Table 1.
Approved Therapies and Pharmacological Chaperones for Lysosomal Storage Disorders
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Pharmacological Chaperones |
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| Disease | Deficient Enzyme | Approved Drug(s)a | Name | Status | References |
| Fabry | α-Galactosidase A | Fabrazyme® (agalsidase beta)Replagal™ (agalsidase alpha) | Galactose | Preclinical | 164 |
| Case Study | 165 | ||||
| DGJ (AT1001; Amigal™) | Phase 3 | 40, 75, 131, 166 | |||
| Gaucher | Acid β-Glucosidase | Cerezyme® (imiglucerase)VPRIV™ (velaglucerase alfa) Zavesca® (miglustat; NB-DNJ) | α-allo-HNJ; α-galacto-HNJ; β-1-C-butyl-DGJ | Preclinical | 167 |
| DIA | Preclinical | 168 | |||
| NN-DNJ | Preclinical | 64, 126, 127, 169, 170 | |||
| N-(7-oxadecyl)DNJ | Preclinical | 127 | |||
| N-(n-octyl)DNJ | Preclinical | 127, 170 | |||
| NOV | Preclinical | 161 | |||
| Castanospermine; N-(n-octyl)IFG; PDMP; morpholine- and piperazine-substituted alkylated nitrogen heterocycles; N-octyl-2,5-dideoxy-2,5-imino-D-glucitol | Preclinical | 126 | |||
| CO-DNJ and CN-DNJ | Preclinical | 170 | |||
| N-hexanoic acid adamantyl amide DNJ | Preclinical | 64 | |||
| Calystegine derivatives; DIX | Preclinical | 171 | |||
| IFG (AT2101) | Phase 2 | 65, 70, 76 | |||
| 5-((4-methylphenyl)thio)-quinazoline 2,4-diamine | Preclinical | 108 | |||
| 5-(3,5-dichlorophenoxy)-N-(4-pyridinyl)-2-furamide | Preclinical | 108 | |||
| NOI-NJ, 6S-NOI-NJ, 6N-NOI-NJ, 6S-NOI-GNJ | Preclinical | 172 | |||
| Diltiazem | Preclinical | 107 | |||
| Ambroxol | Investigator-initiated pilot study | 61, 173, www.Gaucher.org | |||
| NB-DNJ, Aminocyclitol 1, Aminocyclitol 4 | Preclinical | 169 | |||
| Dansyl-capped N-substituted DNJ derivatives 10 and 11 | Preclinical | 173 | |||
| 6S-NDI-NJ | Preclinical | 174 | |||
| 2-O-alkly iminoxylitol derivatives | Preclinical | 175 | |||
| GM1 Gangliosidosis (Morquio B) | Acid β-Galactosidase | None | NOEV | Preclinical | 138, 176 |
| DGJ, NB-DGJ | Preclinical | 138, 177 | |||
| Galactose | Preclinical | 178 | |||
| DLHex-DGJ | Preclinical | 179 | |||
| DGJ derivatives (compounds 17, 18, 22) | Preclinical | 180 | |||
| Fluorous iminoalditols 6–8 | Preclinical | 181 | |||
| GM2 Gangliosidosis (Tay-Sachs / Sandhoff) | Acid β-Hexosaminidase | None | NGT | Preclinical | 59, 182 |
| AdDNJ; ADNJ; ACAS | Preclinical | 182 | |||
| M-22971 (nitro-indan-1-one); M-45373 (pyrrolo[3,4-d]pyridazin-1-one); M-31850 (bisnaphthalimide) | Preclinical | 59 | |||
| Pyrimethamine | Phase 2 | 58, 183 | |||
| N-benzyl LABNAc | Preclinical | 184 | |||
| Pompe | Acid α-Glucosidase | Myozyme® (alglucosidase alfa) Lumizyme® (alglucosidase alfa) | DNJ (AT2220) | Phase 2 | 62, 72, 73 |
| NB-DNJ (miglustat) | Preclinical | 72, 73 | |||
| NO-DNJ | Preclinical | 72 | |||
| Krabbe | Galactocerebrosidase | None | α-Lobeline | Preclinical | 185 |
| Batten | Palmitoyl:protein thioesterase | None | CS38 | Preclinical | 186 |
| MPS I (Hurler / Hurler-Scheie) | α-L-iduronidase | Aldurazyme® (laronidase) | None | ||
| MPS II (Hunter) | Iduronate sulphate sulphatase | Elaprase® (idursulfase) | None | ||
| MPS IIIC (Sanfilippo Syndrome type C) | Heparan sulfate acetyl-CoA: α-glucosaminidine N-acetyltransferase | None | Glucosamine | Preclinical | 187 |
| MPS VI (Maroteaux-Lamy) | N-acetylgalactosamine-4-sulfatase | Naglazyme® (galsulfase) | None | ||
All approved drugs are enzyme replacement therapies, with the exception of Zavesca, which is an substrate reduction therapy.
ACAS, 6-acetamido-6-deoxycastanospermine; AdDNJ, 2-acetamido-1,2-dideoxynojirimycin; ADNJ, 2-aceto-2-deoxynojirimycin; CN-DNJ, α-1-C-nonyl-1-deoxynojirimycin; CO-DNJ, α-1-C-octyl-1-deoxynojirimycin; DGJ, 1-deoxygalactonojirimycin; DIA, 2,5-dideoxy-2,5-imino-D-altritol; DIX, 1,5-dideoxy-1,5-iminoxylitol; DNJ, 1-deoxynojirimycin; HNJ, homonojirimycin; α-allo-HNJ, homoallonojirimycin; DLHex-DGJ, methyl 6-{[N2-(dansyl)-N6-(1,5-dideoxy-D-galactitol-1,5-diyl)-L-lysyl]amino} hexonate; IFG, isofagomine; LABNAc, 2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol; NB-DGJ, N-butyl-1-deoxygalactonojirimycin; NB-DNJ, N-butyl-1-deoxynojirimycin; NGT, N-acetyl-glucosamine-thiazoline; NN-DNJ, N-(n-nonly)-deoxynojirimicin; NO-DNJ, N-(7-oxadecyl) deoxynojirimycin; NOEV, N-octyl-4-epi-β-valienamine; 6S-NDI-NJ, 6-thio-(5N,6S)-[4-(N′-dansylamino)butylmethylidene]nojirimycin; 6S-NOI-GNJ, 5-N,6-thio-(N′-octyliminomethylidene)galactonojirimycin; NOI-NJ, 5-N,6-O-(N′-octyliminomethylidene)nojirimycin; 6N-NOI-NJ, 6-amino-6-deoxy-5,6-di-N-(N′-octyliminomethylidene)nojirimycin; 6S-NOI-NJ, 5-N,6-thio-(N′-octyliminomethylidene)nojirimycin; NOV, N-octyl-β-valienamine; PDMP, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol; MPS, mucopolysaccharidoses.