Bicalutamide analogs or (S)-bicalutamide as exocytosis activating compounds for use in the treatment of a lysosomal storage disorder or glycogenosis
The invention provides a therapy for lysosomal storage diseases and glycogenosis by treatment with compounds that promote exocytosis, preferably lysosomal exocytosis. The treatment of cells from patients affected by different lysosomal storage disorders with exocytosis activating compounds leads to a decrease in the accumulation of toxic substrate in the lysosomes, thus allowing the treatment, prevention and relief of the symptoms of many lysosomal storage disorders.
1. A method of treating and/or preventing clinical symptoms associated with a lysosomal storage disease, a lysosomal storage disorder, a glycogenosis, or a combination thereof in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of (S)-bicalutamide (1),
and/or a pharmaceutically acceptable salt, hydrate and/or a solvate thereof, in an enantiomerically pure form or having an enantiomeric excess of the (S) enantiomer higher than 95%, and wherein the amount of the (R) enantiomer is lower than 2.5%.
2. The method according to claim 1 , wherein the lysosomal storage disease, the lysosomal storage disorder, the glycogenosis, or the combination thereof is selected from the group consisting of α-Mannosidosis, Aspartylglucosaminuria, β-Mannosidosis, Cystinosis, α-N-Acetylgalactosaminidase Deficiency or Schindler disease, Aspartoacylase Deficiency, Aminoacylase Deficiency or Canavan disease, Multiple Sulfatase Deficiency or MSD, Steroid Sulfatase Deficiency, Cholesteryl ester storage disease, Wolman disease, Fabry disease, Farber disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, Fucosidosis, Galactosialidosis, GM1 Gangliosidosis, GM2 Gangliosidosis, Glycogenosis type I or Von Gierke disease, Glycogenosis type II or Pompe disease, Glycogenosis type IIb or Danon disease, Glycogenosis type V or McArdle disease, Glycogenosis type VII or Tarui disease, Metachromatic Leukodystrophy, Neuronal Ceroid Lipofuscinoses, Mucolipidosis type I or Sialidosis, Mucolipidosis type II or I-Cell disease, Mucolipidosis type IIIA or α/β, Pseudo-Hurler polydystrophy, Mucolipidosis type IIIC or γ, Mucolipidosis type IV, Mucopolysaccharidoses type I, Mucopolysaccharidoses type II or Hunter syndrome, Mucopolysaccharidoses type III, Mucopolysaccharidoses type IV, Mucopolysaccharidoses type VI or Maroteaux-Lamy disease, Mucopolysaccharidoses type VII or Sly syndrome, Mucopolysaccharidoses type IX by Hyaluronidase Deficiency, and Pycnodysostosis.
3. The method according to claim 1 , wherein the (S)-bicalutamide and/or the pharmaceutically acceptable salt, hydrate and/or solvate thereof is administered in an amount ranging from 0.1 to 2000 mg per day.
4. The method according to claim 1 , further comprising administering to the subject at least one adjuvant selected from the group consisting of compounds that activate lysosomal exocytosis, pharmacological chaperones that promote protein stabilization, compounds used in substrate reduction therapies (SRT), enzymes used in enzyme replacement therapies (ERT), antioxidant compounds, compounds used in gene therapy of a lysosomal storage disease, a lysosomal storage disorder, glycogenosis, or combination thereof.
5. The method according to claim 4 , wherein the adjuvant is a compound that activates lysosomal exocytosis selected from the group consisting of δ-tocopherol, 2-hydroxypropyl-β-cyclodextrin, and/or mixtures thereof.
6. The method according to claim 4 , wherein the adjuvant is a compound used in substrate reduction therapy selected from the group consisting of N-butyl-deoxynojirimycin or miglustat, migalastat hydrochloride, divoglustat hydrochloride, and/or mixtures thereof.
7. The method according to claim 4 , wherein the adjuvant is a enzyme used in enzyme replacement therapy selected from the group consisting of natural enzymes and/or their recombinant synthetic forms and/or their recombinant synthetic mutants of N-aspartyl-β-glucosaminidase, acetyl-CoA α-glucosaminide N-acetyltransferase, N-acetylglucosamine-6-sulfatase, N-acetylglucosamine-1-phosphotransferase, α-N-acetylglucosaminidase, α-N-acetylneuraminidase, sialidase, acid ceramidase, acid α-glucosidase, acid maltase, aspartoacylase, lysosomal lipase acid, acid sphingomyelinase, arylsulfatase A, arylsulfatase B, α-L-fucosidase, galactocerebrosidase, galactosamine-6-sulfatase, α-galactosidase A, α-galactosidase B, β-galactosidase, galactosylceramidase, β-glucoronidase, β-glucosidase, β-glucocerebrosidase, heparan N-sulfatase, β-hexosaminidase A, β-hexosaminidase A/B, hyaluronidase-1, α-L-iduronidase, iduronate-2-sulfatase, α-D-mannosidase, β-mannosidase and α-neuraminidase, and/or mixtures thereof.
