Treatment for Diseases Caused by RNA Viruses

Abstract

Up-regulation of caspase has been found in COVID-19 patients, and also occurs in patients suffering from diabetes, hypertension, metabolic syndrome, and other conditions. Such up-regulation can be responsible for poor clinical outcomes in patients having such diseases or disorders, as such up-regulation leads to a process called pyroptosis: death and malfunction of immune system cells, particularly of certain types of lymphocytes. An inhibitor of caspase such as a caspase 1 inhibitor, or “pan-caspase” inhibitor (i.e., an inhibitor of multiple caspase types including caspase-1), can be used to treat COVID-19 patients or individuals at risk of infection, by limiting the malfunction of the immune system. A caspase-1 or pan-caspase inhibitor is advantageously administered before or very early in the course of infection by a positive-sense, single-stranded RNA virus such as SARS-CoV, MERS-CoV, or SARS-Cov-2.

We claim: 
     
         1 . A method of treating a human subject to prevent or reduce T-cell lymphopenia or pyroptosis of T cells, comprising:
 administering to the human subject an effective amount of a caspase inhibitor of at least caspase 1, wherein the human subject
 (a) is at risk of contracting an illness caused by a positive-sense, single-stranded RNA virus and has one or more co-morbidities associated with a negative outcome from such illness, if contracted by the subject, or 
 (b) is infected with a positive-sense, single-stranded RNA virus, 
   thereby reducing T-cell lymphopenia or pyroptosis of T cells.   
     
     
         2 . The method of  claim 1  wherein the subject has a condition selected from the group consisting of: hypertension, psoriasis, heart disease, gout, arthritis, inflammatory bowel disease, gouty arthritis, type I and II diabetes, vitiligo, autoimmune Addison’s disease, a cryopyrinopathy, and metabolic syndrome. 
     
     
         3 . The method of  claim 1  wherein the positive-sense, single-stranded RNA virus is selected from the group consisting of SARS-CoV, MERS-CoV, and SARS-CoV-2. 
     
     
         4 . The method of  claim 1  wherein the human subject is infected with SARS-CoV-2. 
     
     
         5 . The method of  claim 1  wherein the human subject has a condition in which caspase 1 activity is increased in its immune cells. 
     
     
         6 . The method of  claim 1  wherein the human subject has a condition in which caspase 1 expression is increased in its immune cells. 
     
     
         7 . The method of  claim 1  wherein the caspase inhibitor is selected from the group consisting of Emricasan, CTS-2090, Belnacasan (VX-765), Pralnacasan (VX-740), and O-desethyl-belnacasan (VRT-043198). 
     
     
         8 . The method of  claim 1  wherein the inhibitor is a peptide. 
     
     
         9 . The method of  claim 1  wherein the caspase inhibitor inhibits one or more of caspases 3, 4, 5, 7, 8, 9 and 11. 
     
     
         10 . The method of  claim 1  wherein the inhibitor is a pan-caspase inhibitor. 
     
     
         11 . The method of  claim 1  wherein the inhibitor is Emricasan. 
     
     
         12 . A method of treating a human subject at risk of SARS-CoV-2 infection or a human subject infected with SARS-Cov2 to reduce morbidity and mortality risk associated with SARS-Cov-2, comprising:
 administering to the human subject an effective amount of a caspase inhibitor of at least caspase 1.   
     
     
         13 . The method of  claim 12  wherein the caspase inhibitor inhibits one or more of caspases 3, 4, 5, 7, 8, 9 and 11. 
     
     
         14 . The method of  claim 12  wherein the human subject has a condition selected from the group consisting of: hypertension, psoriasis, heart disease, gout, arthritis, inflammatory bowel disease, gouty arthritis, type I and II diabetes, vitiligo, autoimmune Addison’s disease, a cryopyrinopathy, and metabolic syndrome. 
     
