JP6522073B2 - アリールスルファターゼaのcns送達の方法および組成物 - Google Patents
アリールスルファターゼaのcns送達の方法および組成物 Download PDFInfo
- Publication number
- JP6522073B2 JP6522073B2 JP2017194508A JP2017194508A JP6522073B2 JP 6522073 B2 JP6522073 B2 JP 6522073B2 JP 2017194508 A JP2017194508 A JP 2017194508A JP 2017194508 A JP2017194508 A JP 2017194508A JP 6522073 B2 JP6522073 B2 JP 6522073B2
- Authority
- JP
- Japan
- Prior art keywords
- nmol
- rhasa
- formulation
- brain
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims description 280
- 102100022146 Arylsulfatase A Human genes 0.000 title claims description 164
- 108010036867 Cerebroside-Sulfatase Proteins 0.000 title claims description 164
- 238000000034 method Methods 0.000 title claims description 100
- 238000009472 formulation Methods 0.000 claims description 240
- 210000004556 brain Anatomy 0.000 claims description 226
- 210000001519 tissue Anatomy 0.000 claims description 214
- 108090000623 proteins and genes Proteins 0.000 claims description 139
- 102000004169 proteins and genes Human genes 0.000 claims description 134
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 125
- 210000000278 spinal cord Anatomy 0.000 claims description 88
- 238000011282 treatment Methods 0.000 claims description 84
- 210000003169 central nervous system Anatomy 0.000 claims description 78
- 239000011780 sodium chloride Substances 0.000 claims description 72
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 56
- 210000004027 cell Anatomy 0.000 claims description 54
- 210000004885 white matter Anatomy 0.000 claims description 54
- 201000011442 Metachromatic leukodystrophy Diseases 0.000 claims description 50
- 239000000872 buffer Substances 0.000 claims description 45
- 238000001990 intravenous administration Methods 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 44
- 210000002569 neuron Anatomy 0.000 claims description 41
- 238000000185 intracerebroventricular administration Methods 0.000 claims description 40
- 230000002132 lysosomal effect Effects 0.000 claims description 40
- 150000001413 amino acids Chemical group 0.000 claims description 38
- 230000002093 peripheral effect Effects 0.000 claims description 32
- 230000001965 increasing effect Effects 0.000 claims description 31
- 238000009825 accumulation Methods 0.000 claims description 29
- 239000004094 surface-active agent Substances 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 23
- 230000002255 enzymatic effect Effects 0.000 claims description 22
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 21
- 210000004185 liver Anatomy 0.000 claims description 21
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 21
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 21
- 229940068977 polysorbate 20 Drugs 0.000 claims description 21
- 210000004705 lumbosacral region Anatomy 0.000 claims description 20
- 239000003381 stabilizer Substances 0.000 claims description 20
- 229910019142 PO4 Inorganic materials 0.000 claims description 19
- 239000010452 phosphate Substances 0.000 claims description 19
- 229920000136 polysorbate Polymers 0.000 claims description 16
- 229950008882 polysorbate Drugs 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- -1 optionally Substances 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 12
- 229920001296 polysiloxane Polymers 0.000 claims description 12
- 229930006000 Sucrose Natural products 0.000 claims description 11
- 210000004498 neuroglial cell Anatomy 0.000 claims description 11
- 239000005720 sucrose Substances 0.000 claims description 11
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 8
- 239000005388 borosilicate glass Substances 0.000 claims description 8
- 230000002490 cerebral effect Effects 0.000 claims description 8
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 210000003734 kidney Anatomy 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 7
- 210000002216 heart Anatomy 0.000 claims description 6
- 230000000750 progressive effect Effects 0.000 claims description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 5
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 5
- 208000016192 Demyelinating disease Diseases 0.000 claims description 5
- 206010012305 Demyelination Diseases 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 230000003376 axonal effect Effects 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 210000004786 perivascular cell Anatomy 0.000 claims description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 5
- 229940068968 polysorbate 80 Drugs 0.000 claims description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims description 5
- 229940071643 prefilled syringe Drugs 0.000 claims description 5
- 239000000600 sorbitol Substances 0.000 claims description 5
- 235000010356 sorbitol Nutrition 0.000 claims description 5
- 239000004475 Arginine Substances 0.000 claims description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 4
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 4
- 210000005260 human cell Anatomy 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000000088 plastic resin Substances 0.000 claims description 4
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 4
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 4
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 4
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 4
- 229940101027 polysorbate 40 Drugs 0.000 claims description 4
- 229940113124 polysorbate 60 Drugs 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 238000002650 immunosuppressive therapy Methods 0.000 claims description 3
- 230000004807 localization Effects 0.000 claims description 3
- 210000004248 oligodendroglia Anatomy 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 238000007914 intraventricular administration Methods 0.000 claims 1
- 125000000185 sucrose group Chemical group 0.000 claims 1
- 238000007913 intrathecal administration Methods 0.000 description 201
- 102000004190 Enzymes Human genes 0.000 description 191
- 108090000790 Enzymes Proteins 0.000 description 191
- 229940088598 enzyme Drugs 0.000 description 191
- 235000018102 proteins Nutrition 0.000 description 131
- 239000003814 drug Substances 0.000 description 118
- 235000002639 sodium chloride Nutrition 0.000 description 82
- 239000000523 sample Substances 0.000 description 81
- 229940124597 therapeutic agent Drugs 0.000 description 78
- 230000001225 therapeutic effect Effects 0.000 description 72
- 238000012360 testing method Methods 0.000 description 70
