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Principal Investigator: Robert Rodick
Organization: VXBIOSCIENCES, INC.
Fiscal Year: 2023
Award: $300,000
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Human cytomegalovirus (CMV) infects a majority of the world’s population and is a leading cause of disease in
transplant patients and newborns, accounting for more congenital birth defects than Down’s syndrome, spina
bifida, or fetal alcohol syndrome. There is no approved vaccine and all current antiviral therapies for CMV
prevention or treatment suffer from toxicity and a low barrier to the evolution of resistance. Consequently, there
is an urgent unmet medical need for effective CMV antivirals that have a high barrier to the evolution of drug
resistance. The mission of VxBiosciences is to develop escape-resistant or resistance-proof therapeutics. The
long-term goal of this work is to develop and clinically translate a first-in-class antiviral that effectively overcomes
CMV antiviral resistance. The specific objectives of this proposal are: (i) to establish in vivo efficacy and dosing
of a first-in-class ‘escape-resistant’ nucleic-acid lipid nanoparticle (LNP) that targets viral transcriptional circuitry
via use of an animal-specific analog (i.e., ‘surrogate’); and (ii) to develop a GMP-grade formulation of the drug
product to enable collection of IND-enabling GLP-toxicology data. The proposed antiviral builds off our studies
mapping an essential transcriptional feedback circuit in CMV (Teng et al. 2012; Vardi et al. 2018; Chaturvedi et
al. 2020), our work isolating feedback disruptors (FD) molecules that inhibit CMV (Chaturvedi et al. 2022), and
recent data showing the systemic delivery of the drug product inhibits CMV in multiple organs in mice, and halts
systemic disease to dramatically increase survival of infected immunocompromised mice. These extensive
preliminary data establish proof-of-concept that the FD drug substance displays strong CMV antiviral efficacy in
vitro and in vivo and have a very high genetic barrier to the evolution of resistance. The rationale for the LNP-
FD drug product approach rests upon FDA-approval and safety profiles of LNP nanomedicines (e.g., Onpattro)
and our successful development of LNP-based drug products for other viruses. Based on our extensive
preliminary data, our central hypothesis is that LNP-FDs will constitute a safe, effective antiviral strategy with a
high barrier to the evolution of resistance. The proposal’s rigor rests upon our published studies, our GMP-
production expertise, and our experience shepherding first-in-class antivirals through the FDA to clinical trials.
The Phase-I specific aims will evaluate efficacy and safety in vivo using a surrogate molecule (based on existing
FDA precedent for use of surrogates) and the expected outcome is reduced CMV disease and improved survival
in this physiologically-relevant model. Phase-II specific aims will establish of GMP-grade production of the
antiviral and collect IND-enabling data. The payoff of these studies will be to establish feasibility of a first-in-
class nanomedicine targeting transcriptional circuitry and demonstrate that such therapeutic strategies have high
barriers to the evolution of resistance. Based on pilot studies showing low toxicity, the drug product may
ultimately be a viable intervention for congenital CMV infections. Ultimately, approval of a therapeutic targeting
viral transcriptional circuitry could enable a new class of antivirals with high barriers to resistance.