     
         15 . The method of  claim 12  wherein the subject has a condition in which caspase 1 activity, is increased in its immune cells. 
     
     
         16 . The method of  claim 12  wherein the subject has a condition in which caspase 1 expression in increased in its immune cells. 
     
     
         17 . The method of  claim 12  wherein the caspase inhibitor is selected from the group consisting of Emricasan, CTS-2090, Belnacasan (VX-765), Pralnacasan (VX-740), and O-desethyl-belnacasan (VRT-043198). 
     
     
         18 . The method of  claim 12  wherein the caspase inhibitor is a peptide. 
     
     
         19 . The method of  claim 12  wherein the caspase inhibitor is a pan-caspase inhibitor. 
     
     
         20 . The method of  claim 12  wherein the caspase inhibitor is Emricasan. 
     
     
         21 . A method of treating a human subject infected or suspected of being infected with SARS-Cov2, comprising:
 administering an effective amount of a caspase inhibitor useful in treating COVID-19, wherein such administration optionally is provided before onset of COVID-19 symptoms or while the subject has mild or moderate severity of COVID-19.   
     
     
         22 . The method of  claim 21  wherein the caspase inhibitor inhibits caspase 1 and caspase 3. 
     
     
         23 . A method of treating a human subject infected with SARS-Cov2, comprising the step of: 
 administering an effective amount of (a) a compound which inhibits a caspase, (b) a compound that binds to an ACE-2 receptor, and (c) a compound which binds to SARS-CoV-2 main protease, wherein the step of administering occurs before onset of COVID-19 symptoms or, during progression beyond mild or moderate COVID-19 symptoms.   
     
     
         24 . The method of  claim 12 ,  21 , or  23  further comprising administering a compound selected from the group consisting of dexamethasone, an antibody or antibody cocktail that specifically binds SARS-CoV-2, an antibody to IL-6, and remdesivir. 
     
     
         25 . A method of testing to predict severity of SARS-Cov-2 disease, comprising:
 testing a blood sample of a subject to ascertain an amount of caspase 1 and comparing the amount of caspase 1 detected to the amount of caspase 1 in one or more control samples of healthy individuals; and   determining that the subject is at higher risk of experiencing a severe form of the disease when the amount of caspase 1 in the subject’s blood sample is statistically significantly higher than amounts of caspase 1 detected in the one or more control samples.   
     
     
         26 . A method of testing to predict severity of SARS-Cov-2 disease in a plurality of human subjects, comprising:
 testing a plurality of blood samples of a plurality of subjects infected with SARS-Cov-2 to ascertain an amount of caspase 1 in each blood sample and comparing the amount of caspase 1 from at least one subject blood sample to amounts of caspase 1 detected in one or more control samples of healthy individuals; and   determining that a subject is at higher risk of experiencing a severe form of the disease when the amount of caspase 1 in the subject’s sample is statistically significantly higher than the amounts of caspase 1 detected in one or more control samples, and determining that a subject is at lower risk of experiencing a severe form of the disease when the amount of caspase 1 in the subject’s sample is not statistically significantly higher than the amount of caspase 1 detected in one or more control samples.   
     
     
         27 . The method of  claim 25  or  26  wherein the testing employs an antibody test. 
     
     
         28 . The method of  claim 25  or  26  wherein the testing employs flow cytometry. 
     
     
         29 . The method of  claim 25  or  26  wherein the testing employs one or more fluorescent-labeled inhibitors of caspase 1. 
     
     
         30 . The method of  claim 25  or  26  wherein the testing employs one or more fluorescent-labeled substrates of caspase 1. 
     
     
         31 . The method of  claim 25  or  26  further comprising the step of treating with an inhibitor of caspase 1 a patient determined to be at higher risk of severe disease. 
     