- 241000282567 Macaca fascicularis Species 0.000 description 56
- 230000000694 effects Effects 0.000 description 55
- 238000002347 injection Methods 0.000 description 51
- 239000007924 injection Substances 0.000 description 51
- 238000013456 study Methods 0.000 description 47
- 238000010186 staining Methods 0.000 description 45
- 229940088679 drug related substance Drugs 0.000 description 44
- 239000008186 active pharmaceutical agent Substances 0.000 description 42
- 208000024891 symptom Diseases 0.000 description 37
- 208000015439 Lysosomal storage disease Diseases 0.000 description 36
- 238000004458 analytical method Methods 0.000 description 35
- 239000008194 pharmaceutical composition Substances 0.000 description 33
- 210000002966 serum Anatomy 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 210000005013 brain tissue Anatomy 0.000 description 31
- 229940079593 drug Drugs 0.000 description 31
- 101000901140 Homo sapiens Arylsulfatase A Proteins 0.000 description 29
- 238000011084 recovery Methods 0.000 description 27
- 239000003981 vehicle Substances 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 25
- 238000004108 freeze drying Methods 0.000 description 25
- 238000003860 storage Methods 0.000 description 23
- 235000001014 amino acid Nutrition 0.000 description 22
- 210000004884 grey matter Anatomy 0.000 description 22
- 229940024606 amino acid Drugs 0.000 description 20
- 210000003712 lysosome Anatomy 0.000 description 20
- 239000000463 material Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 238000011888 autopsy Methods 0.000 description 19
- 230000001868 lysosomic effect Effects 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 239000003085 diluting agent Substances 0.000 description 18
- 238000009826 distribution Methods 0.000 description 18
- 210000002418 meninge Anatomy 0.000 description 18
- 108090000765 processed proteins & peptides Proteins 0.000 description 18
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 230000008859 change Effects 0.000 description 17
- 238000011887 Necropsy Methods 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 16
- 230000009467 reduction Effects 0.000 description 16
- 239000000126 substance Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 230000008014 freezing Effects 0.000 description 14
- 238000007710 freezing Methods 0.000 description 14
- 239000002953 phosphate buffered saline Substances 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000011521 glass Substances 0.000 description 13
- 238000001802 infusion Methods 0.000 description 13
- 230000000366 juvenile effect Effects 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000003139 buffering effect Effects 0.000 description 12
- 230000015556 catabolic process Effects 0.000 description 12
- 239000000306 component Substances 0.000 description 12
- 238000006731 degradation reaction Methods 0.000 description 12
- 239000003018 immunosuppressive agent Substances 0.000 description 12
- 102000004196 processed proteins & peptides Human genes 0.000 description 12
- 102100037182 Cation-independent mannose-6-phosphate receptor Human genes 0.000 description 11
- 101710145225 Cation-independent mannose-6-phosphate receptor Proteins 0.000 description 11
- NBSCHQHZLSJFNQ-QTVWNMPRSA-N D-Mannose-6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@@H]1O NBSCHQHZLSJFNQ-QTVWNMPRSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 210000001638 cerebellum Anatomy 0.000 description 11
- 210000004720 cerebrum Anatomy 0.000 description 11
- 230000007812 deficiency Effects 0.000 description 11
- 238000012377 drug delivery Methods 0.000 description 11
- 230000003902 lesion Effects 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 10
- 238000013019 agitation Methods 0.000 description 10
- 210000000133 brain stem Anatomy 0.000 description 10
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 10
- 230000000875 corresponding effect Effects 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 10
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 10
- 230000002739 subcortical effect Effects 0.000 description 10
- 210000001103 thalamus Anatomy 0.000 description 10
- 230000003442 weekly effect Effects 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 230000008499 blood brain barrier function Effects 0.000 description 9
- 210000001218 blood-brain barrier Anatomy 0.000 description 9
- 239000000945 filler Substances 0.000 description 9
- 238000004007 reversed phase HPLC Methods 0.000 description 9
- 230000008685 targeting Effects 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 210000003710 cerebral cortex Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000000975 dye Substances 0.000 description 8
- 238000002641 enzyme replacement therapy Methods 0.000 description 8
- 210000003979 eosinophil Anatomy 0.000 description 8
- 230000008595 infiltration Effects 0.000 description 8
- 238000001764 infiltration Methods 0.000 description 8
- 230000009545 invasion Effects 0.000 description 8
- 230000007774 longterm Effects 0.000 description 8
- 230000001537 neural effect Effects 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 210000001428 peripheral nervous system Anatomy 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 239000003755 preservative agent Substances 0.000 description 8
- 239000001488 sodium phosphate Substances 0.000 description 8
- 229910000162 sodium phosphate Inorganic materials 0.000 description 8
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 7
- 238000000137 annealing Methods 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 238000009792 diffusion process Methods 0.000 description 7
- 238000011156 evaluation Methods 0.000 description 7
- 239000012530 fluid Substances 0.000 description 7
- 230000028993 immune response Effects 0.000 description 7
- 238000012744 immunostaining Methods 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- 238000003780 insertion Methods 0.000 description 7
- 230000037431 insertion Effects 0.000 description 7
- 210000002540 macrophage Anatomy 0.000 description 7
- 210000001259 mesencephalon Anatomy 0.000 description 7
- 150000007523 nucleic acids Chemical group 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 6
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 6
- 206010067484 Adverse reaction Diseases 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 6
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 6
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 6
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 6
