Treatment of neurodegenerative conditions

Abstract

A method is provided for treating a patient in need of therapy for a neurodegenerative disease comprising administering to that patient a therapeutically effective dose of a lipid glyceride comprising a glycerol moiety and a fatty acid moiety, the fatty acid moiety being selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid characterised in that the selected fatty acid moiety is attached to the glycerol moiety at its sn-2 position. Preferably the method is that wherein the lipid is administered for a duration and at a dose sufficient to maintain or elevate TGF-β1 levels in the patient to therapeutic levels.

1 - 38 . (canceled) 
   
   
       39 . A method of treating a patient in need of therapy for a neurodegenerative disease comprising administering to that patient a therapeutically effective dose of a defined structure lipid glyceride comprising a glycerol moiety esterified with one or more fatty acid moieties, characterised in that the lipid has a fatty acid moiety at the sn-2 position selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid. 
   
   
       40 . A method as claimed in  claim 39  wherein the neurodegenerative disease involves demyelination. 
   
   
       41 . A method as claimed in  claim 39  wherein the treatment specifically arrests underlying neurodegeneration and restores neuronal function. 
   
   
       42 . A method as claimed in  claim 39  which normalizes neuronal membrane composition with respect to γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid lipid content. 
   
   
       43 . A method as claimed in  claim 39  which restores healthy TGF-β1/TNFα ratios as measured from spontaneous release from peripheral blood mononuclear cell release. 
   
   
       44 . A method as claimed in  claim 39  wherein the disease is multiple sclerosis. 
   
   
       45 . A method as claimed in  claim 39  wherein the disease is relapsing remitting multiple sclerosis, primary progressive multiple sclerosis or chronic progressive multiple sclerosis. 
   
   
       46 . A method as claimed in  claim 39  wherein the disease is multiple sclerosis and the treatment restores, in part or completely, neuronal function or neuronal integrity as measured by one or more of MRI scan, CAT scan or by EDSS score. 
   
   
       47 . A method as claimed in  claim 39  wherein the treatment is of cerebral impairment after stroke, head trauma and intracranial bleeding, Alzheimer's disease or Parkinson's disease where there is demyelination or neuronal damage. 
   
   
       48 . A method as claimed in  claim 39  wherein the lipid is administered for a duration and at a dose sufficient to maintain or elevate TGF-β1 levels in the patient to therapeutic levels. 
   
   
       49 . A method as claimed in  claim 39  wherein the lipid is administered for a duration and at a dose sufficient to maintain or elevate TGF-β1 levels in the patient to a TGF-β1/TNF-α ratio released spontaneously from peripheral blood mononuclear cells isolated from the blood of a patient, after 18 months of daily dosing, of 0.4 to 3.0, at least 0.5, more preferably at least 0.75 and most preferably at least 1. 
   
   
       50 . A method as claimed in  claim 49  wherein the dose is such as to produce a TGF-β1/IL-1β ratio in PBMCs isolated from blood of a patient, after 18 months of daily dosing, of at least of at least 0.75. 
   
   
       51 . A method as claimed in  claim 39  wherein the amount of lipid administered is between 0.5 and 30 grams, typically 3 to 5 grams, per day. 
   
   
       52 . A method as claimed in  claim 39  wherein the lipid is a monoglyceride, diglyceride or triglyceride containing the at least one sn-2 γ-linolenic acid, dihomo-γ-linolenic acid or arachidonic acid moiety, the lipid being of general Formula I 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are independently selected from hydrogen and acyl groups, and R 2  is selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid residues having their carbonyl carbon attached to the oxygen of the glycerol moiety. 
     
   
   
       53 . A method as claimed in  claim 39  wherein R 1  and R 3  are saturated fatty acid moieties of formula —CO—(CH 2 ) n —CH 3 , wherein n is an integer selected from 1 to 22. 
   
   
       54 . A method as claimed in  claim 53  wherein R 1  and R 3  are the same and n is an integer of from 5 to 12. 
   
   
       55 . A method as claimed in  claim 54  wherein n is an integer of from 6 to 10. 
   
   
       56 . A method as claimed in  claim 52  wherein R 1  and R 3  are selected from the group consisting of essential fatty acids or physiologically acceptable fatty acids metabolisable by the human body. 
   
   
       57 . A method as claimed in  claim 52  wherein R 1 , R 2  and R 3  are all the same and are selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid residues. 
   
   
       58 . A pharmaceutical composition characterised in that it comprises a defined structure lipid glyceride comprising a glycerol moiety esterified with one or more fatty acid moieties, characterised in that the lipid has a fatty acid moiety at the sn-2 position selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid. 
   
