Sialylation-increasing therapies for diseases associated with oxidative stress

Abstract

Methods are disclosed for treating a subject with a vascular or cardiac disorder associated with oxidative stress. Methods are disclosed for treating a subject with GNE myopathy that has impaired cardiac function. These methods include administering to the subject a therapeutically effective amount of a sialic acid precursor, sialic acid, or one or more sialylated compounds, mannosamine, N-acetyl mannosamine or a derivative thereof. In other embodiments, methods are disclosed for detecting a disorder associated with oxidative stress.

We claim: 
     
         1 . A method for treating a subject with a cardiovascular disorder associated with oxidative stress, comprising
 selecting a subject that has the cardiovascular disorder associated with oxidative stress and does not have a GNE myopathy; and   administering to the subject a therapeutically effective amount of a mannosamine, N-acetyl mannosamine or a derivative thereof, wherein the derivative is:   
       
         
           
           
               
               
           
         
       
       wherein: R 1 , R 3 , R 4 , or R 5  is hydrogen, lower alkanoyl, carboxylate or lower alkyl; and R 2  is lower alkyl, lower alkanoylalkyl, or lower alkyl alkanoyloxy, thereby treating the cardiovascular disorder in the subject. 
     
     
         2 . The method of  claim 1 , wherein the subject has heart failure, atherosclerotic cardiovascular disease, cardiomyopathy, a cardiac arrhythmia, myocardial infarction, ischemic heart disease, stroke, or peripheral arterial disease. 
     
     
         3 . The method of  claim 1 , wherein the mannosamine, N-acetyl mannosamine or the derivative thereof, is microencapsulated. 
     
     
         4 . The method of  claim 1 , wherein the mannosamine, N-acetyl mannosamine or the derivative thereof, is formulated in a coating, envelope or protective matrix made from a liposome. 
     
     
         5 . The method of  claim 1 , wherein the mannosamine, N-acetyl mannosamine or the derivative thereof, is orally administered to the mammal. 
     
     
         6 . The method of  claim 5 , wherein the mannosamine, N-acetyl mannosamine or the derivative thereof, is orally administered in the form of a food product. 
     
     
         7 . The method of  claim 2 , wherein the subject has the heart failure, and wherein the method further comprises administering to the subject a therapeutically effective amount of an angiotensin-converting enzyme (ACE) inhibitor, a beta blocker, an aldosterone antagonist, a diuretic, an angiotensin receptor blocker (ARB), or a vasodilator. 
     
     
         8 . The method of  claim 2 , wherein the subject has the myocardial infarction, and wherein the method further comprises administering to the subject a therapeutically effective amount of an antiplatelet agent, an anticoagulation agent, or a lipid or blood pressure regulating agent. 
     
     
         9 . The method of  claim 8 , wherein the lipid regulating agent is a statin, niacin, PCSK9-targeting drug, bile acid binding resin, or HDL-cholesterol targeting drug. 
     
     
         10 . The method of  claim 1 , wherein the subject has the atherosclerotic cardiovascular disease and wherein the method further comprises administering to the subject a therapeutically effective amount of a statin, niacin, a fibrate, a bile acid binding resin, a cholesterol absorption inhibitor, a PCSK9-targeting drug, an LDL-targeting drug or an HDL-targeting drug. 
     
     
         11 . The method of  claim 1 , further comprising administering to the subject an anti-oxidant. 
     
     
         12 . The method of  claim 11 , wherein the anti-oxidant is N-acetylcysteine. 
     
     
         13 . The method of  claim 1 , wherein the cardiovascular disorder associated with oxidative stress is also associated with hyposialylation. 
     
     
         14 . The method of  claim 1 , wherein the subject has heart damage from administration of a chemotherapeutic agent. 
     
     
         15 . The method of  claim 14 , wherein the chemotherapeutic agent is doxorubicin. 
     
     
         16 . A method for treating impaired cardiac function in a subject that does not have a GNE myopathy, comprising
 selecting a subject that has the impaired cardiac function and does not have the GNE myopathy; and   administering to the subject a therapeutically effective amount of mannosamine, N-acetyl mannosamine or a derivative thereof, wherein the derivative is:   
       
         
           
           
               
               
           
         
         wherein: R 1 , R 3 , R 4 , or R 5  is hydrogen, lower alkanoyl, carboxylate or lower alkyl; and R 2  is lower alkyl, lower alkanoylalkyl, or lower alkyl alkanoyloxy, thereby improving cardiac function in the subject. 
       
     
     
         17 . The method of  claim 16 , further comprising performing a diagnostic test to determine the cardiac function of the subject. 
     
     
         18 . The method of  claim 17 , wherein diagnostic test is a CT scan, cardiac catherization, coronary CT angiogram, echocardiography, ejection fraction testing, electrocardiogram, electrophysiology, exercise stress test, magnetic resonance imaging, tilt-table testing, transesphogeal echocardiogram, or an ultrasound. 
     
     
         19 . The method of  claim 16 , wherein the mannosamine, N-acetyl mannosamine or the derivative thereof, is microencapsulated. 
     
     
         20 . The method of  claim 16 , wherein the, mannosamine, N-acetyl mannosamine or the derivative thereof, is formulated in a coating, envelope or protective matrix made from a liposome. 
     
     
         21 . The method of  claim 16 , wherein the mannosamine, N-acetyl mannosamine or the derivative thereof, is orally administered to the mammal. 
     
     
         22 . The method of  claim 21 , wherein the mannosamine, N-acetyl mannosamine or the derivative thereof, is orally administered in the form of a food product. 
     
     
         23 . The method of  claim 16 , wherein the N-acetyl mannosamine or the derivative thereof is administered at a dose of about 0.02 g/day to about 25 g/day.