- 208000008955 Mucolipidoses Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000006838 adverse reaction Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 208000010877 cognitive disease Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000002950 deficient Effects 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000013467 fragmentation Methods 0.000 description 6
- 238000006062 fragmentation reaction Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 238000002991 immunohistochemical analysis Methods 0.000 description 6
- 239000007951 isotonicity adjuster Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 230000007659 motor function Effects 0.000 description 6
- 210000003463 organelle Anatomy 0.000 description 6
- 210000003594 spinal ganglia Anatomy 0.000 description 6
- 210000000273 spinal nerve root Anatomy 0.000 description 6
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 5
- 241000282693 Cercopithecidae Species 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 102000014944 Lysosome-Associated Membrane Glycoproteins Human genes 0.000 description 5
- 108010064171 Lysosome-Associated Membrane Glycoproteins Proteins 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 5
- 210000001130 astrocyte Anatomy 0.000 description 5
- 159000000007 calcium salts Chemical class 0.000 description 5
- 210000000877 corpus callosum Anatomy 0.000 description 5
- 230000001054 cortical effect Effects 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 238000002651 drug therapy Methods 0.000 description 5
- 108020001507 fusion proteins Proteins 0.000 description 5
- 102000037865 fusion proteins Human genes 0.000 description 5
- 210000001320 hippocampus Anatomy 0.000 description 5
- 210000003016 hypothalamus Anatomy 0.000 description 5
- 229940124589 immunosuppressive drug Drugs 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000000644 isotonic solution Substances 0.000 description 5
- 239000012669 liquid formulation Substances 0.000 description 5
- 210000000274 microglia Anatomy 0.000 description 5
- 230000017074 necrotic cell death Effects 0.000 description 5
- 210000000653 nervous system Anatomy 0.000 description 5
- 229920001542 oligosaccharide Polymers 0.000 description 5
- 150000002482 oligosaccharides Chemical class 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- 210000000449 purkinje cell Anatomy 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 230000002459 sustained effect Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 230000002861 ventricular Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 102100022548 Beta-hexosaminidase subunit alpha Human genes 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 229920002683 Glycosaminoglycan Polymers 0.000 description 4
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102000038460 IGF Type 2 Receptor Human genes 0.000 description 4
- 108010031792 IGF Type 2 Receptor Proteins 0.000 description 4
- 102100035133 Lysosome-associated membrane glycoprotein 1 Human genes 0.000 description 4
- 101710116782 Lysosome-associated membrane glycoprotein 1 Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000008335 axon cargo transport Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 210000000038 chest Anatomy 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 230000003118 histopathologic effect Effects 0.000 description 4
- 229960003444 immunosuppressant agent Drugs 0.000 description 4
- 210000003292 kidney cell Anatomy 0.000 description 4
- 210000001865 kupffer cell Anatomy 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 210000001718 meningeal macrophage Anatomy 0.000 description 4
- 208000005340 mucopolysaccharidosis III Diseases 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 210000004940 nucleus Anatomy 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- 210000000578 peripheral nerve Anatomy 0.000 description 4
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000004417 polycarbonate Substances 0.000 description 4
- 229920000515 polycarbonate Polymers 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000004952 protein activity Effects 0.000 description 4
- 210000002637 putamen Anatomy 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 230000002477 vacuolizing effect Effects 0.000 description 4
- 210000001835 viscera Anatomy 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 208000028698 Cognitive impairment Diseases 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000001905 GM2 Gangliosidoses Diseases 0.000 description 3
- 201000008905 GM2 gangliosidosis Diseases 0.000 description 3
- 101001045440 Homo sapiens Beta-hexosaminidase subunit alpha Proteins 0.000 description 3
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 206010072927 Mucolipidosis type I Diseases 0.000 description 3
- 208000035032 Multiple sulfatase deficiency Diseases 0.000 description 3
- 208000012902 Nervous system disease Diseases 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000013011 aqueous formulation Substances 0.000 description 3
- 210000003050 axon Anatomy 0.000 description 3
- 239000008228 bacteriostatic water for injection Substances 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 210000004958 brain cell Anatomy 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 210000001159 caudate nucleus Anatomy 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 230000003750 conditioning effect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 239000012470 diluted sample Substances 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 239000013022 formulation composition Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000003306 harvesting Methods 0.000 description 3
- 230000008642 heat stress Effects 0.000 description 3
- 230000000971 hippocampal effect Effects 0.000 description 3
- 229940050526 hydroxyethylstarch Drugs 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000006058 immune tolerance Effects 0.000 description 3
- 238000011532 immunohistochemical staining Methods 0.000 description 3
- 230000006057 immunotolerant effect Effects 0.000 description 3
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000011813 knockout mouse model Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000009593 lumbar puncture Methods 0.000 description 3
- 239000012931 lyophilized formulation Substances 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000004660 morphological change Effects 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 210000003007 myelin sheath Anatomy 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 210000000956 olfactory bulb Anatomy 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 210000003067 perivascular macrophage Anatomy 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 238000012636 positron electron tomography Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 230000002123 temporal effect Effects 0.000 description 3
- 238000010257 thawing Methods 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 231100000027 toxicology Toxicity 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 210000000427 trigeminal ganglion Anatomy 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- JSPNNZKWADNWHI-PNANGNLXSA-N (2r)-2-hydroxy-n-[(2s,3r,4e,8e)-3-hydroxy-9-methyl-1-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoctadeca-4,8-dien-2-yl]heptadecanamide Chemical compound CCCCCCCCCCCCCCC[C@@H](O)C(=O)N[C@H]([C@H](O)\C=C\CC\C=C(/C)CCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JSPNNZKWADNWHI-PNANGNLXSA-N 0.000 description 2
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical class O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 2
- 102100027165 Alpha-2-macroglobulin receptor-associated protein Human genes 0.000 description 2
- 101710126837 Alpha-2-macroglobulin receptor-associated protein Proteins 0.000 description 2
- 208000031277 Amaurotic familial idiocy Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010003497 Asphyxia Diseases 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102100037364 Craniofacial development protein 1 Human genes 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- 206010012559 Developmental delay Diseases 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 2
- 101710190709 Eukaryotic translation initiation factor 4 gamma 2 Proteins 0.000 description 2
- 208000015872 Gaucher disease Diseases 0.000 description 2
- 208000010055 Globoid Cell Leukodystrophy Diseases 0.000 description 2
- 208000032007 Glycogen storage disease due to acid maltase deficiency Diseases 0.000 description 2
- 206010053185 Glycogen storage disease type II Diseases 0.000 description 2
- 208000028782 Hereditary disease Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 208000026350 Inborn Genetic disease Diseases 0.000 description 2
- 206010022773 Intracranial pressure increased Diseases 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 208000028226 Krabbe disease Diseases 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010072928 Mucolipidosis type II Diseases 0.000 description 2
- 206010028095 Mucopolysaccharidosis IV Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- 208000002537 Neuronal Ceroid-Lipofuscinoses Diseases 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 208000025820 Sanfilippo syndrome type B Diseases 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 101710132062 Transitional endoplasmic reticulum ATPase Proteins 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000033289 adaptive immune response Effects 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 238000004873 anchoring Methods 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 210000004227 basal ganglia Anatomy 0.000 description 2
- 238000002869 basic local alignment search tool Methods 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- AFYNADDZULBEJA-UHFFFAOYSA-N bicinchoninic acid Chemical compound C1=CC=CC2=NC(C=3C=C(C4=CC=CC=C4N=3)C(=O)O)=CC(C(O)=O)=C21 AFYNADDZULBEJA-UHFFFAOYSA-N 0.000 description 2
- 238000003766 bioinformatics method Methods 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000004161 brilliant blue FCF Substances 0.000 description 2
- 235000012745 brilliant blue FCF Nutrition 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 238000005251 capillar electrophoresis Methods 0.000 description 2
- 238000005277 cation exchange chromatography Methods 0.000 description 2
- 229930183167 cerebroside Natural products 0.000 description 2
- RIZIAUKTHDLMQX-UHFFFAOYSA-N cerebroside D Natural products CCCCCCCCCCCCCCCCC(O)C(=O)NC(C(O)C=CCCC=C(C)CCCCCCCCC)COC1OC(CO)C(O)C(O)C1O RIZIAUKTHDLMQX-UHFFFAOYSA-N 0.000 description 2
- CRQQGFGUEAVUIL-UHFFFAOYSA-N chlorothalonil Chemical compound ClC1=C(Cl)C(C#N)=C(Cl)C(C#N)=C1Cl CRQQGFGUEAVUIL-UHFFFAOYSA-N 0.000 description 2
- 230000008045 co-localization Effects 0.000 description 2
- 230000003930 cognitive ability Effects 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000009260 cross reactivity Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000002716 delivery method Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000011026 diafiltration Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 230000002327 eosinophilic effect Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 210000000609 ganglia Anatomy 0.000 description 2
- 208000016361 genetic disease Diseases 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 238000003205 genotyping method Methods 0.000 description 2
- 230000009688 glial response Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 201000004502 glycogen storage disease II Diseases 0.000 description 2
- 201000008977 glycoproteinosis Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000004326 gyrus cinguli Anatomy 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 230000003862 health status Effects 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 208000003906 hydrocephalus Diseases 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000000819 hypertonic solution Substances 0.000 description 2
- 229940021223 hypertonic solution Drugs 0.000 description 2
- 230000002055 immunohistochemical effect Effects 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
- 208000017476 juvenile neuronal ceroid lipofuscinosis Diseases 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 210000003715 limbic system Anatomy 0.000 description 2
- 238000012792 lyophilization process Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 230000007388 microgliosis Effects 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 238000007491 morphometric analysis Methods 0.000 description 2
- 201000002273 mucopolysaccharidosis II Diseases 0.000 description 2
- 208000022018 mucopolysaccharidosis type 2 Diseases 0.000 description 2
- 208000011045 mucopolysaccharidosis type 3 Diseases 0.000 description 2
- 208000010978 mucopolysaccharidosis type 4 Diseases 0.000 description 2
- 208000012227 mucopolysaccharidosis type IIIB Diseases 0.000 description 2
- 238000000569 multi-angle light scattering Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 210000000478 neocortex Anatomy 0.000 description 2