   
       59 . A pharmaceutical composition for treating neurodegeneration characterised in that it comprises a defined structure lipid glyceride comprising a glycerol moiety esterified with one or more fatty acid moieties, characterised in that the lipid has a fatty acid moiety at the sn-2 position selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid. 
   
   
       60 . A pharmaceutical composition for treating demyelinating disease comprising a glycerol moiety esterified with one or more fatty acid moieties, characterised in that the lipid has a fatty acid moiety at the sn-2 position selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid. 
   
   
       61 . A lipid of formula II 
     
       
         
         
             
             
         
       
       wherein R 1  and R 3  are the same and are —C(O)(CH 2 ) n CH 3  wherein n is selected from 4 to 14, more preferably 6 to 10 and most preferably 7, 8 or 9 and R 2  is selected from γ-linolenyl, dihomo-γ-linolenyl and arachidonyl residues. 
     
   
   
       62 . Use of a defined structure lipid glyceride comprising a glycerol moiety esterified with one or more fatty acid moieties, characterised in that the lipid has a fatty acid moiety at the sn-2 position selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid, for the manufacture of a medicament for the treatment of neurodegenerative disease. 
   
   
       63 . Use as claimed in  claim 62  wherein the degenerative disease is a demyelinating disease. 
   
   
       64 . Use as claimed in  claim 62  wherein the disease is multiple sclerosis. 
   
   
       65 . Use as claimed in  claim 62  wherein the medicament normalises neuronal membrane composition with respect to lipid γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid levels. 
   
   
       66 . Use as claimed in  claim 62  wherein the medicament restores TGF-β1/TNFα ratios spontaneously released from peripheral blood mononuclear cells of a patient to healthy levels. 
   
   
       67 . Use as claimed in  claim 62  wherein treatment is for multiple sclerosis or the degenerative sequelae associated with head trauma, stroke and intracranial bleeds or neuronal damage caused by Alzheimer's or Parkinson 1 s disease. 
   
   
       68 . Use as claimed in  claim 62  wherein the medicament repairs CNS lesions. 
   
   
       69 . Use as claimed in  claim 62  wherein the medicament relieves muscle spasticity and/or pain. 
   
   
       70 . Use as claimed in  claim 62  wherein the medicament eliminates relapses. 
   
   
       71 . Use as claimed in  claim 62  wherein the medicament improves EDSS score by at least 1 unit over a period of 1 years treatment. 
   
   
       72 . Use as claimed in  claim 62  wherein the medicament is sufficient to restore EDSS of a patient with EDSS above 2.5 to below 2 over a period of 1 years treatment. 
   
   
       73 . Use as claimed in  claim 62  wherein there is improvement in bladder control. 
   
   
       74 . A method for synthesis of a compound of general formula III 
     
       
         
         
             
             
         
       
       wherein R 1  and R 3  are the same and are —C(O)(CH 2 ) n CH 3  wherein n is selected from 4 to 14, more preferably 6 to 10 and most preferably 7, 8 or 9 and R 2  is γ-linolenyl residue, dihomo-γ-linolenyl residue or arachidonyl residue comprising 
       reacting 1,3-dihydroxyacetone with a compound of formula X—C(O)(CH 2 ) n CH 3  wherein X is selected from Cl, Br and I, 
     
     to give the corresponding 1,3-di-(C(O)(CH 2 ) n CH 3 ) 2-keto compound reducing the keto group to the corresponding 1,3-di-(C(O)(CH 2 ) n CH 3 ) 2-ol and reacting that with γ-linolenyl halide or dihomo-γ-linolenyl halide or arachidonyl halide, wherein halide is chloride, bromide or iodide. 
   
   
       75 . A method for synthesis of a compound of general formula IV 
     
       
         
         
             
             
         
       
       wherein R 1  to R 3  are the same and selected from γ-linolenyl residue, dihomo-γ-linolenyl residue or arachidonyl residue 
       comprising reacting the corresponding γ-linolenyl halide, dihomo-γ-linolenyl halide or arachidonyl halide, wherein halide is chloride, bromide or iodide, with glycerol. 
     
   
   
       76 . A lipid selected from the group consisting of
 Glycerol 1,3-didecanoate-2-octadecatri(6-Z,9-Z,12-Z)enoate   Glycerol 1,3-didecanoate-2-eicosa-(8Z,11Z,14Z)-trienoate   Glycerol trieicosotetra5-Z,8-Z,11-Z,14Z-eneoate.   
   
   
       77 . A lipid as claimed in  claim 76  for use in therapy.