R01AI158373

Inhalation Therapy Platform for Coronavirus Infection Treatment - Project Summary/Abstract

The newly emerged SARS-CoV-2 coronavirus has demonstrated the deadly threat of pulmonary pathogens in an exposure-naïve world with no existing vaccines or therapeutics at the ready. The development of effective vaccines has provided key prophylactic products, but therapeutics remain important due to slow and incomplete world coverage, along with the emergence of resistance variants.

There is especially a need for polytherapy platforms that can be deployed in formats amenable to global settings, and a need for platforms that can be rapidly developed against future pulmonary threats. This project aims to develop a versatile inhalable therapeutic platform against COVID-19 disease and future coronaviruses. It is designed for nebulizer and distributable inhalation devices to maximize drug activity in the lung.

The polymeric prodrug platform has recently shown strong potentiating activity against highly lethal and antimicrobial-resistant bacterial lung infections. These "drugamer" therapeutics improve the activity of pulmonary drugs by targeting them to specific cell reservoirs in the lung with high and extended dosing profiles.

The inhalable platform could be used by infected patients before hospitalization, to reduce administrations by patients in crowded hospitals, and contribute a key distributable therapeutic and prophylactic modality that is needed to protect caregivers and disadvantaged populations.

The proposal is structured around 4 specific aims:

(1) Develop remdesivir and baricitinib as first drugamer candidates that exploit the lung macrophage as a reservoir to achieve extended dosing, as well as targeted designs against lung epithelium viral reservoirs. Remdesivir and baricitinib prodrug monomers will be developed with corresponding drugamer designs with mannos and peptide targeting ligands for the alveolar macrophage and epithelial compartments, respectively.

(2) Characterize and optimize the drugamer candidates by criteria of how they load drugs into the lung macrophage and epithelial cells with extended dosing times. This will lead to a better understanding of how to optimize targeting strategies in the lung for future antiviral development. The mechanisms will be studied by using quantitative LC-MS pharmacokinetics characterization and safety characterization using lung inflammatory response assessments.

(3) Assess and optimize drugamer activity against SARS-CoV-2 using the HACE2 mouse model. Viral load and survival studies will be used to characterize and develop optimized drugamer and drugamer combinations that could in the future be carried forward into preclinical development.

Compared to current formulation approaches, the drugamers exhibit higher drug loading, the ability to co-formulate widely varying drugs for polytherapy, and individually tailorable drug PK profiles that minimize burst release. The modularity of the platform, together with scaled and rapid manufacturing response attributes, will allow diverse incorporation of other drugs as combinations. These favorable platform attributes motivate this project to develop a new repertoire of current and future coronavirus therapeutic products.

University Of Washington

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]

Seattle, Washington 981951016 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 432% from $634,365 to $3,373,230.