     
         32 . The method of  claim 25  or  26  wherein the subject additionally has a condition selected from the group consisting of: hypertension, psoriasis, heart disease, gout, arthritis, inflammatory bowel disease, gouty arthritis, type I and II diabetes, vitiligo, autoimmune Addison’s disease, a cryopyrinopathy, and metabolic syndrome. 
     
     
         33 . The method of  claim 31  wherein the inhibitor is selected from the group consisting of Emricasan, Belnacasan (VX-765), Pralnacasan (VX-740), and O-desethyl-belnacasan (VRT-043198). 
     
     
         34 . The method of  claim 31  wherein the inhibitor is a peptide. 
     
     
         35 . The method of  claim 31  wherein the inhibitor is a pan-caspase inhibitor. 
     
     
         36 . The method of  claim 31  wherein the inhibitor is Emricasan. 
     
     
         37 . A method of treating a human subject having or at risk of having aberrant red blood cell aggregation or thrombosis, comprising:
 administering to the human subject an effective amount of an inhibitor of caspase-3, wherein the human subject is (a) at risk for contracting an illness caused by a positive-sense, single-stranded RNA virus or (b) is infected with a positive-sense, single-stranded RNA virus, thereby preventing or reducing aberrant red blood cell aggregation or thrombosis.   
     
     
         38 . The method of  claim 37  wherein the positive-sense, single-stranded RNA virus is a beta coronavirus. 
     
     
         39 . The method of  claim 37  wherein the positive-sense, single-stranded RNAvirus is selected from the group consisting of SARS-CoV, MERS-CoV, and SARS-CoV-2. 
     
     
         40 . The method of  claim 37  wherein the human subject is asymptomatic for the positive-sense, single-stranded RNA virus. 
     
     
         41 . The method of  claim 37  wherein the human subject has a condition selected from the group consisting of: hypertension, psoriasis, heart disease, gout, arthritis, inflammatory bowel disease, gouty arthritis, type I and II diabetes, vitiligo, autoimmune Addison’s disease, a cryopyrinopathy, and metabolic syndrome. 
     
     
         42 . The method of  claim 37  wherein the subject has a condition in which caspase-3 activity, is increased in one or more cell types in the subject. 
     
     
         43 . The method of  claim 37  wherein the subject has a condition in which caspase-3 expression is increased in one or more cell types in the subject. 
     
     
         44 . The method of  claim 37  wherein the caspase inhibitor is a pan-caspase inhibitor. 
     
     
         45 . The method of  claim 37  wherein the caspase inhibitor is Emricasan. 
     
     
         46 . A method of treating a human subject at risk of SARS-CoV-2 infection or a subject infected with SARS-Cov2 to reduce morbidity and mortality risk associated with SARS-Cov-2, comprising:
 administering to the human subject an effective amount of an inhibitor of caspase-3, thereby reducing the risk of adverse outcomes associated with SARS-Cov-2.   
     
     
         47 . The method of  claim 46  wherein administering the effective amount of the inhibitor reduces pyroptosis of red blood cells. 
     
     
         48 . The method of  claim 46  wherein the subject has a condition selected from the group consisting of: hypertension, psoriasis, heart disease, gout, arthritis, inflammatory bowel disease, gouty arthritis, type I and II diabetes, vitiligo, autoimmune Addison’s disease, a cryopyrinopathy, and metabolic syndrome. 
     
     
         49 . The method of  claim 46 , wherein the caspase-3 inhibitor is a pan-caspase inhibitor. 
     
     
         50 . The method of  claim 46  wherein the caspase-3 inhibitor is Emricasan. 
     
     
         51 . A method of treating a human subject having, or at risk of developing late sequelae of Covid-19 infection, comprising:
 administering to the human subject an effective amount of a caspase inhibitor of at least caspase 1.   
     
     
         52 . The method of  claim 51  wherein the caspase inhibitor inhibits one or more of caspase 3, 4, 5, 7, 8, 9 and 11. 
     
     
         53 . A method as in  claim 51  wherein the caspase inhibitor is Emricasan.