Compositions and methods for the treatment of hemoglobinopathies and thalassemias

1. 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) an arginine amino acid entity 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

iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising creatine;

b) a citrulline amino acid entity chosen from L-citrulline or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-citrulline;

c) a N-acetylcysteine (NAC)-entity chosen from NAC or a salt thereof or a dipeptide or salt thereof comprising NAC;

(d) a glutamine amino acid entity chosen from L-glutamine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-glutamine;

(e) one or both of i) a serine amino acid entity chosen from L-serine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-serine or ii) a carnitine entity chosen from L-carnitine or a salt thereof, or a dipeptide or salt thereof, comprising L-carnitine;

one, two, or more of: (f) a valine amino acid entity chosen from L-valine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-valine, (g) a histidine amino acid entity chosen from L-histidine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-histidine, or (h) a lysine amino acid entity chosen from L-lysine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-lysine, and/or (i) a leucine amino acid entity 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,

(i) wherein the composition does not comprise a peptide of more than 20 amino acid residues in length, 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 (in dry form);

(ii) at least 50 wt. % of the total wt. of the composition (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,

thereby treating the hemoglobinopathy or the thalassemia in the subject.

2. The method of claim 1 , wherein at least: 42 wt. % of the total wt. of the composition (in dry form) is one, two, three, four, five, six, seven, eight, or more of (a)-(i) in free amino acid form in the composition.

3. The method of claim 1 , wherein the total wt. % of (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 (in dry form).

4. The method of claim 1 , wherein the composition comprises a combination of 18 or fewer amino acid entities.

5. The method of claim 1 , wherein the composition 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.

6. The method of claim 1 , wherein the hemoglobinopathy or thalassemia is chosen from: a sickle cell disease, α-thalassemia, or β-thalassemia.

7. The method of claim 1 , wherein the composition is formulated with a pharmaceutically acceptable carrier.

8. The method of claim 1 wherein the composition is formulated as a dietary composition.

9. The method of claim 1 , wherein the composition is a pharmaceutical grade dry blended preparation (PGDBP).

10. The method of claim 1 , wherein one, two, or three of the following:

(i) the wt. % of the citrulline amino acid entity in the composition (in dry form) is at least 50% 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. % of the amino acid entity components or total components in the composition (in dry form), but not more than 80 wt. % of the amino acid entity components or total components in the composition (in dry form); or

(iii) the wt. % of the citrulline amino acid entity is at least: 5 wt. % of the amino acid entity components in the composition (in dry form), but not more than 60 wt. % of the amino acid entity components in the composition (in dry form).

11. The method of claim 1 , 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. % of the amino acid entity components or total components in the composition (in dry form), but not more than 90 wt. % of the amino acid entity components or total components in the composition (in dry form);

(ii) the wt. % of the citrulline amino acid entity in the composition (in dry form) is at least 50% greater than the wt. % of the carnitine amino acid entity;

(iii) the wt. % of the glutamine amino acid entity in the composition (in dry form) is at least 40% greater than the wt. % of the citrulline amino acid entity; or

(iv) the wt. % of the citrulline amino acid entity in the composition (in dry form) is at least 20% greater than the wt. % of the carnitine amino acid entity.

12. The method of claim 1 , wherein the composition comprises two, three, or all of: (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.

13. The method of claim 6 , wherein the sickle cell disease is chosen from: 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.

14. The method of claim 1 , wherein the composition comprises:

a) L-arginine or a salt thereof,

b) L-citrulline or a salt thereof,

c) NAC or a salt thereof,

d) L-carnitine or a salt thereof, and

e) L-glutamine or a salt thereof.