Inhibitors of gangliosides metabolism for the treatment of motor neuron diseases

Abstract

The present invention relates to inhibitors of gangliosides metabolism for treating motor neuron diseases, in particular hereditary spastic paraplegias.

1 - 12 . (canceled) 
     
     
         13 . A method for treating a motor neuron disease in a subject, comprising administering to the subject at least one inhibitor of gangliosides metabolism, wherein said inhibitor of gangliosides metabolism is an inhibitor of GM3 synthase. 
     
     
         14 . The method according to  claim 13 , wherein said inhibitor of ganglioside metabolism is selected from the group consisting of small organic molecules, antibodies, antagonists, inhibitor scaffold, aptamers, ribozymes, peptides, chemical chaperones, ribonucleic acid interference (RNAi), oligonucleotide antisense, small interfering RNA (siRNA), antisense RNA (asRNA), morpholinos, and engineered nucleases. 
     
     
         15 . The method according to  claim 13 , wherein said inhibitor of gangliosides metabolism is an inhibitor of glucosylceramide synthase selected from the group consisting of imino sugars, analogs of D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP), ceramide analogs, carboxamides, carbamates, glycoside hydrolase chaperones. 
     
     
         16 . The method according to  claim 13 , wherein said inhibitor of gangliosides metabolism is an inhibitor of glucosylceramide synthase selected from the group consisting of N-butyldeoxynojirimycin (NB-DNJ), quinuclidin-3-yl (2-(4′-fluoro-[1, -biphenyl]-3-yl)propan-2-yl)carbamate (GZ161), N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide, N-(5-adamantane-1-yl-methoxypentyl) deoxynojirimycin (AMP-DNJ); N-butyl-1-deoxy-nojirimycin (KTB-DNJ); N-ethyl-1-dexynojirimycin (NE-DNJ); N-butyldeoxymannojixamycin; N-5-carboxyl-1-deoxynojiramycin; N-docecyl-1-deoxynojirimycin; nojirimycin bisulfate; nojiximycin-1-sulfonic acid; N-(n-nonyl)-1-deoxynojirimycin; N-(7-oxadecyl)-1-deoxynojirimycin; N-(7-oxa-9,9,9,-trifluorononyl)-1-deoxynojirimycin; (2R,3S,4R,5S)-2-(Hydroxymethyl)-3,4,5-piperidinetriol; N-butyldeoxygalactonojirimycin (NB-DGJ); N-(n-nonyl)deoxynojirimycin; (3S,4S)-3-(hydroxymethyl)pyrrolidine-3,4-diol (isoLAB); 1,4-dideoxy-1,4-imino-D-arabinitol, (2S,3R,4S,5R)-3,4,5-trihydroxy-6-oxopiperidine-2-carboxylic acid, D-glucaro-delta-lactam, 1,4-dideoxy-2-hydroxymethyl-1,4-imino-D-threitol; (2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol, isoDGDP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP); enantiomers of PDMP, L-threo- and DL-erythro-1-phenyl-2-amino-1,3-propanediol, the D-threo (R,R) enantiomer; 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol; 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4), D-threo-1-ethylenedioxyphenyl-2-palmitoyl-3-pyrrolidino-propanol (EtDO-P4); DL-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (DL-threo-P4); 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)nonanamide; BML-119; IV-231B, (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (S)-2-hydroxysuccinate (GZ 452), quinuclidin-3-yl (2-(4′-fluoro-[1, -biphenyl]-3-yl)propan-2-yl)carbamate, (1R,2R)-octanoic acid[2-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid, EXEL-0346, isofagomine, trans-4-(2-amino-3,5-dibrombenzylamino)-cyclohexanol, 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, (3R,4R,5R)-5-(hydroxymethyl)-3,4-piperidinediol, ambroxol, imiglucerase), α-homogalactonojirimycin, α-homoallonojirimycin, β-1-C-butyl-DGJ, and N-nonyl-DNJ. 
     
     
         17 . The method according to  claim 13 , wherein said inhibitor of gangliosides metabolism is an inhibitor of GM3 synthase being a miRNA. 
     
     
         18 . The method according to  claim 13 , wherein said inhibitor of gangliosides metabolism is an inhibitor of GM3 synthase selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4 and function conservative variants thereof. 
     
     
         19 . The method according to  claim 13 , wherein said inhibitor of gangliosides metabolism is an inhibitor of GM3 synthase being the carbon-linked analog of cytidine monophospho-N-acetylneuraminic acid. 
     
     
         20 . The method according to  claim 13 , wherein the composition is administered by oral, topical, transdermal, intramuscular, subcutaneous, intravenous, parenteral, intranasal administration. 
     
     
         21 . The method according to  claim 13 , wherein the motor neuron disease is selected from the group comprising hereditary spastic paraplegia (HSP), hereditary spastic paraparesis, familial spastic paraplegias, French settlement disease, or Strumpell-Lorrain disease, infantile-onset ascending hereditary spastic paralysis, MASA syndrome, also called CRASH syndrome and Gareis-Mason syndrome, cataracts with motor neuronopathy, short stature and skeletal abnormalities, MAST syndrome, Allan-Herndon-Dudley syndrome, Troyer syndrome, Lison syndrome, spastic ataxia (in particular), SPOAN syndrome, hereditary and sensory motor neuropathies (HMSN), peripheral neuropathies, Kjellin syndrome. 
     
     
         22 . The method according to  claim 13 , wherein the motor neuron disease is HSP presenting peripheral neuropathy. 
     
     
         23 . The method according to  claim 13 , wherein the motor neuron disease is hereditary spastic ataxia. 
     
     
         24 . The method according to  claim 13 , wherein the motor neuron disease is HSP. 
     
     
         25 . The method according to  claim 13 , wherein the motor neuron disease is selected from SPG11, SPG15, SPG48, SPG4 and SPG7.