- 210000005044 neurofilament Anatomy 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 201000007607 neuronal ceroid lipofuscinosis 3 Diseases 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000004279 orbit Anatomy 0.000 description 2
- 229910052762 osmium Inorganic materials 0.000 description 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 2
- 239000006174 pH buffer Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000001936 parietal effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 238000011020 pilot scale process Methods 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000004845 protein aggregation Effects 0.000 description 2
- 239000012460 protein solution Substances 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 210000003625 skull Anatomy 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- FYKDNWHPKQOZOT-UHFFFAOYSA-M sodium;dihydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].OP(O)([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FYKDNWHPKQOZOT-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 210000003523 substantia nigra Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 210000003934 vacuole Anatomy 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- 125000003287 1H-imidazol-4-ylmethyl group Chemical group [H]N1C([H])=NC(C([H])([H])[*])=C1[H] 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- KKMIHKCGXQMFEU-UHFFFAOYSA-N 2-[dimethyl(tetradecyl)azaniumyl]acetate Chemical group CCCCCCCCCCCCCC[N+](C)(C)CC([O-])=O KKMIHKCGXQMFEU-UHFFFAOYSA-N 0.000 description 1
- DIHXSRXTECMMJY-MURFETPASA-N 2-[dimethyl-[(9z,12z)-octadeca-9,12-dienyl]azaniumyl]acetate Chemical group CCCCC\C=C/C\C=C/CCCCCCCC[N+](C)(C)CC([O-])=O DIHXSRXTECMMJY-MURFETPASA-N 0.000 description 1
- LMVGXBRDRZOPHA-UHFFFAOYSA-N 2-[dimethyl-[3-(16-methylheptadecanoylamino)propyl]azaniumyl]acetate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=O LMVGXBRDRZOPHA-UHFFFAOYSA-N 0.000 description 1
- TYIOVYZMKITKRO-UHFFFAOYSA-N 2-[hexadecyl(dimethyl)azaniumyl]acetate Chemical compound CCCCCCCCCCCCCCCC[N+](C)(C)CC([O-])=O TYIOVYZMKITKRO-UHFFFAOYSA-N 0.000 description 1
- SNQVCAOGQHOSEN-UHFFFAOYSA-N 2-[methyl(octadecyl)amino]acetic acid Chemical compound CCCCCCCCCCCCCCCCCCN(C)CC(O)=O SNQVCAOGQHOSEN-UHFFFAOYSA-N 0.000 description 1
- FZLJPEPAYPUMMR-RTRLPJTCSA-N 2-acetamido-2-deoxy-D-glucopyranose 1-phosphate Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1OP(O)(O)=O FZLJPEPAYPUMMR-RTRLPJTCSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- YRNWIFYIFSBPAU-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=CC=C(N(C)C)C=C1 YRNWIFYIFSBPAU-UHFFFAOYSA-N 0.000 description 1
- GGZZISOUXJHYOY-UHFFFAOYSA-N 8-amino-4-hydroxynaphthalene-2-sulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C2C(N)=CC=CC2=C1O GGZZISOUXJHYOY-UHFFFAOYSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102100035028 Alpha-L-iduronidase Human genes 0.000 description 1
- 208000029602 Alpha-N-acetylgalactosaminidase deficiency Diseases 0.000 description 1
- 102100034561 Alpha-N-acetylglucosaminidase Human genes 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- 101150007653 Arsa gene Proteins 0.000 description 1
- 206010068220 Aspartylglucosaminuria Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000019300 CLIPPERS Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 206010010582 Congenital osteodystrophy Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 206010011777 Cystinosis Diseases 0.000 description 1
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 1
- 206010011906 Death Diseases 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 208000007652 Dysostoses Diseases 0.000 description 1
- 201000001324 Dysostosis Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283070 Equus zebra Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000024720 Fabry Disease Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- 201000008892 GM1 Gangliosidosis Diseases 0.000 description 1
- 208000017462 Galactosialidosis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101001019502 Homo sapiens Alpha-L-iduronidase Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108700037017 Hyaluronidase Deficiency Proteins 0.000 description 1
- 208000005503 Hyaluronidase deficiency Diseases 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102100029199 Iduronate 2-sulfatase Human genes 0.000 description 1
- 101710096421 Iduronate 2-sulfatase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000761557 Lamina Species 0.000 description 1
- 102100033448 Lysosomal alpha-glucosidase Human genes 0.000 description 1
- 208000033868 Lysosomal disease Diseases 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 208000007650 Meningeal Carcinomatosis Diseases 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 206010051696 Metastases to meninges Diseases 0.000 description 1
- 206010061296 Motor dysfunction Diseases 0.000 description 1
- 206010072929 Mucolipidosis type III Diseases 0.000 description 1
- 206010056886 Mucopolysaccharidosis I Diseases 0.000 description 1
- 206010056893 Mucopolysaccharidosis VII Diseases 0.000 description 1
- 208000028781 Mucopolysaccharidosis type 1 Diseases 0.000 description 1
- 208000025797 Mucopolysaccharidosis type 4A Diseases 0.000 description 1
- 208000025923 Mucopolysaccharidosis type 4B Diseases 0.000 description 1
- 208000025915 Mucopolysaccharidosis type 6 Diseases 0.000 description 1
- 208000000149 Multiple Sulfatase Deficiency Disease Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101000822667 Mus musculus Something about silencing protein 10 Proteins 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- WJXSXWBOZMVFPJ-NENRSDFPSA-N N-[(2R,3R,4R,5S,6R)-4,5-dihydroxy-6-methoxy-2,4-dimethyloxan-3-yl]-N-methylacetamide Chemical compound CO[C@@H]1O[C@H](C)[C@@H](N(C)C(C)=O)[C@@](C)(O)[C@@H]1O WJXSXWBOZMVFPJ-NENRSDFPSA-N 0.000 description 1
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 1
- 102100031688 N-acetylgalactosamine-6-sulfatase Human genes 0.000 description 1
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 1
- 102100027661 N-sulphoglucosamine sulphohydrolase Human genes 0.000 description 1
- 102000008763 Neurofilament Proteins Human genes 0.000 description 1
- 108010088373 Neurofilament Proteins Proteins 0.000 description 1
- 208000014060 Niemann-Pick disease Diseases 0.000 description 1
- 201000000788 Niemann-Pick disease type C1 Diseases 0.000 description 1