Terms: <0-4 weeks old><Accounting><Address><Animals><Antiviral Agents><Antiviral Drugs><Antiviral Therapy><Antiviral resistance><Antiviral resistant><Antivirals><Assay><Benefits and Risks><Bioassay><Bioavailability><Biologic Assays><Biological Assay><Biological Availability><Birth Defects><Blindness><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><CMV><Cause of Death><Cessation of life><Clinical><Clinical Trials><Collection><Congenital Abnormality><Congenital Anatomic Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Cytomegalovirus><Data><Death><Development><Disease><Disorder><Dose><Dose Limiting><Down Syndrome><Down's Syndrome><Downs Syndrome><Drug Delivery><Drug Delivery Systems><Drug Formulations><Drug Kinetics><Drug Targeting><Drug resistance><Drugs><ELISA><Enzyme-Linked Immunosorbent Assay><Evolution><Failure><Feedback><Fetal Alcohol Syndrome><Formulation><Frequencies><Ganciclovir><Gancyclovir><Gene Transcription><Genetic><Genetic Diversity><Genetic Transcription><Genetic Variation><Goals><HCMV><HHV 5><HHV5><Herpesviridae><Herpesvirus 1 (beta), Murid><Herpesvirus 5 (beta), Human><Herpesviruses><Human><Human Herpesvirus 5><Immediate-Early Genes><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunodeficiency Disorder><Immunodeficiency Syndrome><Immunologic Deficiency Syndromes><Immunological Deficiency Syndromes><Immunosuppressed Host><In Vitro><Intervention><Intervention Strategies><Langdon Down syndrome><Liver><Maps><Marrow Transplantation><Medical><Medication><Mental Retardation><Mice><Mice Mammals><Mission><Modeling><Modern Man><Molecular><Mongolism><Morbidity><Morbidity - disease rate><Mouse Cytomegalovirus><Murid herpesvirus 1><Murine><Murine Cytomegalovirus><Mus><Nature><Neutropenia><Newborn Infant><Newborns><Nordeoxyguanosine><Nucleic Acids><Organ><Outcome><PK/PD><Pathogenesis><Patients><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phase><Physiologic><Physiologic Availability><Physiological><Pilot Projects><Population><Pregnant Women><Prevention><Probability><Production><Proteins><Publications><Publishing><RNA Expression><Regulator Genes><Resistance><Rest><SCID Mice><Safety><Salivary Gland Viruses><Salivary Glands><Salivary Glands Head and Neck><Schistorrhachis><Scientific Publication><Severe Combined Immunodeficient Mice><Solid><Spina Bifida><Spinal Dysraphia><Spinal Dysraphism><Spleen><Spleen Reticuloendothelial System><Survival Analyses><Survival Analysis><Systemic disease><Therapeutic><Toxic effect><Toxicities><Toxicology><Transcription><Transcriptional Regulatory Elements><Translating><Transplant Recipients><Trisomy 21><Vaccines><Viral><Viral Burden><Viral Load><Viral Load result><Virus><Work><alcoholic embryopathy><analog><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral resistance><anti-viral resistant><anti-viral therapeutic><anti-viral therapy><anti-virals><antiviral compound><antiviral efficacy><antiviral medication><antiviral therapeutic><chromosome 21 trisomy syndrome><cleft spine><congenital CMV><congenital acromicria syndrome><congenital cytomegalovirus><congenital cytomegalovirus infection><cytomegalovirus group><cytotoxic><deafness><design><designing><determine efficacy><developmental><drug efficacy><drug resistant><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><embryofetal alcohol syndrome><embryopathia alcoholica><enzyme linked immunoassay><evaluate efficacy><examine efficacy><expectant mother><expecting mother><experience><hepatic body system><hepatic organ system><herpes virus><human betaherpesvirus 5><hydrocele spinalis><hypoimmunity><immune deficiency disorder><immunodeficiency><immunosuppressed patient><improved><in vivo><interventional strategy><lipid based nanoparticle><lipid nanoparticle><morbus Down><mortality><nano medicinal><nano medicine><nanomedicinal><nanomedicine><nanoparticle drug><neonatal mice><newborn child><newborn children><organ transplant recipient><pharmacokinetics and pharmacodynamics><phase 2 study><phase 3 trial><phase II study><phase III trial><pilot study><pregnant mothers><pseudohypertrophic progressive muscular dystrophy><rachischisis posterior><regulatory gene><resistance to Drug><resistant><resistant to Drug><response><standard of care><therapeutic target><trans acting element><transplant model><transplant patient><trisomy 21 syndrome><viral infectious disease treatment><viral resistance><virology><virus resistance><vision loss><visual loss>