Inhibitors of gangliosides metabolism for the treatment of motor neuron diseases

1. A method for reducing ganglioside metabolism in a subject suffering from a motor neuron disease, comprising administering to the subject an inhibitor of glucosylceramide synthase (GCS), and wherein said motor neuron disease is a hereditary spastic paraplegia (HSP) selected from the group consisting of SPG11, SPG4, and SPG7, wherein said inhibitor of GCS is selected from the group consisting of an imino sugar, a ceramide analog, a carboxamide, a carbamate, a glycoside hydrolase chaperone, imiglucerase and a nucleic acid inhibitor of gene expression.

2. The method according to claim 1 , wherein said nucleic acid inhibitor of gene expression is selected from the group consisting of ribozyme, ribonucleic acid interference (RNAi), an antisense oligonucleotide, a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a microRNA (miRNA), a DNAzyme, a peptide nucleic acid (PNA), a modified or synthetic DNA or RNA degradation-resistant polynucleoside amide, a locked nucleic acid (LNA), an antisense RNA (asRNA), or a morpholino.

3. The method according to claim 1 , wherein said inhibitor of GCS is an imino sugar 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 or Miglustat);

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 acids;

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);

L-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol;

DL-erythro-1-phenyl-2-amino-1,3-propanediol;

D-threo (R,R)-1-phenyl-2-amino-1,3-propanediol;

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;

α-homogalactonojirimycin;

α-homoallonojirimycin;

β-1-C-butyl-DGJ; and

N-nonyl-DNJ.

4. The method according to claim 1 , wherein the inhibitor is administered by oral, topical, transdermal, intramuscular, subcutaneous, intravenous, parenteral, intranasal or perispinal administration.

5. The method according to claim 1 , wherein said inhibitor of GCS is an imino sugar.

6. The method according to claim 1 , wherein the subject with HSP presents with peripheral neuropathy.

7. The method according to claim 1 , wherein the subject with HSP presents with ataxia.

8. The method according to claim 1 , wherein the inhibitor of GCS is Miglustat.

9. The method according to claim 1 , wherein said inhibitor of GCS is an analog of D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP).

10. The method according to claim 1 , wherein said inhibitor of GCS is a ceramide analog.

11. The method according to claim 1 , wherein said inhibitor of GCS is a carboxamide.

12. The method according to claim 1 , wherein said inhibitor of GCS is a carbamate.

13. The method according to claim 1 , wherein said inhibitor of GCS is a glycoside hydrolase chaperone.

14. The method according to claim 1 , wherein the inhibitor of GCS is imiglucerase.