Methods of treating anemia and red blood cell dysfunction with lecithin cholesterol acyltransferase

Abstract

Disclosed are methods for treating conditions characterized by anemia or red blood cells dysfunction by administering an agent that increases the level of endogenous LCAT or LCAT activity. Additionally disclosed are methods of treating conditions wherein red blood cells have reduced function in relation to deformability, oxygenation, increased adhesion and aggregability, reduced nitric oxide function, or decreased life-span, increased free cholesterol, or abnormal phospholipid content. Also disclosed are methods for treating conditions characterized by an abnormal concentration of free cholesterol in red blood cells and methods of normalizing the free cholesterol content of red blood cells.

What is claimed is: 
     
         1 . A method of treating a patient having a condition characterized by anemia or red blood cell dysfunction comprising administering to the patient a therapeutically effective amount of an agent which increases the activity of LCAT or increases the plasma level of LCAT or both. 
     
     
         2 . The method according to  claim 1  wherein he agent is LCAT. 
     
     
         3 . The method according to  claim 1  wherein the agent is a drug that increases the activity or level of endogenous LCAT. 
     
     
         4 . The method according to  claim 1  wherein the agent is a gene therapy vector. 
     
     
         5 . The method of  claim 2  wherein the amount of LCAT is an amount that increases LCAT concentration to above normal LCAT levels or LCAT activity to above normal LCAT activity. 
     
     
         6 . The method according to  claim 5  wherein the condition is characterized by red blood cells with reduced ability to deform, reduced oxygenation, increased aggregation and adhesion, reduced nitric oxide function, decreased life-span, or any combination thereof. 
     
     
         7 . The method according to  claim 5  wherein the condition is anemia. 
     
     
         8 . The method of  claim 5  wherein the condition is sickle cell disease, diabetes, thalassemia, rheumatoid disease, autoimmune disease, arthritis, liver disease, cirrhosis, hepatitis, acanthosytosis, sepsis, dementia, anemia, or microvascular disorders, inflammatory disorders, parasitic disease, erectile dysfunction, cancer, pre-eclampsia, critical illness or trauma. 
     
     
         9 . The method of  claim 8  wherein the inflammatory disorder is sepsis, rheumatoid disease, anemia of inflammation, or post-surgical inflammation. 
     
     
         10 . The method of  claim 8  wherein the microvascular disorder is dementia, or retinopathy. 
     
     
         11 . The method of  claim 8  wherein the condition is parasitic disease and the parasitic disease is malaria, sleeping sickness, filariasis, or leishmaniasis. 
     
     
         12 . The method of  claim 8  wherein the condition is an Alzheimer's related dementia. 
     
     
         13 . The method of  claim 8  wherein the condition is sickle cell disease. 
     
     
         14 . The method of  claim 8  wherein the condition is thalassemic disease. 
     
     
         15 . The method of  claim 8  wherein the LCAT is a modified LCAT. 
     
     
         16 . The method of  claim 5  wherein the modified LCAT comprises an amino acid substitution at position 31. 
     
     
         17 . A method of improving a condition characterized by one or more of the following: anemia, red blood cells with reduced ability to deform, reduced RBC oxygenation, increased RBC aggregation and adhesion, reduced nitric oxide function, decreased RBC life-span comprising:
 obtaining a base-line measurement of one or more than one of the following: hemoglobin level, hematocrit level, RBC deformability, RBC oxygenation, RBC aggregation and adhesion, or RBC life-span;
 a) administering to a patient in need thereof a therapeutically effective amount of an agent which increases the activity of LCAT or increases the plasma level of LCAT or both; 
 b) obtaining a post-treatment measurement of one or more of the following: hemoglobin level, hematocrit level, RBC deformability, RBC oxygenation, RBC aggregation and adhesion, or RBC life-span; 
 c) comparing the baseline measurement with the post-treatment measurement wherein the occurrence of one or more of the following: an increase in hemoglobin level, hematocrit level, an increase in RBC deformability, an increase in RBC oxygenation, a decrease in RBC aggregation and adhesion or an increase in RBC life-span, indicates an improvement in the condition. 
   
     
     
         18 . The method according to  claim 17  wherein the agent is a drug that increases the activity or level of endogenous LCAT. 
     
     
         19 . The method according to  claim 17  wherein the agent is a gene therapy vector. 
     
     
         20 . The method according to  claim 17  wherein the therapeutically effective amount of an agent is therapeutically effective amount of LCAT. 
     
     
         21 . The method of  claim 20  wherein the RBC deformability is increased following the administration of LCAT. 
     
     
         22 . The method of  claim 20  wherein RBC oxygenation is increased following the administration of LCAT. 
     
     
         23 . The method in  claim 20  wherein the hematocrit level is increased following the administration of LCAT. 
     
     
         24 . The method in  claim 20  wherein the hemoglobin level is increased following the administration of LCAT. 
     
     
         25 . The method in  claim 20  wherein nitric oxide function is increased following the administration of LCAT. 
     
     
         26 . The method of  claim 20  wherein RBC life-span is increased following the administration of LCAT. 
     
     
         27 . The method of  claim 20  wherein RBC aggregation and adhesion is decreased following the administration of LCAT. 
     
