Compositions and methods for the treatment of hemoglobinopathies and thalassemias

Abstract

This disclosure provides compositions and methods for improving erythrocyte dysfunction or treating a hemoglobinopathy or a thalassemia (e.g., sickle cell disease or β-thalassemia).

What is claimed is: 
     
         1 . A method of improving one, two, three, four, five, six or more (e.g., all) of erythrocyte function, turnover, or synthesis; hemoglobin function, turnover, or synthesis; or vascular function, comprising administering to a subject in need thereof an effective amount of a composition comprising:
 a) a leucine amino acid entity,   b) a arginine amino acid entity,   c) glutamine amino acid entity; and   d) a N-acetylcysteine (NAC)-entity,   wherein the composition does not comprise a peptide of more than 20 amino acid residues in length (e.g., whey protein), or if a peptide of more than 20 amino acid residues in length is present, the peptide is present at less than: 10 wt. % of the total wt. of the composition (e.g., in dry form);   thereby improving one two, three, four, five, six or more (e.g., all) of erythrocyte function, turnover, or synthesis; hemoglobin function, turnover, or synthesis; or vascular function in the subject.   
     
     
         2 . A method of treating a hemoglobinopathy or a thalassemia, comprising administering to a subject in need thereof an effective amount of a composition comprising:
 a) a leucine amino acid entity,   b) a arginine amino acid entity,   c) glutamine amino acid entity; and   d) a N-acetylcysteine (NAC)-entity   wherein the composition does not comprise a peptide of more than 20 amino acid residues in length (e.g., whey protein), or if a peptide of more than 20 amino acid residues in length is present, the peptide is present at less than: 10 wt. % of the total wt. of the composition (e.g., in dry form);   thereby treating the hemoglobinopathy or the thalassemia in the subject.   
     
     
         3 . A composition for use in a method of improving one, two, three, four, five, six or more (e.g., all) of erythrocyte function, turnover, or synthesis; hemoglobin function, turnover, or synthesis; or vascular function in a subject in need thereof, wherein the composition comprises an effective amount of:
 a) a leucine amino acid entity,   b) a arginine amino acid entity,   c) glutamine amino acid entity; and   d) a N-acetylcysteine (NAC)-entity,   wherein the composition does not comprise a peptide of more than 20 amino acid residues in length (e.g., whey protein), or if a peptide of more than 20 amino acid residues in length is present, the peptide is present at less than: 10 wt. % of the total wt. of the total components of the composition (e.g., in dry form).   
     
     
         4 . A composition for use in a method of treating a hemoglobinopathy or a thalassemia in a subject in need thereof, wherein the composition comprises an effective amount of:
 a) a leucine amino acid entity,   b) a arginine amino acid entity,   c) glutamine amino acid entity; and   d) a N-acetylcysteine (NAC)-entity   wherein the composition does not comprise a peptide of more than 20 amino acid residues in length (e.g., whey protein), or if a peptide of more than 20 amino acid residues in length is present, the peptide is present at less than: 10 wt. % of the total wt. of the total components of the composition (e.g., in dry form).   
     
     
         5 . The method of  claim 1  or  2  or the composition for use of  claim 3  or  4 , wherein the composition further comprises: (e) one or both of a serine amino acid entity or a carnitine entity; and/or
 one, two, three, or more (e.g., all) of (f) a valine amino acid entity, (g) a histidine amino acid entity, (h) a lysine amino acid entity, or (i) a citrulline amino acid entity. 
 
     
     
         6 . A composition comprising:
 a) a leucine amino acid entity,   b) an arginine amino acid entity,   c) a glutamine amino acid entity,   d) a N-acetylcysteine (NAC) entity,   e) a citrulline amino acid entity,   f) a carnitine entity,   g) a serine amino acid entity,   h) a valine amino acid entity,   i) a histidine amino acid entity, and   j) a lysine amino acid entity.   
     
     
         7 . The method of  claim 1  or  2 , the composition for use of  claim 3  or  4 , or the composition of  claim 6 , wherein the composition does not comprise a peptide of more than 20 amino acid residues in length (e.g., whey protein), or if a peptide of more than 20 amino acid residues in length is present, the peptide is present at less than: 10 wt. %, 9 wt. %, 8 wt. %, 7 wt. %, 6 wt. %, 5 wt. %, 4 wt. %, 3 wt. %, 2 wt. %, 1 wt. %, 0.5 wt. %, 0.1 wt. %, 0.05 wt. %, 0.01 wt. %, 0.001 wt. %, or less of the total wt. of the total components of the composition (e.g., in dry form). 
     
