Development of Monothiol Human Thioredoxin-1 (ORP100S) as an Inhaled Treatment for Acute Viral Lung Injury
Abstract
Background and Rationale: Pulmonary damage associated with viral infection is a primary driver of acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). ALI/ARDS may be caused by novel viruses such as SARS-CoV-2 and related emerging coronaviruses, certain influenza strains, and other established respiratory agents such as adenovirus and herpes simplex virus. ALI/ARDS is responsible for ~190,000 U.S. cases annually and has a high annual mortality rate exceeding 40%. The emergence of the COVID-19 pandemic has increased the number of respiratory infections globally by a further 217 million, many of them severe, resulting in over 4.5 million deaths. Despite rapid development of vaccines, highly infectious new variants and limited efficacy of available treatments have only increased the urgency for development of safe and effective therapies for acute and chronic lung injury/disorders. OrPro’s research is focused on thioredoxin (TRX), a secreted lung protein that can help prevent runaway inflammation, clear excess fluid from the airway, and stimulate anti-microbial defenses. However, supplementary treatment with TRX itself is not feasible as the natural protein is rapidly cleared if injected, and if allowed to enter cells and nuclei in an active form can induce potentially harmful off-target effects. To solve this problem, OrPro has developed ORP100S, an optimized version of TRX designed for safety and maximum activity in the lung. OrPro has completed preclinical studies showing that ORP100S reaches the desired target sites and remains bound to the mucus membranes of the lung surface long enough to provide effective treatment, without migrating to other areas that could lead to adverse side effects. Initial single-dose safety studies showed no toxicity. Laboratory studies using relevant human cells have confirmed the anti-inflammatory activity of ORP100S, and when tested in rodents, aerosol ORP100S also demonstrated similar anti-inflammatory activity. Additional laboratory studies using samples of sputum and mucus from cystic fibrosis patients showed that ORP100S can restore normal sputum thickness/stiffness, allowing proper clearance of sputum from the airway. Our results, along with the scientific literature on TRX, suggest that ORP100S has excellent potential to be a safe and effective treatment for serious airway diseases, including ALI/ARDS associated with COVID-19 and other viruses. Objective: Our overall objective is to advance ORP100S to human clinical trials. Key components of our development plan include establishing minimum effective dose levels based on an understanding of the pharmacodynamic effect of ORP100S in vitro and in vivo for relevant viral diseases (COVID-19 and influenza), as well as establishing a validated bioanalytical method for the detection and quantification of ORP100S in plasma/serum and lung fluids from humans and non-clinical toxicology species (rat and non-human primate). Proposed Research: In the current proposal we plan to complete the following specific aims: 1) In vitro pharmacodynamics of ORP100S in 3-D lung organoids that authentically recapitulate disease. 2) In vivo pharmacodynamics of ORP100S in a Syrian golden hamster SARS-CoV-2 post-exposure prophylaxis infection model. 3) In vivo pharmacodynamics of inhaled ORP100S in a mouse influenza model. 4) Develop and validate a hybrid immunocapture-LC-MS/MS bioanalytical method for the quantitation of ORP100S in bronchiolar lavage fluid and serum/plasma matrices. Impact: Near term, the proposed project will enable us to conduct Investigational New Drug (IND)-enabling toxicology studies and build a pharmacology data package to support first-in-human trials via a U.S. Food and Drug Administration (FDA) IND filing. These are critical development milestones toward clinical evaluation of ORP100S. Subsequent efforts will encompass clinical studies to demonstrate safety and efficacy in order to advan
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210613
Entities
People
- Peter Heifetz
Organizations
- Orpro Therapeutics (United States)
- United States Army