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Principal Investigator: Thomas William Geisbert
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2023
Award: $723,636
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY - Research Project 3
Members of the filovirus genera Ebolavirus and Marburgvirus are HHS Tier 1 Category A priority pathogens that
cause severe and often fatal hemorrhagic fever (HF) in humans and nonhuman primates (NHPs). There are
presently no approved therapeutics for ebolavirus or marburgvirus infections, and a broad spectrum
postexposure treatment that confers protection across all medically relevant filoviruses does not exist. Genevant
currently is developing RNA interference (RNAi) therapeutics targeting clinically relevant ebolaviruses and
marburgviruses. A key component of a RNAi therapeutic approach is the need for delivery technologies to ensure
uptake of the small interfering RNA (siRNA). Genevant’s N-acetylgalactosamine (GalNAc) conjugate and lipid
nanoparticle (LNP) platforms stabilize siRNA and ensure effective delivery to disease sites and target cells that
are the primary sites of infection for filoviruses. The goal of this research proposal is to generate a single broad
spectrum siRNA-conjugate targeting the most clinically relevant ebolaviruses and marburgviruses. This
therapeutic will then be used in a combinatorial treatment strategy with either fully human anti-filovirus
monoclonal antibodies or the RNA polymerase inhibitors GS-5734 or favipiravir (T-705). This combinatorial
strategy is intended to provide an effective and complementary treatment of filovirus infection that is more
effective than each therapeutic alone. In order to generate anti-filoviral siRNA conjugates, work is proposed in
two parts that will focus on optimizing the GalNAc ligand and siRNA components in parallel. To ensure potent
delivery of anti-filoviral siRNAs, novel GalNAc ligands will be synthesized and assessed for binding avidity and
ranked for their ability to mediate RNA silencing (Aim 1). The most effective ligand-conjugate delivery platform
will then be selected for conjugation to anti-filoviral siRNAs selected in Aim 2. Lead siRNAs, delivered via LNP,
have already been identified with demonstrated efficacy against EBOV, SUDV, BDBV, MARV, and RAVV in our
current U19 CETR grant. These anti-filoviral parental siRNA sequences will undergo chemical modification to
enable compatibility with a ligand conjugate delivery platform. Chemically modified siRNAs retaining silencing
activity against each clinically relevant filovirus will then be combined with the most effective ligands identified in
Aim 1 and assessed for broad spectrum efficacy in NHP models of filovirus infection. Different combinations of
siRNA-conjugates, monoclonal antibodies, and direct acting antiviral small molecules will be tested in filovirus-infected NHPs in Aim 3, with the goal of determining whether any of these combinatorial approaches will yield
benefit in improving protection during late stages of disease.
Terms: <ASGP-R><Acetylgalactosamine><Address><Area><Asialoglycoprotein Receptor><Asialoorosomucoid Receptor><Asialoorosomucoid-Binding Protein><Avidity><BDBV><Binding><Bundibugyo ebola virus><Bundibugyo ebolavirus><Bundibugyo virus><Category A pathogen><Category A priority pathogen><Cell Body><Cells><Chemicals><Chemistry><Clinical Treatment Moab><Combined Modality Therapy><Complementary therapies><Complementary treatment><Data><Development><Disease><Disorder><Drugs><EBOV><Ebola virus><Ebola-like Viruses><Encapsulated><Ensure><Epidemic><Filoviridae><Filoviridae Infections><Filovirus><Frankfurt-Marburg Syndrome Virus><Funding><GS-5734><Goals><Grant><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><In Vitro><Infection><Intravenous><Lead><Ligands><Liver Cells><Luciferase Immunologic><Luciferases><Marburg><Marburg virus><Marburg-like Viruses><Marburgvirus><Mediating><Medical><Medication><Modeling><Modern Man><Modification><Molecular Interaction><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><N acetylgalactosamine><NIAID><National Institute of Allergy and Infectious Disease><Oligo><Oligonucleotides><Pb element><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Production><Quelling><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Interference><RNA Interference Therapy><RNA Polymerase Inhibitor><RNA Sequences><RNA Silencing><RNA based therapeutics><RNA based therapy><RNA interference therapeutics><RNA interference-based therapy><RNA therapy><RNAi><RNAi therapeutics><RNAi therapy><RNAi-based therapeutics><RNAi-based therapy><Reporter><Research Grants><Research Project Grants><Research Project Summaries><Research Projects><Research Proposals><Research Resources><Resources><SUDV><Science><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Site><Small Interfering RNA><Sudan Ebola virus><Sudan ebolavirus><Sudan virus><System><Technology><Testing><Therapeutic><Therapeutic Index><Vaccines><Variant><Variation><Veklury><Viral><Viral Diseases><Viral Hemorrhagic Fevers><Virus Diseases><Work><ZEBOV><Zaire Ebola virus><Zaire ebolavirus><analog><anti-viral efficacy><antiviral efficacy><base><bases><clinical relevance><clinically relevant><combination therapy><combinatorial><combined modality treatment><combined treatment><design><designing><determine efficacy><developmental><drug/agent><ebolavirus><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experience><filovirus infections><heavy metal Pb><heavy metal lead><hemorrhagic fever><improved><lipid based nanoparticle><lipid nanoparticle><mAbs><manufacture><member><monoclonal Abs><multi-modal therapy><multi-modal treatment><non-human primate><nonhuman primate><novel><oligos><pharmaceutical><programs><prototype><remdesivir><risk mitigation><scaffold><scaffolding><siRNA><small molecule><small molecule inhibitor><small molecule therapeutics><subcutaneous><subdermal><therapeutic RNA><therapeutic target><treatment strategy><uptake><viral infection><virus infection><virus-induced disease>