     
         8 . The method of  claim 1  or  2 , the composition for use of  claim 3  or  4 , or the composition of  claim 6  or  7 , wherein two, three, four, five, six, seven, eight, nine, ten, or more (e.g., all) of (a)-(j) or (a)-(i) are in free amino acid form in the composition, e.g., at least: 42 wt. %, 45 wt. %, 50 wt. %, 55 wt. %, 60 wt. %, 65 wt. %, 70 wt. %, 75 wt. %, 80 wt. %, 85 wt. %, 90 wt. %, 95 wt. %, 97 wt. %, 98 wt. %, or more, of the total wt. of the composition (e.g., in dry form) is one, two, three, four, five, six, seven, eight, nine, or more (e.g., all) of (a)-(j) in free amino acid form in the composition. 
     
     
         9 . The method of  claim 1  or  2 , the composition for use of  claim 3  or  4 , or the composition of any of  claims 6 - 8 , wherein the total wt. % of (a)-(j) or (a)-(i) is greater than the total wt. % of one, two, or three of other amino acid entity components, non-amino acid entity protein components, or non-protein components in the composition (e.g., in dry form), e.g., (a)-(j) or (a)-(i) is at least: 50 wt. %, 55 wt. %, 60 wt. %, 65 wt. %, 70 wt. %, 75 wt. %, 80 wt. %, 85 wt. %, 90 wt. %, 95 wt. %, 97 wt. %, 98 wt. %, or more, of the total wt. of one, two, or three of other amino acid entity components, non-amino acid entity protein components, or total components in the composition (e.g., in dry form). 
     
     
         10 . The method of  claim 1  or  2 , the composition for use of  claim 3  or  4 , or the composition of any of  claims 6 - 9 , wherein the composition comprises a combination of 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, or 11 or fewer amino acid entities. 
     
     
         11 . The method of  claim 1  or  2 , the composition for use of  claim 3  or  4 , or the composition of any of  claims 6 - 10 , wherein the composition (e.g., the Active Moiety) comprises:
 a) the leucine amino acid entity is chosen from:
 i) L-leucine or a salt thereof, 
 ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-leucine, or 
 iii) β-hydroxy-β-methylbutyrate (HMB) or a salt thereof; 
 
 b) the arginine amino acid entity is chosen from:
 i) L-arginine or a salt thereof, 
 ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-arginine, 
 iii) creatine or a salt thereof, or 
 v) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising creatine; 
 
 c) the glutamine amino acid entity is L-glutamine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-glutamine; 
 d) the NAC entity is NAC or a salt thereof or a dipeptide or salt thereof comprising NAC; 
 e) the citrulline amino acid entity is L-citrulline or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-citrulline; 
 f) the carnitine entity is L-carnitine or a salt thereof, or a dipeptide or salt thereof, comprising L-carnitine; 
 g) the serine amino acid entity is L-serine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-serine; 
 h) the valine amino acid entity is L-valine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-valine; 
 i) the histidine amino acid entity is L-histidine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-histidine; and 
 j) the lysine amino acid entity is L-lysine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-lysine. 
 
     
     
         12 . The method of  claim 1  or  2 , the composition for use of  claim 3  or  4 , or the composition of any of  claims 6 - 11 , wherein the composition (e.g., the Active Moiety) comprises:
 a) L-leucine or a salt thereof, 
 b) L-arginine or a salt thereof, 
 c) L-glutamine or a salt thereof, 
 d) NAC or a salt thereof, 
 e) L-citrulline or a salt thereof, 
 f) L-carnitine or a salt thereof, 
 g) L-serine or a salt thereof, 
 h) L-valine or a salt thereof, 
 i) L-histidine or a salt thereof, and 
 j) L-lysine or a salt thereof. 
 