- 201000000785 Niemann-Pick disease type C2 Diseases 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 102100026456 POU domain, class 3, transcription factor 3 Human genes 0.000 description 1
- 101710133393 POU domain, class 3, transcription factor 3 Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000013608 Salla disease Diseases 0.000 description 1
- 208000021811 Sandhoff disease Diseases 0.000 description 1
- 208000025816 Sanfilippo syndrome type A Diseases 0.000 description 1
- 208000025802 Sanfilippo syndrome type C Diseases 0.000 description 1
- 208000025804 Sanfilippo syndrome type D Diseases 0.000 description 1
- 208000000828 Sialic Acid Storage Disease Diseases 0.000 description 1
- 208000017460 Sialidosis type 2 Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 208000022292 Tay-Sachs disease Diseases 0.000 description 1
- 241000718541 Tetragastris balsamifera Species 0.000 description 1
- 108700001567 Type I Schindler Disease Proteins 0.000 description 1
- LFTYTUAZOPRMMI-CFRASDGPSA-N UDP-N-acetyl-alpha-D-glucosamine Chemical compound O1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](NC(=O)C)[C@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-CFRASDGPSA-N 0.000 description 1
- LFTYTUAZOPRMMI-UHFFFAOYSA-N UNPD164450 Natural products O1C(CO)C(O)C(O)C(NC(=O)C)C1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 244000000188 Vaccinium ovalifolium Species 0.000 description 1
- 208000026589 Wolman disease Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- KDXHLJMVLXJXCW-UHFFFAOYSA-J alcian blue stain Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cu+2].[N-]1C(N=C2C3=CC(CSC(N(C)C)=[N+](C)C)=CC=C3C(N=C3C4=CC=C(CSC(N(C)C)=[N+](C)C)C=C4C(=N4)[N-]3)=N2)=C(C=C(CSC(N(C)C)=[N+](C)C)C=C2)C2=C1N=C1C2=CC(CSC(N(C)C)=[N+](C)C)=CC=C2C4=N1 KDXHLJMVLXJXCW-UHFFFAOYSA-J 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 108010009380 alpha-N-acetyl-D-glucosaminidase Proteins 0.000 description 1
- 201000008333 alpha-mannosidosis Diseases 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000576 arachnoid Anatomy 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 201000003554 argininosuccinic aciduria Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000013584 assay control Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 201000006486 beta-mannosidosis Diseases 0.000 description 1
- 229940064804 betadine Drugs 0.000 description 1
- 238000003236 bicinchoninic acid assay Methods 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 239000001055 blue pigment Substances 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003591 cerebellar nuclei Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000024042 cholesterol ester storage disease Diseases 0.000 description 1
- 208000013760 cholesteryl ester storage disease Diseases 0.000 description 1
- 210000002987 choroid plexus Anatomy 0.000 description 1
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013479 data entry Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940012882 elaprase Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000005670 electromagnetic radiation Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 210000004055 fourth ventricle Anatomy 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 239000012520 frozen sample Substances 0.000 description 1
- 201000008049 fucosidosis Diseases 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 108010089932 heparan sulfate sulfatase Proteins 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 230000036732 histological change Effects 0.000 description 1
- 102000044162 human IGF1 Human genes 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 108010072166 idursulfase Proteins 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 208000015978 inherited metabolic disease Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 201000009941 intracranial hypertension Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 210000003140 lateral ventricle Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000002535 lyotropic effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 108010045758 lysosomal proteins Proteins 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 210000001767 medulla oblongata Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 1
- 239000002052 molecular layer Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000007769 mucolipidosis Diseases 0.000 description 1
- 208000020460 mucolipidosis II alpha/beta Diseases 0.000 description 1
- 208000000690 mucopolysaccharidosis VI Diseases 0.000 description 1
- 208000036709 mucopolysaccharidosis type 3B Diseases 0.000 description 1
- 208000036707 mucopolysaccharidosis type 3C Diseases 0.000 description 1
- 208000036725 mucopolysaccharidosis type 3D Diseases 0.000 description 1
- 208000025919 mucopolysaccharidosis type 7 Diseases 0.000 description 1
- 208000020004 mucopolysaccharidosis type 9 Diseases 0.000 description 1
- 208000012226 mucopolysaccharidosis type IIIA Diseases 0.000 description 1
- 208000012224 mucopolysaccharidosis type IIIC Diseases 0.000 description 1
- 208000027333 mucopolysaccharidosis type IIID Diseases 0.000 description 1
- 208000012091 mucopolysaccharidosis type IVB Diseases 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 238000004848 nephelometry Methods 0.000 description 1
- 210000001682 neurofibril Anatomy 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 1
- 210000000869 occipital lobe Anatomy 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 210000001026 paleocortex Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000005426 pharmaceutical component Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108020001775 protein parts Proteins 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000463 red nucleus Anatomy 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000001202 rhombencephalon Anatomy 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 210000001991 scapula Anatomy 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000013458 shaking study Methods 0.000 description 1
- 208000011985 sialidosis Diseases 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- HSFQBFMEWSTNOW-UHFFFAOYSA-N sodium;carbanide Chemical group [CH3-].[Na+] HSFQBFMEWSTNOW-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 238000004781 supercooling Methods 0.000 description 1
- 210000003863 superior colliculi Anatomy 0.000 description 1
