Use of lipid conjugates in the treatment of diseases of the nervous system
View Patent ↗The invention provides a method for treating a subject suffering from a disease of the central nervous system which is associated with an inflammatory response, including, inter alia, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS), meningitis, Alzheimer's disease, pain, HIV-associated dementia, stroke, traumatic brain injury, encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, cerebral ischemia-induced injury or any combination thereof. This invention further provides for the use of a conjugate, or composition comprising the same, for treating the subject, wherein the conjugate comprises a lipid or phospholipid moiety bonded to a physiologically acceptable monomer, dimer, oligomer, or polymer.
1. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (I):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X, wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
2. The method of claim 1 , wherein said glycosaminoglycan is hyaluronic acid, heparin, heparin sulfate, heparin, heparan sulfate, chondroitin sulfate, keratin, keratan sulfate, dermatan sulfate or a derivative thereof.
3. The method of claim 1 , wherein said glycosaminoglycan is hyaluronic acid.
4. The method of claim 1 , wherein said glycosaminoglycan is chondroitin sulfate.
5. The method of claim 4 , wherein said chondroitin sulfate is chondroitin-4-sulfate.
6. The method of claim 4 , wherein said chondroitin sulfate is chondroitin-6-sulfate.
7. The method of claim 1 , wherein said glycosaminoglycan is di- and trisaccharide unit monomers of glycosaminoglycans.
8. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (II):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
9. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (III):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Z is either nothing, inositol, choline, or glycerol;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
10. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (IV):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
11. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (V):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
12. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (VI):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the phospholipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the phospholipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
13. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (VII):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the lipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the lipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
14. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (VIII):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Z is either ethanolamine, serine, inositol, choline, or glycerol;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the lipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the lipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
15. A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (IX):
wherein
R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
Z is either choline, phosphate, inositol, or glycerol;
Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof;
wherein if Y is nothing the lipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the lipid moiety via an amide bond;
X is a glycosaminoglycan; and
n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000;
wherein said damage to the nervous system in said subject is ameliorated.
16. The method of claim 1 , wherein said subject is administered a composition comprising said conjugate.
17. The method of claim 16 , wherein said composition further comprises a pharmaceutically acceptable carrier or excipient.
18. The method of claim 1 , wherein said damage to the nervous system is caused by inflammation.