Treating neurodegenerative disease
As described herein, lactosylceramide (LacCer) levels are up-regulated in the CNS during chronic experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). LacCer acts in an autocrine manner to trigger transcriptional programs that promote the recruitment and activation of CNS infiltrating monocytes and microglia, and neurodegeneration. In addition, increased B4GALT6 expression and LacCer levels were detected in CNS MS lesions in human patients. Finally, the inhibition of LacCer synthesis suppressed local CNS innate immunity and neurodegeneration in EAE, and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 is a therapeutic target for MS and other neuroinflammatory disorders.
1. A method of treating progressive multiple sclerosis (MS) in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of lactosylceramide (LacCer) synthesis, wherein the inhibitor of LacCer synthesis is an inhibitor of B4GALT6 or of glucosylceramide (GlcCer) synthesis.
2. A method of treating progressive multiple sclerosis (MS) in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of LacCer synthesis, wherein the inhibitor of LacCer synthesis is an inhibitor of glucosylceramide (GlcCer) synthesis.
3. The method of claim 2 , wherein the inhibitor of GlcCer synthesis is selected from the group consisting of 1-(3′,4′-ethylenedioxy)phenyl-2-nonanoylamino-3-pyrrolidino-1-propanol; 1-(3′,4′-ethylenedioxy)phenyl-2-octanoylamino-3-pyrrolidino-1-propanol; D-threo-(1R,2R)-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and analogs thereof including D-PDMP; PPMP (DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol), D-threo-EtDO-P4; ((1R, 2R)-nonanoic acid[2-(2′,3′-dihydro-benzo [1,4] dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt; CCG0203586 (1-hydroxy-3-(pyrrolidin-1-yl)acetamide); Genz-112638 (eliglustat); Genz-529468; deoxynojiromycin-based GlcCer inhibitors; GZ-161; Genz-682452; EXEL-0346; OGT2378; and Genz-123346.
4. The method of claim 3 , wherein the deoxynojiromycin-based GlcCer inhibitor is N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), N-butyl-deoxynojirimycin (miglustat) or a long-chain N-alkyl derivative of 1,5-dideoxy-1,5-imino-D-glucitol having from nine to about 20 carbon atoms in the alkyl chain.
5. The method of claim 4 , wherein the N-alkyl substituent is selected from the group consisting of nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, cis-11-hexadecenyl, octadecyl, cis-13-octadecenyl, and eicosyl.
6. The method of claim 1 , wherein the inhibitor of LacCer synthesis is an inhibitor of B4GALT6 selected from the group consisting of a small molecule, an inhibitory nucleic acid targeting B4GALT6, or an inhibitory antibody that binds specifically to B4GALT6 and inhibits LacCer synthesis.
7. The method of claim 6 , wherein the inhibitory nucleic acid targeting B4GALT6 is selected from the group consisting of antisense, siRNA, shRNA, and miRNA.
8. The method of claim 1 , comprising administering an inhibitor of B4GALT6 and an inhibitor of GlcCer synthesis.
9. The method of claim 1 , comprising selecting the subject on the basis that the subject has progressive MS.
10. The method of claim 1 , further comprising administering an activator of glucocerebrosidase.
11. The method of claim 10 , wherein the activator of glucocerebrosidase is Saposin C or an active fragment thereof; NCGC00182186 (5-cyclopropylidene-7-(difluoromethyl)-N-(2-phenylsulfanylphenyl)-1H-pyrazolo[1,5-a]pyrimidine-3-carboxamide); NCGC00182510 ([2-(tert-butylamino)-2-oxoethyl] 2-[2-(4-bromoanilino)-2-oxoethoxy]benzoate) or phosphatidylserine.
12. The method of claim 1 , wherein the compound is administered orally, nasally, intravenously, or intrathecally.
13. The method of claim 1 , wherein the subject has SPMS and/or is selected on the basis that they have SPMS.
14. The method of claim 1 , wherein the progressive multiple sclerosis (MS) is primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS).
15. A method of treating progressive multiple sclerosis (MS) in a subject, the method comprising administering to the subject a therapeutically effective amount of N-butyl-deoxynojirimycin (miglustat).
16. The method of claim 15 , wherein the progressive multiple sclerosis (MS) is primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS).