><Transfection><Translating><Translations><Universities><adult youth><advisory team><anti-cancer therapy><base><bases><blood-brain tumor barrier><blood-tumor barrier><bloodbrain tumor barrier><cancer therapy><cancer-directed therapy><career><combat><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><deliver mRNA><deliver messenger RNA><delivery system for mRNA><determine efficacy><developmental><diffuse midline glioma><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><epigenetic gene silencing><epigenetic silencing><epigenetically><evaluate efficacy><examine efficacy><extracellular vesicles><gene repair therapy><gene therapy><gene-based therapy><gene-based treatment><gene-directed therapy><gene-targeted therapy><gene-targeted treatment><genetic therapy><genome editing><genome mutation><genomic editing><genomic therapy><gitter cell><immune competent><immunogen><in vivo><insight><kids><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA delivery><malignancy><membrane permeability><mesoglia><messenger RNA delivery><microglial cell><microgliocyte><mouse model><murine model><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nucleic acid delivery><oncohistone><pediatric brain neoplasm><pediatric brain tumor><perivascular glial cell><post-doc><post-doctoral><post-doctoral trainee><pre-clinical><preclinical><radiation treatment><radio-sensitivity><radiosensitive><research associates><site targeted delivery><standard of care><targeted delivery><technology platform><technology system><therapeutic RNA><trafficking><translation><treatment with radiation><tumor><tumors in the brain><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID><young adult><young adulthood><youngster>