SBIR-STTR Award

Transplant patients are quite susceptible to opportunistic viral infection resulting from immune suppression necessary for maintenance of their graft. In the case of renal transplant, 17,604 patients in 2011, a new graft means being taken off dialysis, improving quality of life and saving U.S. healthcare nearly $1 B annually. Therefore it is essential that the graft survive. A distinct threat to survival is the cumulative efect of cytomegalovirus (CMV), and polyomavirus (BKV and JCV) infections that directly target the kidney, are immune modifying, and infect concurrently. Diagnosis is difficult as patients are asymptomatic and unable to mount detectable immune responses required for serologic tests; an infection comprising immunomodulatory viruses like CMV, BKV, or JCV amplifies immune suppression medications; thereby the intuitive response to reduce immunosuppression further unbridles infection. Due to the indistinct patient presentation providers are apt to admit patients resulting in average hospital stays of 10.5 days, costing $63,000 for each admission. Existing antiviral treatments target a single virus and carry black box warnings of nephrotoxicity and cytopenia; which further challenge the immune system and kidney. Furthermore, BKV and JCV infections lack therapy, and are managed by reducing immunosuppression, putting the graft organ at risk of rejection. The present project proposes to validate a paradigm-shifting antiviral mechanism-of-action, the activation of host-encoded viral restriction factors, human sirtuins, by a single small molecule to treat multiple opportunistic viral infections. Sirtuins are NAD+-dependent deacetylases known for their role in life-span increasing effects of caloric restriction and the red wine ingredient, resveratrol. A small molecule screen of Sirtuin modulators has been completed demonstrating effectiveness in inhibiting viral growth in culture. Proposed SBIR Phase I goals are to validate proprietary chemical scaffolds identified in the screen and validate the mechanism of Sirtuin modulation as a host-targeted pan-viral. The focus will be on antiviral activity against CMV, BKV, and JCV, which show cooperativity and commonality across many immunosuppressed conditions beyond transplants, such as HIV infection, and multiple sclerosis, or other conditions by new immunosuppressive therapies. Many of these latter therapies such as rituximab, natalizumab, and efalizumab have been pulled off the market or received black box warnings for reactivation of JC virus leading to progressive multifocal leukoencephalopathy, a rare but fatal inflammation of the brain. Our novel mechanism of action may extend to additional opportunistic viruses to be tested in SBIR Phase II. Minimally, an antiviral against CMV, BKV, and JCV will address unmet medical need for the treatment of these infections, and improve management of immune suppressed patients.

Thesaurus Terms:
Address;Adenoviruses;Admission Activity;Adult;Adverse Effects;Agonist;Allogenic;Antiviral Agents;Asthma;Base;Binding (Molecular Function);Biochemical;Biological Sciences;Bk Virus;Boxing;Caloric Restriction;Central Nervous System Demyelinating Disorder;Chemicals;Cidofovir;Clinical;Commercialization;Communities;Cost;Cystitis;Cytomegalovirus;Cytopenia;Cytotoxic;Data;Deacetylase;Development;Diagnosis;Dialysis Procedure;Disease;Disease Management;Dissociation;Drug Resistance;Efalizumab;Effective Therapy;Effectiveness;Encephalitis;Enzyme Activation;Ganciclovir;Genetic;Goals;Graft Rejection;Growth;Healthcare;Hematopoietic Stem Cell Transplantation;Hepatitis B Virus;Hepatitis C Virus;Hepatitis Viruses;Herpesviridae;Herpesvirus 1, Human;High Risk;Hiv;Hiv Infections;Hospitalization;Human;Immune;Immune Response;Immune System;Immunocompromised Host;Immunoregulation;Immunosuppressed;Immunosuppressive Agents;Improved;In Vitro;In Vitro Assay;In Vitro Testing;In Vivo;Indexing;Infection;Influenza;Inhibitory Concentration 50;Intellectual Property;Jc Virus;Kidney;Kidney Diseases;Kidney Transplantation;Latent Virus;Lead;Length Of Stay;Licensing;Life;Longevity;Maintenance;Marketing;Maximum Tolerated Dose;Measures;Mediating;Medical;Meetings;Mission;Morbidity - Disease Rate;Mortality Vital Statistics;Mouse Model;Multiple Sclerosis;Natalizumab;Natural Immunosuppression;Nephrotoxic;Nephrotoxicity;Novel;Nuclear Magnetic Resonance;Opportunistic Infections;Organ;Organ Transplantation;Pathogen;Patients;Pharmaceutical Preparations;Phase;Plasma;Polyomavirus;Polyomavirus Infections;Progressive Multifocal Leukoencephalopathy;Property;Provider;Public Health Relevance;Quality Of Life;Red Wine;Respiratory Virus;Response;Resveratrol;Risk;Rituximab;Role;Scaffold;Seeds;Serologic Tests;Sirtuins;Small Business Innovation Research Grant;Small Molecule;Staging;Structure;Sum;Testing;Therapeutic;Therapeutic Immunosuppression;Therapeutic Index;Time;Transplant Recipients;Transplantation;Universities;Validation;Vigilance;Viral;Virus;Virus Diseases;Work;