     
     
         13 . A method of improving one, two, three, four, five, six, seven, eight, or more (e.g., all) of erythrocyte function, turnover, or synthesis; hemoglobin function, turnover, or synthesis; vascular function; oxidative stress (e.g., one or both of blood or systemic oxidative stress); or inflammation, comprising administering to a subject in need thereof an effective amount of a composition (e.g., an Active Moiety) of any of  claims 6 - 12 , thereby improving one, two, three, four, five, six, seven, eight, or more (e.g., all) of erythrocyte function, turnover, or synthesis; hemoglobin function, turnover, or synthesis; vascular function, oxidative stress (e.g., one or both of blood or systemic oxidative stress); or inflammation in the subject. 
     
     
         14 . A method of treating a hemoglobinopathy or a thalassemia, comprising administering to a subject in need thereof an effective amount of a composition (e.g., an Active Moiety) of any of  claims 6 - 12 , thereby treating the hemoglobinopathy or the thalassemia in the subject. 
     
     
         15 . A composition for use in a method of improving one, two, three, four, five, six, seven, eight, or more (e.g., all) of erythrocyte function, turnover, or synthesis; hemoglobin function, turnover, or synthesis; vascular function; oxidative stress (e.g., one or both of blood or systemic oxidative stress); or inflammation, comprising an effective amount of a composition (e.g., an Active Moiety) of any of  claims 6 - 12 . 
     
     
         16 . A composition for use in a method of treating a hemoglobinopathy or a thalassemia, comprising an effective amount of a composition (e.g., an Active Moiety) of any of  claims 6 - 12 . 
     
     
         17 . The method of  claim 1 ,  2 ,  5 , or  7 - 14  or the composition for use of  claim 3 ,  4 ,  5 ,  7 - 12 ,  15 , or  16  wherein the subject is at risk of, or has been diagnosed with a hemoglobinopathy (e.g., a β-hemoglobinopathy) or a thalassemia optionally wherein the hemoglobinopathy or thalassemia is chosen from: a sickle cell disease (e.g., sickle cell anemia (HbSS), Hemoglobin SC disease (HbSC), sickle β + -thalassemia (HbS/β+), sickle β 0 -thalassemia)(HbS/β 0 ), hemoglobin SE disease, hemoglobin SD disease, or hemoglobin SO disease), α-thalassemia, or β-thalassemia. 
     
     
         18 . The method or composition of any of the foregoing claims, wherein the composition is formulated with a pharmaceutically acceptable carrier. 
     
     
         19 . The method or composition of any of the foregoing claims, wherein the composition is formulated as a dietary composition. 
     
     
         20 . The method or composition of any of the foregoing claims, wherein the composition is a dry blended preparation, e.g., pharmaceutical grade dry blended preparation (PGDBP). 
     
     
         21 . A method of manufacturing a dry blended preparation, e.g., PGDBP, comprising at least 4 pharmaceutical grade amino acid entities, said method comprising:
 forming a combination of at least 4 pharmaceutical grade amino acid entities and blending the combination for a time sufficient to achieve a dry blended preparation, e.g., PGDBP,   wherein the dry blended preparation, e.g., PGDBP, comprises:
 a) a leucine amino acid entity, 
 b) a arginine amino acid entity, 
 c) glutamine amino acid entity; and 
 d) a N-acetylcysteine (NAC)-entity. 
   
     
     
         22 . The method of  claim 21 , wherein the dry blended preparation, e.g., PGDBP, further comprises one, two, three, four, five, or more (e.g., all) of:
 e) a citrulline amino acid entity,   f) a carnitine entity,   g) a serine amino acid entity,   h) a valine amino acid entity,   i) a histidine amino acid entity, and   j) a lysine amino acid entity.   
     
     
         23 . The method of any of  claims 20 - 22 , wherein:
 (i) blending occurs at a temperature lower than 40° C.;   (ii) blending comprises blending or mixing in a blender or mixer at a speed of less than 1000 rpm; or   (iii) the method further comprises one, two, or three of direct blending, roller compaction, or wet granulation of the dry blended preparation, e.g., PGDBP.   
     
     
         24 . A composition comprising:
 a) an arginine amino acid entity,   b) a citrulline amino acid entity; and   c) a N-acetylcysteine (NAC)-entity,   wherein:   (i) the composition does not comprise a peptide of more than 20 amino acid residues in length (e.g., whey protein), or if a peptide of more than 20 amino acid residues in length is present, the peptide is present at less than: 10 wt. % of the total wt. of the composition (e.g., in dry form);   (ii) at least 50 wt. % of the total wt. of the composition (e.g., in dry form) is one or more amino acid entities in free form; and   (iii) the wt. % of the citrulline amino acid entity is greater than the wt. % of the NAC-entity.   
     
