Animal model for SARS-CoV-2-spike induced coagulopathy
Inventors
Akassoglou, Katerina • Greene, Warner • Ryu, Jae Kyu • Montano, Mauricio
Assignees
Publication Number
US-12016934-B2
Publication Date
2024-06-25
Expiration Date
2041-12-16
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Abstract
Described herein is an animal model useful for identifying therapeutic agents that can inhibit the physiological effects or symptoms of COVID-19 infection, including the effects of the following on one or more organs of the animal: inflammation, oxidative stress, fibrin deposition, blood brain barrier breakdown, clotting, and vascular problems.
Core Innovation
The invention provides an animal model useful for identifying therapeutic agents that can inhibit physiological effects or symptoms of COVID-19 infection. These effects include inflammation, oxidative stress, fibrin deposition, blood brain barrier breakdown, clotting, and vascular problems in one or more organs of the animal. The animal model involves administering pseudotyped virions expressing the SARS-CoV-2 Spike protein to animals, such as rodents, to replicate conditions observed in SARS-CoV-2 infection.
The problem addressed by the invention is the urgent need for effective therapeutic approaches to manage both acute COVID-19 and Long COVID symptoms. Existing approaches like vaccines are limited by hesitancy and viral variants, and effective antithrombotic therapy is difficult due to diminished clot breakdown. Additionally, no effective therapies are currently identified for Long COVID, which can involve multiple organs and symptoms related to clotting and inflammation.
The animal model mimics both acute SARS-CoV-2 infection and Long COVID by varying the dosage and frequency of administering pseudotyped virions displaying the SARS-CoV-2 Spike protein. Acute models use higher doses (1 ng to 10,000 ng HIV p24Gag), while Long COVID models involve repeated low-dose administration (0.01-1 ng HIV p24Gag weekly). This model demonstrates physiological effects similar to human SARS-CoV-2 infection, including macrophage infiltration, oxidative stress, fibrin deposition, blood brain barrier disruption, inflammation, and clot formation in organs such as lungs, heart, and brain.
Claims Coverage
The patent contains one independent claim focusing on a method involving administration of pseudotyped virions expressing SARS-CoV-2 Spike to rodents and measuring physiological effects.
Method of administering SARS-CoV-2 Spike pseudotyped virions to rodents lacking human ACE2 receptors
Administering virions pseudotyped with SARS-CoV-2 Spike to a rodent and detecting or measuring physiological effects of the Spike protein on at least one organ of the rodent, wherein human ACE2 receptors are not present.
Repeated or continuous administration of pseudotyped virions
Administering the SARS-CoV-2 Spike pseudotyped virions repeatedly or continuously to the rodent to model acute or long COVID effects.
Co-administration of test agents to evaluate therapeutic efficacy
Administering a test agent, such as a small molecule, polypeptide, or antibody, to the rodent and measuring physiological effects after test agent administration to assess efficacy.
Targeting physiological effects including multiple organs and symptoms
Measuring physiological effects encompassing inflammation, oxidative stress, fibrin deposition, clot formation, virion binding to fibrin or fibrinogen, SARS-CoV-2 Spike protein binding to fibrin or fibrinogen, and Mac-1 protein binding to fibrin or fibrinogen in organs including lung, brain, gut, blood vessel, or heart.
Measuring test agent impact by reductions in binding and inflammation
Measuring whether test agents reduce markers of inflammation, oxidative stress, fibrin deposition, clot formation, and viral or protein binding interactions by more than 50% compared to a negative control.
The claims cover a method of using pseudotyped SARS-CoV-2 Spike virions administered to rodents without human ACE2 receptors to model COVID-19 pathology and screen therapeutic agents based on their ability to mitigate symptoms and pathological markers across multiple organs.
Stated Advantages
Provides an animal model that exhibits physiological effects similar to human SARS-CoV-2 infection despite lack of Spike binding to mouse ACE2.
Enables screening and identification of therapeutic agents to treat acute and long-term symptoms of COVID-19 including inflammation, clotting, and fibrin deposition.
Allows evaluation of antibodies, including anti-fibrin and anti-fibrinogen antibodies, that inhibit SARS-CoV-2 Spike protein binding and associated inflammation.
Facilitates modeling of both acute infection and Long COVID by adjusting virion dosage and administration frequency.
Documented Applications
Identifying therapeutic agents that inhibit physiological effects or symptoms of SARS-CoV-2 infection including inflammation, oxidative stress, fibrin deposition, blood brain barrier breakdown, clotting, and vascular problems.
Screening test agents such as small molecules, polypeptides, or antibodies for treatment efficacy against COVID-19 symptoms.
Evaluating anti-fibrin(ogen) antibodies for inhibiting Spike protein binding and reducing inflammation.
Modeling acute COVID-19 and Long COVID in rodents via administration of pseudotyped SARS-CoV-2 Spike protein virions.
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