- 210000001590 sural nerve Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229940104261 taurate Drugs 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 210000000211 third ventricle Anatomy 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 210000002972 tibial nerve Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000607 toxicokinetics Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229950004616 tribromoethanol Drugs 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000004785 virchow-robin space Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/761—Adenovirus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/65—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
- C12N9/2405—Glucanases
- C12N9/2434—Glucanases acting on beta-1,4-glucosidic bonds
- C12N9/2437—Cellulases (3.2.1.4; 3.2.1.74; 3.2.1.91; 3.2.1.150)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/06—Sulfuric ester hydrolases (3.1.6)
- C12Y301/06008—Cerebroside-sulfatase (3.1.6.8)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/06—Sulfuric ester hydrolases (3.1.6)
- C12Y301/06013—Iduronate-2-sulfatase (3.1.6.13)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01045—Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01046—Galactosylceramidase (3.2.1.46)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/0105—Alpha-N-acetylglucosaminidase (3.2.1.50)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y310/00—Hydrolases acting on sulfur-nitrogen bonds (3.10)
- C12Y310/01—Hydrolases acting on sulfur-nitrogen bonds (3.10) acting on sulfur-nitrogen bonds (3.10.1)
- C12Y310/01001—N-Sulfoglucosamine sulfohydrolase (3.10.1.1)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Hematology (AREA)
- Mycology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychology (AREA)
- Obesity (AREA)
- Biotechnology (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
Description
本願は、米国特許仮出願第61/358,857号(2010年6月25日出願);第61/360,786(2010年7月1日出願);第61/387,862号(2010年9月29日出願);第61/435,710号(2011年1月24日出願);第61/442,115号(2011年2月11日出願);第61/476,210号(2011年4月15日出願);および第61/495,268号(2011年6月9日出願)に対する優先権を主張し、これらの記載内容は各々、参照により本明細書に援用される。
実際、脳の表面での拡散に対するバリア、ならびに有効且つ便利な送達方法の欠如は、任意の疾患に関する脳における適切な治療効果を達成するには大きすぎる障害物である、と多くの人々が考えていた。
(項目1)
髄腔内投与用の安定な製剤であって、アリールスルファターゼA(ASA)タンパク質と、塩と、ポリソルベート界面活性剤とを含む安定な製剤。
(項目2)
前記ASAタンパク質が約0〜100mg/mLの範囲の濃度で存在する、項目1に記載の安定な製剤。
(項目3)
前記ASAタンパク質が、10mg/mL、30mg/mL、50mg/mL、または100mg/mLから選択した濃度で存する、項目1または2に記載の安定な製剤。
(項目4)
前記ASAタンパク質が配列番号1のアミノ酸配列を含む、項目1〜3のいずれか一項に記載の安定な製剤。
(項目5)
前記ASAタンパク質がヒト細胞株から生成される、項目1〜4のいずれか一項に記載の安定な製剤。
(項目6)
前記ASAタンパク質がCHO細胞から生成される、項目1〜4のいずれか一項に記載の安定な製剤。
(項目7)
前記塩がNaClである、項目1〜6のいずれか一項に記載の安定な製剤。
(項目8)
前記NaClが、約0〜300mMの範囲の濃度で存在する、項目7に記載の安定な製剤。
(項目9)
前記NaClが、約137〜154mMの範囲の濃度で存在する、項目7に記載の安定な製剤。
(項目10)
前記NaClが、約154mMの濃度で存在する、項目9に記載の安定な製剤。
(項目11)
前記ポリソルベート界面活性剤が、ポリソルベート20、ポリソルベート40、ポリソルベート60、ポリソルベート80、およびこれらの組み合わせからなる群から選択される、項目1〜10のいずれか一項に記載の安定な製剤。
(項目12)
前記ポリソルベート界面活性剤がポリソルベート20である、項目11に記載の安定な製剤。
(項目13)
前記ポリソルベート20が、約0〜0.2%の範囲の濃度で存在する、項目12に記載の安定な製剤。
(項目14)
ポリソルベート20が、約0.005%の濃度で存在する、項目13に記載の安定な製剤。
(項目15)
緩衝剤をさらに含む、項目14に記載の安定な製剤。
(項目16)
前記緩衝剤が、リン酸塩、酢酸塩、ヒスチジン、コハク酸塩、クエン酸塩、トリス、およびこれらの組み合わせからなる群から選択される、項目15に記載の安定な製剤。
(項目17)
前記緩衝剤がリン酸塩である、項目1〜16のいずれか一項に記載の安定な製剤。
(項目18)
前記リン酸塩が50mM以下の濃度で存在する、項目17に記載の安定な製剤。
(項目19)
前記リン酸塩が20mM以下の濃度で存在する、項目17に記載の安定な製剤。
(項目20)
pHが約3〜8.0である、項目1〜19のいずれか一項に記載の安定な製剤。
(項目21)
pHが約6.0〜6.5である、項目20に記載の安定な製剤。
(項目22)
pHが約6.0である、項目21に記載の安定な製剤。
(項目23)
液状製剤である、項目1〜22のいずれか一項に記載の安定な製剤。
(項目24)
凍結乾燥粉末として調合される、項目1〜15のいずれか一項に記載の安定な製剤。
(項目25)
安定化剤をさらに含む、項目17に記載の安定な製剤。
(項目26)
前記安定化剤が、ショ糖、グルコース、マンニトール、ソルビトール、PEG4000、ヒスチジン、アルギニン、リジン、リン脂質、およびこれらの組み合わせからなる群から選択される、項目25に記載の安定な製剤。
(項目27)
髄腔内投与用の安定な製剤であって、アリールスルファターゼA(ASA)タンパク質と、塩と、緩衝剤とを含む安定な製剤。
(項目28)
前記ASAタンパク質が、約0〜100mg/mLの範囲の濃度である、項目27に記載の安定な製剤。
(項目29)
前記緩衝剤が、リン酸塩、酢酸塩、ヒスチジン、コハク酸塩、クエン酸塩、トリス、およびこれらの組み合わせからなる群から選択される、項目27または28に記載の安定な製剤。
(項目30)
前記緩衝剤がリン酸塩である、項目29に記載の安定な製剤。
(項目31)
前記リン酸塩が、約20mM以下の濃度である、項目30に記載の安定な製剤。
(項目32)
前記リン酸塩が、約50mM以下の濃度である、項目31に記載の安定な製剤。
(項目33)
ポリソルベート界面活性剤をさらに含む、項目27〜31のいずれか一項に記載の安定な製剤。
(項目34)
前記ポリソルベート界面活性剤が、ポリソルベート20、ポリソルベート40、ポリソルベート60、ポリソルベート80、およびこれらの組み合わせからなる群から選択される、項目33に記載の安定な製剤。
(項目35)
前記ポリソルベート界面活性剤が約0〜0.2%の範囲の濃度で存在する、項目33または34に記載の安定な製剤。
(項目36)
pHが約6.0〜6.5である、項目27〜35のいずれか一項に記載の安定な製剤。
(項目37)
項目1〜36のいずれか一項に記載の安定な製剤の単一剤形を含む容器。
(項目38)
アンプル、バイアル、カートリッジ、レザバー、Lyo−ject、または前充填した注射器から選択される、項目37に記載の容器。
(項目39)
前充填した注射器である、項目37または38のいずれか一項に記載の容器。
(項目40)
前記前充填した注射器が、シリコーンの焼付コーティングを有するホウケイ酸ガラス注射器、スプレーしたシリコーンを有するホウケイ酸ガラス注射器、または、シリコーンを含まないプラスチック樹脂注射器から選択される、項目39に記載の容器。
(項目41)
前記安定な製剤が約50.0mL未満の体積で存在する、項目37〜40のいずれか一項に記載の容器。
(項目42)
前記安定な製剤が約5.0mL未満の体積で存在する、項目37〜40のいずれか一項に記載の容器。
(項目43)
異染性白質ジストロフィー(MLD)症の治療方法であって、
治療の必要な対象に、項目1〜29のいずれか一項に記載の製剤を髄腔内投与するステップ
を含む方法。
(項目44)
前記製剤の髄腔内投与によって、前記対象において実質的な副作用が生じない、項目43に記載の方法。
(項目45)
前記製剤の髄腔内投与によって、前記対象において、実質的なT細胞媒介性適応免疫反応が生じない、項目44に記載の方法。
(項目46)
前記製剤の髄腔内投与によって、ASAタンパク質を深部の脳白質の乏突起グリア細胞に送達する、項目43〜45のいずれか一項に記載の方法。
(項目47)
前記ASAタンパク質をニューロン、グリア細胞、血管周囲細胞、および/または髄膜細胞に送達する、項目43〜46のいずれか一項に記載の方法。
(項目48)
前記ASAタンパク質をさらに脊髄のニューロンに送達する、項目43〜47のいずれか一項に記載の方法。
(項目49)
前記製剤の髄腔内投与によってさらに、末梢標的組織中の前記ASAタンパク質を全身送達する、項目43〜48のいずれか一項に記載の方法。
(項目50)
前記末梢標的組織が、肝臓、腎臓、および/または心臓から選択される、項目49に記載の方法。
(項目51)
前記製剤の髄腔内投与によって、脳標的組織、脊髄ニューロン、および/または末梢標的組織におけるリソソーム局在化が生じる、項目43〜50のいずれか一項に記載の方法。
(項目52)
前記製剤の髄腔内投与によって、脳標的組織、脊髄ニューロン、および/または末梢標的組織におけるスルファチド蓄積量が減少する、項目43〜51のいずれか一項に記載の方法。
(項目53)
前記スルファチド蓄積量が対照と比較して少なくとも20%、40%、50%、60%、80%、90%、1倍、1.5倍、または2倍減少する、項目52に記載の方法。
(項目54)
前記製剤の髄腔内投与によって、CNSおよびPNS内での進行性脱髄および軸索消失が低減される、項目43〜53のいずれか一項に記載の方法。
(項目55)
前記製剤の髄腔内投与によって、脳標的組織、脊髄ニューロン、および/または末梢標的組織におけるASAの酵素活性が増大する、項目43〜54のいずれか一項に記載の方法。
(項目56)
前記ASAの酵素活性が対照と比較して少なくとも1倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、または10倍増大する、項目56に記載の方法。
(項目57)
前記増大したASAの酵素活性が少なくとも約10nmol/時・mg、20nmol/時・mg、40nmol/時・mg、50nmol/時・mg、60nmol/時・mg、70nmol/時・mg、80nmol/時・mg、90nmol/時・mg、100nmol/時・mg、150nmol/時・mg、200nmol/時・mg、250nmol/時・mg、300nmol/時・mg、350nmol/時・mg、400nmol/時・mg、450nmol/時・mg、500nmol/時・mg、550nmol/時・mg、または600nmol/時・mgである、項目55または56に記載の方法。
(項目58)
前記ASAの酵素活性が腰部領域で増大する、項目55に記載の方法。
(項目59)
前記腰部領域で増大したASAの酵素活性が少なくとも約2000nmol/時・mg、3000nmol/時・mg、4000nmol/時・mg、5000nmol/時・mg、6000nmol/時・mg、7000nmol/時・mg、8000nmol/時・mg、9000nmol/時・mg、または10,000nmol/時・mgである、項目58に記載の方法。
(項目60)
前記製剤の髄腔内投与によって、MLD症の少なくとも1つの症状または特徴の強度、重症度、もしくは頻度が低減されるか、またはMLDの少なくとも1つの症状または特徴が遅発する、項目43〜59のいずれか一項に記載の方法。
(項目61)
MLD症の前記少なくとも1つの症状または特徴が、頭蓋内圧増大、真空水頭症、中枢および末梢神経系と内臓器官とにおけるミエリン鞘中の硫酸化糖脂質蓄積、CNSおよびPNS内の進行性脱髄および軸索損失、ならびに/または運動および認知機能障害である、項目60に記載の方法。
(項目62)
前記髄腔内投与を2週間に1回実施する、項目43〜61のいずれか一項に記載の方法。
(項目63)
前記髄腔内投与を1ヶ月に1回実施する、項目43〜61のいずれか一項に記載の方法。
(項目64)
前記髄腔内投与を2ヶ月に1回実施する、項目43〜61のいずれか一項に記載の方法。
(項目65)
前記髄腔内投与を静脈内投与と併用する、項目43〜64のいずれか一項に記載の方法。
(項目66)
前記静脈内投与が1ヶ月に1回以下の頻度である、項目65に記載の方法。
(項目67)
