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Principal Investigator: RUSSELL R BROADDUS
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2020
Award: $162,000
Funding agency: National Cancer Institute
The 2019 novel coronavirus, SARS-CoV-2 causes COVID-19, a pandemic viral disease. This disease has resulted in world-wide fatalities, particularly in patients with cardiovascular disease, and arterial hypertension. As of June 2020, close to 6.6 million cases and death of 393,000 were reported worldwide; 1.95 million cases and more than 111,000 deaths in the US. COVID-19 poses a specific and substantial immediate burden on cancer patients who are already facing the tribulations of cancer treatment and survivorship. SARS-CoV-2 will continue to be a major threat to the lives of the above high risk groups including current and future cancer patients irrespective of the type and stage of cancer, unless a treatment that does not interfere with current cancer chemotherapies is developed urgently. CoVs are enveloped with a positive sense, single-strand RNA genome; and belong to the Coronaviridae family. CoVs are composed of at least 5 major fundamental proteins: replicase encoding polypeptide (pp1ab), Spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. The viral life cycle begins with the infection, entry of the virion into cells by the binding to the host cell receptor and endocytosis (S protein), release of the viral genome into the cytoplasm and its transport to the host nucleus (N protein) where it replicates (pp1ab) and new virus particles are released. This results in respiratory, enteric, hepatic, and neurologic diseases. pp1ab, E and N proteins, unique to SARS-CoV-2 and not natively expressed in mammalian cells, offer potential opportunities for therapeutic targeting to cure COVID-19. Current drug and treatment strategies include blocking of RNA-polymerase, mRNA-based vaccines to induce antibody production, antibody treatments, and isolation of plasma and antibodies from the survivors of Covid-19. Since there are several unwarranted side effects of targeting the proteins essential to SARS-CoV-2 infection and spread, limited benefits of the current drugs, and limited availability of COVID-19 disease animal models, our strategy is to use and prioritize siRNA candidates based on the greatest inhibition of SARS-CoV-2 proteins (in model cell lines transfected with individual SARS-CoV-2 proteins) for further evaluation. We aim to use the siRNA-based therapeutic candidates with either an aerosolized (through a collision nebulizer) neutral phospholipid 1,2- dioleoyl-sn-glycero-3-phosphatidylcholine nanoliposomes (DOPC) or plant-derived vesicles (PDV) to specifically target the vital proteins of SARS-CoV-2 to inhibit its replication and virus assembly. We expect this approach will have a potent anti-viral RNAi response leading to viral clearance.
Terms: <2019 novel coronavirus><2019-nCoV><Ab response><Aerosols><Animal Disease Models><Antibodies><Antibody Formation><Antibody Production><Antibody Therapy><Antiviral Agents><Antiviral Drugs><Antivirals><Binding><Blood Plasma><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Cancer Patient><Cancer Survivorship><Cancer Treatment><Cancers><Cardiovascular Diseases><Cell Body><Cell Line><Cell Nucleus><Cell model><CellLine><Cells><Cellular model><Cessation of life><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy, Cancer, General><Chemotherapy-Oncologic Procedure><China><Choline Glycerophospholipids><Choline Phosphoglycerides><Combination Chemotherapy Regimen><Coronaviridae><Coronavirus><Cytoplasm><DNA><DNA-Dependent RNA Polymerases><DNA-Directed RNA Polymerase><Death><Deoxyribonucleic Acid><Disease><Disorder><Drug Therapy><Drugs><Endocytosis><Enteral><Enteric><Envelope Protein><Evaluation><Family><Future><Genome><Hepatic Disorder><Hypertension><Individual><Infection><Lecithin><Life Cycle><Life Cycle Stages><Liver diseases><Lung><Lung Respiratory System><Mainland China><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Molecular Interaction><Nebulizer><Nervous System Diseases><Neurologic Disorders><Neurological Disorders><Non-Polyadenylated RNA><Nucleocapsid Proteins><Nucleus><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Phosphatides><Phosphatidylcholines><Phospholipids><Plants><Plasma><Plasma Serum><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteins><Quelling><Quimioterapia><RNA><RNA Gene Products><RNA Interference><RNA Polymerases><RNA Silencing><RNAi><Receptor Cell><Reporting><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Sequence-Specific Posttranscriptional Gene Silencing><Severe acute respiratory syndrome coronavirus 2><Short interfering RNA><Small Interfering RNA><Strains Cell Lines><Surface Proteins><Survivors><Vaccines><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vesicle><Viral><Viral Diseases><Viral Genome><Virion><Virus Assembly><Virus Diseases><Virus Particle><Wuhan coronavirus><aerosolized><anti-cancer therapy><anti-viral agents><anti-viral drugs><anti-virals><antibody based therapies><antibody biosynthesis><antibody treatment><antibody-based therapeutics><antibody-based treatment><anticancer therapy><base><cancer chemotherapy><cancer therapy><cardiovascular disorder><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><cultured cell line><drug treatment><drug/agent><env Antigens><env Gene Products><env Polyproteins><env Protein><experience><hepatic disease><hepatopathy><high blood pressure><high risk group><high risk population><hyperpiesia><hyperpiesis><hypertensive disease><immunoglobulin biosynthesis><life course><liver disorder><mRNA><malignancy><nano formulation><nano liposome><nanoformulation><nanoliposomal><nanoliposome><neoplasm/cancer><nervous system disorder><neurological disease><pandemic><pandemic disease><polypeptide><pulmonary><replicase><respiratory><response><siRNA><siRNA therapy><siRNA-based therapeutic><side effect><therapeutic candidate><therapeutic siRNA><therapeutic target><treatment strategy><viral assembly><viral infection><virus genome><virus infection><virus-induced disease>