8. The method according to claim 4 , wherein the adjuvant is a pharmacological chaperone selected from the group consisting of 1-deoxynojirimycin, nojirimycin-1-sulfonic acid, N-(7-oxadecyl)-1-deoxynojirimycin, 2-acetamido-deoxynojirimycin, 2-acetamido-1,2-dideoxynojirimycin, 1-deoxygalactonojirimycin, N-butyl-deoxygalactonojirimycin, castanospermine, N-acetylglucosamine thiazoline, galactose, nitroindanone, pyrimethamine, miglustat, migalastat hydrochloride, divoglustat hydrochloride, 2,5-dideoxy-2,5-imino-D-altritol, isofagomine, ambroxol, diltiazem, glucosamine, their structural analogues, their salts and/or mixtures thereof.
9. The method according to claim 4 , wherein the adjuvant is an antioxidant compound selected from the group consisting of Vitamin A or retinol, Vitamin C or ascorbic acid, Vitamin E, tocotrienol and tocopherols, coenzyme Q10, manganese, iodide, idebenone, melatonine, α-carotene, astaxanthine, β-carotene, cantaxanthine, lutein, licopen, zeaxanthine, flavones, apigenin, luteolin, tangeritin, flavonols, isoramnetine, kaempferol, myricetin, proanthocyanidins, quercetin, rutin, flavanones, eriodictyol, hesperetin, naringenin, flavanols and their polymers, catechin, gallocatechin, epicatechin, epigallocatechin, theaflavin, thearubigin, phytoestrogens, isoflavones, daidzein, genistein, glycitein, stilbenoids, resveratrol, pterostilbene, anthocyanins, cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, phenolic acids and their esters, cichoric acid, chlorogenic acid, cinnamic acid, ferulic acid, ellagic acid, ellagitannin, gallic acid, gallotannins, rosmarinic acid, salicylic acid, flavonolignans, silymarin, xanthones, eugenol, capsaicin, bilirubin, citric acid, oxalic acid, phytic acid, N-acetylcysteine, R-α-lipoic acid, uric acid, carnosin and their derivatives, carnitin and their derivatives, Lipochroman-6 (Dimethylmethoxy Chromanol), Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), tert-butylhydroquinone (TBHQ) and/or mixtures thereof.
10. A method of treating and/or preventing clinical symptoms associated with a lysosomal storage disease, a lysosomal storage disorder, glycogenosis, or combination thereof in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (S)-bicalutamide and/or a pharmaceutically acceptable salt, hydrate and/or solvate thereof, in an enantiomerically pure form or having an enantiomeric excess of the (S) enantiomer higher than 95%, and wherein the amount of the (R) enantiomer is lower than 2.5%.
11. The method according to claim 10 , wherein the (S)-bicalutamide and/or the pharmaceutically acceptable salt, hydrate and/or solvate thereof is incorporated into a delivery system and/or sustained release system selected from the group consisting of liposomes, milliparticles, microparticles, nanoparticles, sponges, vesicles, micelles, millispheres, microspheres, nanospheres, lipospheres, millicapsules, microcapsules, nanocapsules, microemulsions and nanoemulsions.
12. The method according to claim 10 , wherein the pharmaceutical composition further comprises at least one adjuvant selected from the group consisting of compounds that activate lysosomal exocytosis, pharmacological chaperones that promote protein stabilization, compounds used in substrate reduction based therapies (SRT), enzymes used in enzyme replacement therapies (ERT), antioxidant compounds, and/or compounds used in gene therapy of a lysosomal storage disease, a lysosomal storage disorder, glycogenosis, or combination thereof.
13. The method according to claim 10 , wherein the administering is performed by a topical, an enteral or a parenteral route.
14. The method according to claim 2 , wherein the Mucopolysaccharidoses type III is Sanfilippo syndrome type A/MPS III A, Sanfilippo syndrome type B/MPS III B, Sanfilippo syndrome type C/MPS III C or Sanfilippo syndrome type D/MPS III D.
15. The method according to claim 2 , wherein the Mucopolysaccharidoses type I is Hurler, Scheie or Hurler-Scheie syndrome.
16. The method according to claim 2 , wherein the Mucopolysaccharidoses type IV is Morquio type A/MPS IVA or Morquio type B/MPS IVB.
17. The method according to claim 2 , wherein the Niemann-Pick disease is Niemann-Pick disease type A/B or Niemann-Pick disease type C.
18. The method according to claim 2 , wherein the GM2 Gangliosidosis is the activator deficiency variant, Sandhoff disease or Tay-Sachs disease.
19. The method according to claim 1 , wherein the lysosomal storage disease, lysosomal storage disorder, glycogenosis, or a combination thereof is selected from the group consisting of Sanfilippo syndrome type A, Sanfilippo syndrome type B, Hurler syndrome, Tay-Sachs disease, Gaucher disease, Fabry disease, Pompe disease and Niemann-Pick disease type A/B.
20. The method according to claim 2 , wherein the lysosomal storage disease, the lysosomal storage disorder, the glycogenosis, or the combination thereof is selected from the group consisting of Sanfilippo syndrome type A, Sanfilippo syndrome type B, Hurler syndrome, Tay-Sachs disease, Gaucher disease, Fabry disease, Pompe disease and Niemann-Pick disease type A/B.