     
         28 . The method according to any one of  claims 1 ,  2 ,  5 - 16  and  20 - 27  wherein the therapeutically effective amount of LCAT is an amount that raises the LCAT concentration or LCAT activity to above normal LCAT levels. 
     
     
         29 . The method according to any one of  claims 1 ,  2 ,  5 - 16  and  20 - 28  wherein the administration of LCAT is by intravenous injection, subcutaneous injection or intra-muscular injection. 
     
     
         30 . The method according to any one of  claims 1 ,  2 ,  5 - 16  and  20 - 29  and wherein the amount of LCAT administered is from about 10 mg to about 5000 mg. 
     
     
         31 . The method according to any one of  claims 1 ,  2 ,  5 - 16  and  20 - 29  wherein the amount of LCAT administered is between 1-times and 1000-times the normal level of LCAT. 
     
     
         32 . A method of treating a patient having a condition characterized by a high PC/SM ratio in RBC membranes comprising administering to the patient 
     
     
         33 . The method according to  claim 32  wherein the condition is sickle cell disease, diabetes, thalassemia, rheumatoid disease, autoimmune disease, arthritis, liver disease, cirrhosis, hepatitis, acanthosytosis, sepsis, dementia, anemia, or microvascular disorders, inflammatory disorders, parasitic disease, erectile dysfunction, cancer, pre-eclampsia, critical illness or trauma. 
     
     
         34 . The method according to  claim 33  further comprising determining a baseline ratio of PC to SM and determining the ratio of PC to SM following administration of LCAT wherein a decrease in the ratio of PC to SM indicates an improvement in the condition. 
     
     
         35 . A method of treating a patient having a condition characterized by a high Fe content comprising administering to the patient in need thereof, a therapeutically effective amount of LCAT. 
     
     
         36 . The method according to  claim 35  wherein the condition is sickle cell disease, diabetes, thalassemia, rheumatoid disease, autoimmune disease, arthritis, liver disease, cirrhosis, hepatitis, acanthosytosis, sepsis, dementia, anemia, or microvascular disorders, inflammatory disorders, parasitic disease, erectile dysfunction, cancer, pre-eclampsia, critical illness or trauma. 
     
     
         37 . The method of  claim 36  wherein the blood cell is a red blood cell, monocyte, platelet, neutrophil or leukocyte. 
     
     
         38 . The method of  claim 37  wherein the blood cell is a red blood cell. 
     
     
         39 . A method of improving a condition characterized a high level of FC in RBC membranes comprising:
 obtaining a base-line measurement of the ratio of FC to PL;
 a) administering to a patient in need thereof a therapeutically effective amount of LCAT; 
 b) obtaining a post-treatment measurement of the ratio of FC to PL; 
 c) comparing the baseline measurement with the post-treatment measurement wherein a decrease in the ratio of FC to PL indicates an improvement in the condition. 
   
     
     
         40 . The method according to any of  claims 32 - 39  wherein the LCAT is administered by intravenous injection, subcutaneous injection or intra-muscular injection. 
     
     
         41 . The method according to any one of  claims 32 - 40  wherein the amount of LCAT administered is from about 10 mg to about 5000 mg. 
     
     
         42 . The method according to any one of  claims 32 - 40  wherein the amount of LCAT administered is between 1-times and 1000-times the normal level of LCAT. 
     
     
         43 . The method according to any one of  claims 32 - 42  wherein the LCAT is a modified LCAT. 
     
     
         44 . The method according to  claim 43  wherein the modified LCAT comprises an amino acid substitution at position 31. 
     
     
         45 . A method of treating a patient having a condition characterized by anemia or red blood cell dysfunction comprising administering to a subject in need thereof, a therapeutically effective amount of LCAT wherein the plasma HDL-C level in the subject is rapidly increased after administration of the LCAT. 
     
     
         46 . The method of  claim 45  wherein the condition is sickle cell disease, diabetes, thalassemia, rheumatoid disease, autoimmune disease, arthritis, liver disease, cirrhosis, hepatitis, acanthosytosis, sepsis, dementia, anemia, or microvascular disorders, inflammatory disorders, parasitic disease, erectile dysfunction, cancer, pre-eclampsia, critical illness or trauma. 
     
     
         47 . The method of  claim 46  wherein the inflammatory disorder is sepsis, rheumatoid disease, anemia of inflammation, or post-surgical inflammation. 
     
     
         48 . The method of  claim 46  wherein the microvascular disorder is dementia, or retinopathy. 
     
     
         49 . The method of  claim 46  wherein the condition is parasitic disease and the parasitic disease is malaria, sleeping sickness, filariasis, or leishmaniasis. 
     
     
         50 . The method of  claim 46  wherein the condition is an Alzheimer's related dementia. 
     
     
         51 . The method of  claim 46  wherein the condition is sickle cell disease. 
     
     
         52 . The method of  claim 46  wherein the condition is thallasemic disease. 
     
     
         53 . The method according to any one of  claims 44 - 52  wherein the plasma HDL-C level in the subject 4 hours post administration of the LCAT is increased by at least 50% of the plasma HDL-C level prior to LCAT administration. 
     
     
         54 . The method according to  claim 44 - 52  wherein the plasma HDL-C level in the subject 24 hours post administration of the LCAT is increased by at least 100% of the plasma HDL-C level prior to LCAT administration.