Inhalation Therapy Platform for Coronavirus Infection Treatment

治疗冠状病毒感染的吸入治疗平台

• 批准号: 10364186
• 负责人: Patrick S. Stayton
• 金额: $ 63.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364186
• 关键词: 2019-nCoV; Alveolar Macrophages; Alveolus; Anti-Inflammatory Agents; Antibiotics; Antimicrobial Resistance; Antiviral Agents; Azithromycin; Biological Availability; Biomedical Engineering; Burkholderia pseudomallei; COVID-19; COVID-19 outbreak; COVID-19 pandemic; COVID-19 therapeutics; Caregivers; Cells; Cessation of life; Clinical; Coronavirus; Coronavirus Infections; Crowding; Development; Diffusion; Disadvantaged; Disease; Disease model; Dose; Doxycycline; Drug Combinations; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Enzymes; Epithelial; Epithelial Cells; Evolution; Exhibits; Formulation; Future; Gap Junctions; Histologic; Hospitalization; Hospitals; Human; Individual; Inflammatory Response; Inhalation; Inhalation Device; Inhalation Drug Administration; Inhalation Therapy; Intensive Care; Lead; Leadership; Life; Ligands; Lung; Lung infections; Mannose; Mediating; Melioidosis; Methods; Modality; Modeling; Nebulizer; Oral; Organ; Patients; Peptides; Pharmaceutical Preparations; Polymers; Population; Positioning Attribute; Procedures; Prodrugs; Property; Pulmonology; Ramp; Research Personnel; Resistance; Resources; Rodent Diseases; Rodent Model; SARS-CoV-2 variant; Safety; Schedule; Solubility; Source; Structure; Testing; Therapeutic; Time; Toxic effect; Tularemia; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viral reservoir; Work; alveolar epithelium; bacterial resistance; clinical development; coronavirus disease; coronavirus therapeutics; density; design; disadvantaged population; drug candidate; experience; improved; liquid chromatography mass spectrometry; macrophage; monomer; mouse model; novel vaccines; pandemic disease; pathogen; pharmacokinetics and pharmacodynamics; polymerization; preclinical development; prophylactic; pulmonary agents; remdesivir; respiratory pathogen; response; uptake; viral entry inhibitor

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 emergence of resistance variants. There is especially a need for polytherapy platforms that can be deployed in formats amenable to global settings, and 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 baracitinib 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 baracitinib prodrug monomers will be developed with corresponding drugamer designs with mannose 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 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.

项目总结/文摘