R01AI163042

New Generation of Long Acting Nucleos(t)ides and Immune Stimulant for Treatment of Chronic Hepatitis B

There is a global aim to reduce the burden of chronic hepatitis B (CHB) infection and prevent the development of HBV-associated end-stage liver disease and cancer. The improvement of existing therapeutics is expected to help achieve this goal. Specifically, the usage of once two-month injectable nucleos(t)ide analogs in combination with immunomodulating antiviral compounds instead of life-long daily pills has the strong potential to help achieve a functional cure for CHB.

To this end, we propose to transform water-soluble antiviral drugs, first-line drugs tenofovir (TFV) and entecavir (ETV), and immunomodulating drug tizoxanide (TIZ) into hydrophobic lipophilic crystalline prodrugs. We will formulate them as nanosuspensions suitable for intramuscular injection. The efficient optimization of physicochemical properties of nanocrystals is expected to improve their pharmacokinetics (PK) and pharmacodynamics (PD) profiles. This optimization will enhance uptake of the prodrug nanocrystals by liver macrophages and hepatocytes to ensure a slow release and sustained therapeutic drug concentrations at the site of hepatitis B viral replication.

The treatment with long-acting TFV, ETV, and TIZ is expected to decrease dosing frequency, limit toxicity, and facilitate sustained viral suppression and treatment. A functional cure for HBV is expected to be achieved via multifactorial mechanisms, including inhibition of viral polymerase, prevention of CCCDNA formation, and the clearance of HBV micro-chromosomes via stimulation of host innate immunity by TIZ.

Thus, the overall objective of this proposal is to develop clinically translatable, long-acting, injectable, antiviral drug nanoformulations to increase adherence and enhance drug delivery to sites of persistent HBV infection, thereby facilitating sustained viral suppression and finite cure. To this end, three specific aims are proposed:

Aim 1: Develop long-acting anti-HBV prodrug nanoformulations and evaluate the drug efficacy. Here, we will apply pronucleotide (proTide) and a modified HepDirect prodrug technology to transform existing drugs into hydrophobic prodrugs suitable for formulation as nanosuspensions to achieve prolonged therapeutic active drug concentrations in hepatocytes. This is expected to improve drug biodistribution to infected hepatocytes without compromising drug potency and safety profile. The prodrug formulations will be screened in vitro in human macrophages as a potential drug depot and in infected hepatocytes as final targets. The anti-HBV activity of prodrug nanocrystals will be examined in vitro and in vivo using HBV-infected humanized mice.

Aim 2: To develop long-acting TIZ nanoformulation and evaluate the mechanisms by which TIZ suppresses HBV replication in infected hepatocytes.

Aim 3: To evaluate the synergistic efficacy of the selected long-acting TIZ and NUC formulations and evaluate the ability of this combination to eliminate HBV CCCDNA from hepatocytes and significantly reduce the concentration of HBsAg.

Board Of Regents Of The University Of Nebraska

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Omaha, Nebraska 681987835 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 400% from $610,511 to $3,055,207.