Methods and compositions to treat and prevent viral infections and acute respiratory distress syndrome

Inventors

Karin, Michael • Sanchez-Lopez, Elsa • Xian, Hongxu

Assignees

University of California San Diego UCSD

Abstract

Provided herein is a method for one or mor of preventing, treating, reducing the severity of acute respiratory distress syndrome (ARDS) in a subject at risk for contracting ARDS and infected with a coronavirus or SARS-CoV-2, comprising administering to the subject metformin, an analog or a derivative thereof, thereby preventing, treating, or reducing the severity of ARDS in the subject.

Core Innovation

The disclosure describes administering metformin or metformin analogs/derivatives to prevent, treat, or reduce the severity and incidence of acute respiratory distress syndrome (ARDS) in a subject at risk for contracting a coronavirus and infected with a coronavirus, including SARS-CoV-2. It frames ARDS in the context of coronavirus infection and an inflammatory pathogenesis involving NLRP3 inflammasome activation in myeloid cells.

The disclosure states that mitochondrial dysfunction reduces ATP production through targeting electron transfer chain complex I (ETC-I), thereby abrogating POLγ-dependent mtDNA synthesis. It further states that oxidized mtDNA (Ox-mtDNA) generation triggers NLRP3 inflammasome activation, leading to IL-1β processing and secretion.

Metformin is described as inhibiting NLRP3 inflammasome activation and IL-1β processing/secretion in this pathway. The disclosure also reports that short-term metformin reduces LPS- and SARS-CoV-2-induced ARDS in mice and diminishes IL-6 secretion, and that the anti-inflammasome effects of metformin are independent of AMPK and NF-κB.

Claims Coverage

The independent claim covers a method comprising administering an effective amount of metformin to prevent, treat, or reduce ARDS severity in subjects at risk for contracting and infected with a coronavirus. Across the claim set, six inventive features refine the subject context, coronavirus specificity, metformin administration, and mechanistic targets including POLγ-dependent mtDNA synthesis, Ox-mtDNA generation, and NLRP3 inflammasome activation, with optional addition of a second therapy.

Overall, the claim coverage centers on metformin administration to prevent, treat, or reduce coronavirus-infected ARDS severity, with refinements specifying mechanistic engagement of POLγ-dependent mtDNA synthesis and Ox-mtDNA and inhibition of NLRP3 inflammasome activation, and optionally narrowing to SARS-CoV-2, particular administration routes, comorbidity-defined subjects, and selection by assaying for coronavirus infection.

Stated Advantages

Documented Applications