Current standard-of-care antiviral regimens rely on direct-acting antivirals (DAAs) possessing inherent liabilities. DAAs are generally active against only one virus or a closely related, family of viruses. Because a viral protein is targeted, the virus can readily develop resistance mutations. To address the shortcomings of DAAs, FORGE Life Science is developing host-targeted antivirals (HTAs). HTAs have the potential to block the growth of multiple different viruses. Since a host-cell protein is targeted, viruses are much less likely to evolve drug resistance. Specifically, FORGE is developing small molecule drugs that target human sirtuin proteins. Sirtuins are a family of seven protein-deacylases that modulate many cellular processes critical for virus replication. This proposal seeks to develop a sirtuin-modulating drug that is simultaneously effective against multiple different opportunistic viruses causing life-threatening disease in immunosuppressed transplant patients. Initially, the program is focused on human cytomegalovirus (HCMV). In Phase 1, a chemical series of uncompetitive sirtuin 2 (SIRT2) inhibitors was developed that block the production of HCMV progeny in cultured human cells more potently than standard-of-care, ganciclovir. Strikingly, these SIRT2 inhibitors not only affect HCMV, but they also inhibited the growth of influenza A and B, hepatitis B and C viruses, and the polyomaviruses, BKV and JCV. The compound series demonstrates structure activity relationship to antiviral potency, excellent oral bioavailability, and good tolerability in mice. In vivo validation of anti-HCMV activity was achieved in immunosuppressed mice carrying human lung-tissue implants. This application proposes to move the program forward to SBIR Phase II to optimize a development candidate for progression into preclinical development. Three aims will be pursued. (1) A mouse model supporting development of recently approved DAA letermovir will be adapted for use with SIRT2 inhibitors. This model allows for HCMV infection of human fibroblasts seeded to a Gelfoam implant placed into immunodeficient SCID mice. (2) A medicinal chemistry campaign will refine the current lead SIRT2 inhibitor to improve anti-HCMV activity in the Gelfoam/SCID mouse with a target to achieve a therapeutic index equivalent or better than oral-dosing valganciclovir and letermovir. The selected development candidate will additionally satisfy in vitro ADME and pharmaceutical criteria, including minimizing drug-drug interactions, for administration to transplant patients. (3) Compounds demonstrating sufficient efficacy in the Gelfoam/SCID mouse model will be validated with respect to providing a high barrier to acquired viral drug-resistance and to synergize with existing direct-acting antivirals. The pan-viral profile will be expanded to multiple opportunistic viruses. This project has the potential to produce a paradigm shift, introducing broad-spectrum antivirals that solve the problem of viral resistance.

Public Health Relevance Statement:
An overwhelming number of Americans require immune suppression of variable duration at some point in their lives due to various diseases from asthma to HIV to rheumatologic diseases to organ transplant - during the time at which their immune system is being suppressed these individuals are at great risk for developing an opportunistic viral infection. Standard of care therapeutic interventions for these patients are restricted by highly focused targeting of only select pathogens, the emergence of drug resistant strains, drug:drug interactions and adverse side effects. Successful completion of this application will result in the development of broad based antiviral compounds that 1) provide protection against highly diverse viruses, 2) limit the acquisition of drug resistance and 3) limit the liabilities associated with adverse side effects observed with current antivirals.

NIH Spending Category:
Antimicrobial Resistance; Digestive Diseases; Hepatitis; Hepatitis - B; Infectious Diseases; Liver Disease; Organ Transplantation; Transplantation

Project Terms:
Absorbable Gelatin Sponge; acquired drug resistance; Address; Adenoviruses; Affect; American; Animal Model; Antibiotics; Antipsychotic Agents; Antiviral Agents; Asthma; base; Biological Availability; Biological Sciences; candidate validation; Cavia; Cell physiology; Cells; Chemicals; Chemistry; clinical development; commercialization; Communities; Cytomegalovirus; Data; Detection; Development; Disease; Dose; Drug Exposure; Drug Interactions; Drug resistance; Drug Targeting; Effectiveness; Enzymes; expectation; Exposure to; Family; Fibroblasts; Ganciclovir; Goals; good laboratory practice; Graft Rejection; Growth; Hematopoietic Stem Cell Transplantation; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Hepatitis Viruses; Herpesviridae; Herpesvirus 1; high risk; HIV; Human; Immune system; Immunity; immunosuppressed; Immunosuppression; Implant; improved; In Vitro; in vivo; Individual; Infection; Influenza A virus; Influenza B Virus; inhibitor/antagonist; Intravenous; Investigational Drugs; Latent Virus; Lead; lead optimization; Life; Macaca mulatta; Measures; minimal risk; Mission; Modeling; Morbidity - disease rate; mortality; mouse model; Mus; nephrotoxicity; next generation; novel; Opportunistic Infections; Oral; Organ; Organ Transplantation; pathogen; Patients; penis foreskin; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polyomavirus; post-transplant; pre-clinical; preclinical development; Primary Infection; Problem Solving; Production; programs; Prophylactic treatment; Proteins; Regimen; Reproducibility; Resistance; Resistance development; resistance mutation; resistant strain; respiratory virus; Risk; Route; SCID Mice; Series; side effect; Sirtuins; Small Business Innovation Research Grant; small molecule; standard of care; Structure of parenchyma of lung; Structure-Activity Relationship; synergism; Technology; Therapeutic; Therapeutic immunosuppression; Therapeutic Index; Therapeutic Intervention; Time; Toxicity Tests; Transplant Recipients; Transplantation; Triage; Universities; Valganciclovir; Validation; Vasoconstrictor Agents; Viral; Viral Drug Resistance; Viral Proteins; viral resistance; Virus; Virus Diseases; Virus Latency; Virus Replication