     
         25 . The composition of  claim 24 , wherein one, two, or three of the following:
 (i) the wt. % of the citrulline amino acid entity in the composition (e.g., in dry form) is at least 50% greater than the wt. % of the NAC-entity, e.g., the wt. % of the citrulline amino acid entity is at least 60%, 65%, 70%, 75%, or 80% greater than the wt. % of the NAC-entity;   (ii) the wt. % of the leucine amino acid entity, the citrulline amino acid entity, and the NAC entity is at least: 20 wt. %, 25 wt. %, 30 wt. %, or 35 wt. % of the amino acid entity components or total components in the composition (e.g., in dry form), but not more than 80 wt. % of the amino acid entity components or total components in the composition (e.g., in dry form); or   (iii) the wt. % of the citrulline amino acid entity is at least: 5 wt. %, 10 wt. %, 11 wt. %, 12 wt. %, 13 wt. %, or more of the amino acid entity components in the composition (e.g., in dry form), but not more than 60 wt. % of the amino acid entity components in the composition (e.g., in dry form).   
     
     
         26 . The composition of  claim 24  or  25 , wherein the composition further comprises one or both of: (d) a carnitine amino acid entity; or (e) a glutamine amino acid entity. 
     
     
         27 . The composition of any of  claims 24 - 26 , wherein one, two, three, or four of the following:
 (i) the wt. % of the leucine amino acid entity, the citrulline amino acid entity, the NAC entity, the carnitine amino acid entity, and the glutamine amino acid entity is at least: 40 wt. %, 45 wt. %, 50 wt. %, 55 wt. %, or 60 wt. % of the amino acid entity components or total components in the composition (e.g., in dry form), but not more than 90 wt. % of the amino acid entity components or total components in the composition (e.g., in dry form);   (ii) the wt. % of the citrulline amino acid entity in the composition (e.g., in dry form) is greater than the wt. % of the carnitine amino acid entity, e.g., the wt. % of the citrulline amino acid entity in the composition (e.g., in dry form) is at least 50% greater than the wt. % of the carnitine amino acid entity, e.g., the wt. % of the citrulline amino acid entity is at least 60%, 65%, 70%, 75%, or 80% greater than the wt. % of the carnitine amino acid entity;   (iii) the wt. % of the glutamine amino acid entity in the composition (e.g., in dry form) is greater than the wt. % of the citrulline amino acid entity, e.g., the wt. % of the glutamine amino acid entity in the composition (e.g., in dry form) is at least 40% greater than the wt. % of the citrulline amino acid entity, e.g., the wt. % of the glutamine amino acid entity is at least 60%, 45%, 50%, 55%, 60%, or 65% greater than the wt. % of the citrulline amino acid entity; or   (iv) the wt. % of the citrulline amino acid entity and the arginine amino acid entity in combination in the composition (e.g., in dry form) is greater than the wt. % of the glutamine amino acid entity, e.g., the wt. % of the citrulline amino acid entity in the composition (e.g., in dry form) is at least 20% greater than the wt. % of the carnitine amino acid entity, e.g., the wt. % of the citrulline amino acid entity is at least 30%, 35%, 40%, 45%, or 50% greater than the wt. % of the carnitine amino acid entity.   
     
     
         28 . The composition of any of  claims 24 - 27 , wherein the composition further comprises one, two, or three of: (f) a leucine amino acid entity, (g) a serine amino acid entity, (h) a valine amino acid entity, (i) a histidine amino acid entity, or (j) a lysine amino acid entity. 
     
     
         29 . A method of treating a hemoglobinopathy or a thalassemia, comprising administering to a subject in need thereof an effective amount of a composition (e.g., an Active Moiety) of any of  claims 24 - 28 , thereby treating the hemoglobinopathy or the thalassemia in the subject. 
     
     
         30 . A composition for use in a method of treating a hemoglobinopathy or a thalassemia, comprising an effective amount of a composition (e.g., an Active Moiety) of any of  claims 24 - 29 .