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Principal Investigator: Brian H. Johnston
Organization: SOMAGENICS, INC.
Fiscal Year: 2020
Award: $965,488
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Hepatitis D virus (HDV) infection is the most severe type of viral hepatitis, often causing
accelerated liver damage that leads to end-stage liver disease. About 15–20 million
individuals are infected by HDV worldwide. The absence of an effective treatment for
acute forms of the disease and the limited efficacy of current treatments for the chronic
infection justify novel strategies towards the development of anti-HDV therapeutics. The
lack of HDV-encoded “druggable” targets that are suitable for conventional therapeutic
modalities such as small molecules and antibodies makes RNA interference an
attractive alternative approach to target this virus. However, the highly structured, GC-
rich circular genome of this smallest of RNA viruses make it a challenging target for
RNA-targeting approaches such as RNAi. In Phase I of this project, we were able to
identify inhibitors of HDV using SomaGenics' sshRNA® (synthetic small shRNAs)
platform. These sshRNAs potently inhibit viral replication at multiple target sites in a cell
culture infection model. The sshRNAs were then chemically modified to improve their
drug-like properties. In Phase 2, we plan to move the program forward into preclinical
studies using a transgenic mouse model that supports HDV infection. We will pursue
dual approaches to delivery of our therapeutic sshRNAs to liver: formulation with lipid
nanoparticles and use of a targeting ligand. Patterns of chemical modification will be
optimized for each candidate delivery method to permit a careful comparison, and the
most promising approach will be selected. Finally, combinations of sshRNAs will be
assessed for ability to provide increased efficacy and forestall the development of
resistance to therapy. By the end of Phase II, we expect to have established a cocktail of
inhibitors ready for IND-enabling safety studies and then commencement of clinical
studies.
Terms: <Acute><Alferon><Antibodies><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Reticuloendothelial System><Cell Culture Techniques><Chemicals><Chronic><Clinical Research><Clinical Study><Collaborations><Delta Agent><Delta Virus><Development><Disease><Disorder><Dose><Drugs><Formulation><Genome><Genomics><HBV><HCV infection><HDAg><Head><Health><Health Care Costs><Health Costs><Healthcare Costs><Hepatic Disorder><Hepatic Transplantation><Hepatitis B Virus><Hepatitis C><Hepatitis C virus infection><Hepatitis D Antigens><Hepatitis D Virus><Hepatitis Delta Virus><Hepatitis delta Antigens><Hepatitis δ Antigens><Hepatitis δ Virus><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Homologous Serum Hepatitis Virus><IFN Alpha><IFN-α><IFNa><IFNα><Individual><Infection><Injections><Injury to Liver><Interferon Alfa-n3><Interferon-alpha><Interferon-α><Lead><Leukocyte Interferon><Ligands><Liver><Liver Grafting><Liver Transplant><Liver diseases><Lymphoblast Interferon><Lymphoblastoid Interferon><Measures><Medication><Messenger RNA><Methods><Mice><Mice Mammals><Modality><Modeling><Modification><Murine><Mus><Non-Polyadenylated RNA><Nuclear><Patients><Pattern><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Plasmids><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Property><Quelling><RNA><RNA Gene Products><RNA Interference><RNA Silencing><RNA Viruses><RNAi><Relapse><Resistance development><Resistant development><Ribonucleic Acid><Safety><Savings><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Site><Small Interfering RNA><Structure><Testing><Therapeutic><Transgenic Mice><Transgenic Organisms><Viral><Viral Diseases><Viral hepatitis><Viremia><Virus><Virus Diseases><Virus Replication><anti-hepatitis D><anti-viral agents><anti-viral drugs><anti-virals><base><cell culture><chronic infection><combat><curative intervention><curative therapeutic><curative therapy><curative treatments><delta Antigen><developing resistance><developmental><drug withdrawal><drug/agent><druggable target><effective therapy><effective treatment><efficacy study><efficacy testing><heavy metal Pb><heavy metal lead><hep C><hepatic body system><hepatic damage><hepatic disease><hepatic injury><hepatic organ system><hepatitis non A non B><hepatitis virus infection><hepatopathy><improved><in vivo><inhibitor><inhibitor/antagonist><knock-down><knockdown><lipid nanoparticle><liver damage><liver disorder><liver injury><liver transplantation><mRNA><mouse model><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><new approaches><non A, non B hepatitis><non-A, non-B hepatitis><novel approaches><novel strategies><novel strategy><nuclease><persistent infection><pre-clinical study><preclinical study><programs><resistance to therapy><resistant to therapy><safety study><shRNA><short hairpin RNA><siRNA><small hairpin RNA><small molecule><success><therapeutic agent development><therapeutic development><therapeutic resistance><therapy resistant><transgenic><treatment resistance><viraemia><viral RNA><viral infection><viral multiplication><viral replication><viral sepsis><virus RNA><virus infection><virus multiplication><virus-induced disease><virusemia>