前記静脈内投与が2ヶ月に1回以下の頻度である、項目65に記載の方法。
(項目68)
前記髄腔内投与を静脈内投与の非存在下で用いる、項目43〜64のいずれか一項に記載の方法。
(項目69)
前記髄腔内投与を併用免疫抑制療法の非存在下で用いる、項目43〜68のいずれか一項に記載の方法。
本発明は、中枢神経系(CNS)への治療薬の直接送達のための有効且つ低侵襲性のアプローチを提供する。本発明は、一部は、酵素が種々の表面を横断して有効に且つ広範に拡散して、深部脳領域を含めて脳を横断する種々の領域に浸透するよう、リソソーム蓄積症(例えばMLD)のための補充酵素(例えばアリールスルファターゼA(ASA))が高濃度(例えば、約3mg/mg以上、4mg/ml、5mg/ml、10mg/ml以上)での治療を必要とする対象の脳脊髄液(CSF)中に直接的に導入され得る、という予期せぬ発見に基づいている。さらに意外なことに、単なる生理食塩水または緩衝液ベースの製剤を用いて、そして対象において実質的副作用、例えば重篤な免疫応答を誘導することなく、このような高タンパク質濃度送達を実施することができることを本発明人等は実証した。したがって、本発明は、CNS構成成分を有する種々の疾患および障害、特にリソソーム蓄積症の治療のための直接CNS送達のための非常に効率的な、臨床的に望ましい、且つ患者に優しいアプローチを提供する。本発明は、CNSターゲッティングおよび酵素補充療法の分野における有意の進歩を示す。
本発明をより容易に理解するために、一定の用語を先ず以下で定義する。以下の用語および他の用語に関する付加的な定義は、本明細書全体を通して記述されている。
治療用タンパク質
その他のリソソーム蓄積症および補充酵素
BALB/cマウス骨髄腫株(NSO/l、ECACC番号:85110503);ヒト網膜芽細胞(PER.C6、CruCell,Leiden,The Netherlands);SV40により形質転換されたサル腎臓CV1株(COS−7、ATCC CRL 1651);ヒト胚性腎臓株(293または293細胞(懸濁液培養中での増殖のためにサブクローン化)、Graham et al.,J.Gen Virol.,36:59,1977);ヒト繊維肉腫細胞株(例えば、HT1080);ハムスター幼仔腎細胞(BHK、ATCC CCL 10);チャイニーズハムスター卵巣細胞+/−DHFR(CHO、Urlaub and Chasin,Proc.Natl.Acad.Sci.USA,77:4216,1980);マウスセルトリ細胞(TM4、Mather,Biol.Reprod.,23:243−251,1980);サル腎細胞(CV1 ATCC CCL 70);アフリカミドリザル腎細胞(VERO−76、ATCC CRL−1 587);ヒト子宮頚部癌細胞(HeLa、ATCC CCL 2);イヌ腎細胞(MDCK、ATCC CCL 34);バッファローラット肝細胞(BRL 3A、ATCC CRL 1442);ヒト肺細胞(W138、ATCC CCL 75);ヒト肝細胞(Hep G2、HB 8065);マウス乳癌(MMT 060562、ATCC CCL51);TRI細胞(Mather et al.,Annals N.Y.Acad.Sci.,383:44−68,1982);MRC 5細胞;FS4細胞;およびヒト肝細胞癌株(Hep G2)。
製剤
安定な製剤
等張度
安定化剤
充填剤
界面活性剤
凍結乾燥
再構成
CNS送達
髄腔内送達
髄腔内送達のための器具
標的組織への送達
脊髄
生体分布およびバイオアベイラビリティ
異染性白質ジストロフィー症(MLD)の治療
免疫寛容
投与
キット
他の髄腔内投与した組換え酵素がCNSの細胞および組織内に分布する能力を評価するために、幼若の(12か月齢未満)カニクイザルにおいて1か月の期間にわたりGLP試験を行って、組換えにより調製したヒトアリールスルファターゼA(rhASA)の反復髄腔内(IT)投与を毒性学および安全性薬理学の観点から評価した。pH6.0の154mM NaCl、0.005%ポリソルベート20の溶媒で、rhASAの製剤を調製し製剤化した。
実施例2:放射体標識タンパク質による生体内分布
実施例3:IT投与用アリールスルファターゼA製剤
プレフォーミュレーションスクリーニング調査−緩衝剤の種類およびpHの影響
pH記憶
賦形剤の選択
製剤のロバストネス調査−安定性調査
凍結融解調査
安定性調査
総合的に、プレフォーミュレーション、凍結融解、および攪拌調査の結果によって、3つの製剤のみが、さらなる開発に適していることが暗示されている。これらの3つの製剤で、0.005%のP20の存在下にて、長期安定性調査を開始した。表27、表28、および表29に、所定の時点における3つの製剤の安定性データの概要が示されている。
実施例4−毒性
・新皮質(前頭皮質、頭頂皮質、側頭皮質および後頭皮質を含む:脳切片1〜8(および存在すればスライス9)
・古皮質(嗅球および/または梨状葉):脳切片1〜3
・大脳基底核(尾状核および被殻を含む):脳切片3および4
・辺縁系(海馬および帯状回を含む):脳切片4および5
・視床/視床下部、および黒質を含めた中脳領域:脳切片4および5
・小脳、脳橋および延髄:脳切片6〜8(および存在すればスライス9)。
アリールスルファターゼA(rhASA)の染色
等級の説明(染色された可能性のある細胞の%)
1 10%未満
2 10〜25%
3 25〜50%
4 50〜75%
5 75%以上
終了時に殺処分した個体(6か月間のEOW投与):rhASA染色切片
・脳、血管周囲、マクロファージ(全用量群、雌雄)
・脳、グリア細胞(全用量群、雌雄)
・脊髄、髄膜、マクロファージ(全用量群、雌雄)
・脊髄、血管周囲、マクロファージ(全用量群、雌雄)
・脊髄、グリア細胞(中用量および高用量の雌雄)
・肝臓、Kupffer細胞(全用量群、雌雄)
回復後に殺処分した個体(6か月間のEOW投与後に、1か月間の無投与期間)
・脳、髄膜、浸潤(中用量および高用量群、雌雄)(図16および17)
・脳、髄膜、浸潤、好酸球の%(中用量の雄;高用量の雌)
・脳、血管周囲、浸潤(中用量の雄;高用量の雌)(図18)
・脳、血管周囲、浸潤、好酸球の%(中用量の雄;高用量の雌)
・脳、灰白質、浸潤(全用量群、雌雄)
・脳、灰白質、浸潤、好酸球の%(低用量の雄)
・脳、灰白質、好酸球、壊死(低用量の雄)
・脊髄、髄膜、浸潤(中用量および高用量の雄;低用量および高用量の雌)
・脊髄、髄膜、浸潤、好酸球の%(中用量の雄;低用量の雌)
・脊髄、灰白質、浸潤(低用量の雌)
・脊髄、灰白質、浸潤、好酸球の%(低用量の雌)
・後根神経節および神経根、神経上膜、浸潤(中用量の雌)
・脊髄神経根および神経節、浸潤、好酸球(中用量および高用量の雄;全用量の雌)
・三叉神経節、浸潤、好酸球(中用量の雌雄)
実施例5−薬物動態データ
6か月の個体のデータ
血清中およびCSF中濃度
実施例6−有効性
種 マウス(Mus musculus)
系統 hASAC69S/ASA(−/−)マウスおよび野生型対照
齢数 到着時で約14〜17か月齢
群数 6
個体数 ASAノックアウトマウス34匹+野生型対照11匹
到着後、健康状態を評価するために各個体を検査した。
飼育
マウスを、CareFresh紙床敷と給水ボトルとを備えた高温ポリカーボネート製のフィルタートップケージで集団飼育した。各ゲージを、計画、群番号および個体番号、ならびに雌雄を明記したケージカードでわかりやすく標識した。耳パンチ方式を用いて、各個体を1個体ずつ区別した。個体は、連邦のガイドラインに従って処置した。
個体の室内環境および光周期の目標条件は以下の通りであった:
温度 22℃±3℃
湿度 50%±20%
光周期 12時間の明期と12時間の暗期
被検試料
アイデンティティ rhASA
種類 ヒト組換えアリールスルファターゼA(rhASA)
保管条件 約4℃
溶媒
アイデンティティ rhASA溶媒(154mM NaCl、0.005%ポリソルベート20、pH約6.0)
保管条件 約4℃
溶媒の調製
投与製剤の調製
注射剤を追跡するための色素:
rhASAまたは溶媒の腰仙部IT注射
rhASAの静脈内注射
血清(全個体)
光学顕微鏡検査用の組織(群A〜F;1群当たりマウス5匹)
脂質解析用の組織(群A、BおよびF;それぞれ6、4および5個体)
実施例7−生体内分布2
概略
組織採取
脳、肝臓および脊髄抽出物の調製ならびにrhASA濃度の決定
実施例8:薬物動態および生体内分布試験
コホート1:5患者(最低用量)
コホート2:5患者(中間用量)
コホート3:5患者(最高用量)
無作為に5患者を無治療とする。
、または矛盾もしくは不一致が生じることが当業者に明らかでない限り、列挙されている1つ以上の請求項の1つ以上の制限、要素、条項、記述用語などが、基本請求項に従属する別の請求項に(または関連する他の任意の請求項として)組み込まれるすべての変更、組合せおよび置換を包含するということを理解するべきである。要素が列挙されている場合(例えば、マーカッシュ群またはこれと同様の形式において)、要素の各下位グループも開示され、任意の要素(1つまたは複数)がそのグループから除外され得ることを理解するべきである。一般に、本発明または本発明の態様が特定の要素、特徴などを含むという場合、本発明の特定の実施形態または本発明の特定の態様は、このような要素、特徴などからなる、またはこのような要素、特性などから本質的になるということを理解するべきである。簡潔にするために、これらの実施形態があらゆる場合に正確に本明細書に具体的に記載されているわけではない。本発明の任意の実施形態または態様が、本明細書において具体的に除外されることが記載されているか否かにかかわらず、請求項から明確に除外され得ることも理解するべきである。本発明の背景を説明するために、および本発明の実施に関するさらなる詳細を提供するために本明細書において参照される刊行物、ウェブサイトおよびその他の参考資料は、参照により本明細書に組み込まれる。
Claims (16)
- 異染性白質ジストロフィー(MLD)症の治療方法における使用のための安定な製剤であって、前記製剤は、対象に脳室内投与されることを特徴とし、前記安定な製剤は、アリールスルファターゼA(ASA)タンパク質と、緩衝剤とを含み、前記アリールスルファターゼA(ASA)タンパク質が、少なくとも5mg/mLの濃度で存在し、そして、前記緩衝剤が、リン酸塩であって、50mM以下の濃度で存在し、前記製剤が3〜8.0のpHを有することをさらに特徴とする、使用のための安定な製剤。
- 塩、および、ポリソルベート界面活性剤をさらに含む、請求項1に記載の使用のための安定な製剤。
- 前記ポリソルベート界面活性剤が、0〜0.2%の範囲の濃度で存在する、請求項2に記載の使用のための安定な製剤。
- 請求項1〜3のいずれか一項に記載の使用のための安定な製剤であって、
(i)前記製剤の脳室内投与によって、前記ASAタンパク質を深部の脳白質の乏突起グリア細胞に送達する、
(ii)前記ASAタンパク質をニューロン、グリア細胞、血管周囲細胞、および/または髄膜細胞に送達する、
(iii)前記ASAタンパク質をさらに脊髄のニューロンに送達する、
(iv)前記製剤の脳室内投与によってさらに、末梢標的組織中で前記ASAタンパク質を全身送達し、任意に、前記末梢標的組織が、肝臓、腎臓、および/または心臓から選択される、
(v)前記製剤の脳室内投与によって、脳標的組織、脊髄ニューロン、および/または末梢標的組織におけるリソソーム局在化が生じる、
(vi)前記製剤の脳室内投与によって、脳標的組織、脊髄ニューロン、および/または末梢標的組織におけるスルファチド蓄積量が減少し、任意に、前記スルファチド蓄積量が対照と比較して少なくとも20%、40%、50%、60%、80%、90%、1倍、1.5倍、または2倍減少する、そして/あるいは
(vii)前記製剤の脳室内投与によって、CNSおよびPNS内での進行性脱髄および軸索消失が低減される、
使用のための安定な製剤。 - 前記製剤の脳室内投与によって、脳標的組織、脊髄ニューロン、および/または末梢標的組織におけるASAの酵素活性が増大し、任意に:
(i)前記ASAの酵素活性が対照と比較して少なくとも1倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、または10倍増大する、そして/あるいは
(ii)前記増大したASAの酵素活性が少なくとも10nmol/時・mg、20nmol/時・mg、40nmol/時・mg、50nmol/時・mg、60nmol/時・mg、70nmol/時・mg、80nmol/時・mg、90nmol/時・mg、100nmol/時・mg、150nmol/時・mg、200nmol/時・mg、250nmol/時・mg、300nmol/時・mg、350nmol/時・mg、400nmol/時・mg、450nmol/時・mg、500nmol/時・mg、550nmol/時・mg、または600nmol/時・mgである、あるいは
(iii)前記ASAの酵素活性が腰部領域で増大し、任意に、前記腰部領域で増大したASAの酵素活性が少なくとも2000nmol/時・mg、3000nmol/時・mg、4000nmol/時・mg、5000nmol/時・mg、6000nmol/時・mg、7000nmol/時・mg、8000nmol/時・mg、9000nmol/時・mg、または10,000nmol/時・mgである、
請求項1〜4のいずれか一項に記載の使用のための安定な製剤。 - 請求項1〜5のいずれか一項に記載の使用のための安定な製剤であって、
(i)前記脳室内投与を静脈内投与と併用し、任意に、前記静脈内投与が1ヶ月に1回以下の頻度もしくは2ヶ月に1回以下の頻度である、または
(ii)前記脳室内投与を静脈内投与の非存在下で用いる、そして/または
(iii)前記脳室内投与を2週間に1回、1ヶ月に1回、もしくは2ヶ月に1回実施する、そして/または
(iv)前記脳室内投与を併用免疫抑制療法の非存在下で用いる、
使用のための安定な製剤。 - アリールスルファターゼA(ASA)タンパク質と、塩と、ポリソルベート界面活性剤および緩衝剤とを含む、脳室内投与用の安定な製剤であって、前記ASAタンパク質が、少なくとも5mg/mLの濃度で存在し、前記緩衝剤が、50mM以下の濃度のリン酸塩であり、そして、前記製剤が、異染性白質ジストロフィーの治療に使用される、安定な製剤。
- 前記ASAタンパク質が100mg/mlの濃度で、または100mg/mlまでの濃度で存在し、任意に、前記ASAタンパク質が、30mg/ml、50mg/ml、または100mg/mlから選択した濃度で存在する、請求項1〜7のいずれか一項に記載の安定な製剤または使用のための安定な製剤。
- 前記ASAタンパク質が配列番号1のアミノ酸配列を含む、請求項1〜8のいずれか一項に記載の安定な製剤または使用のための安定な製剤。
- 請求項1〜9のいずれか一項に記載の安定な製剤または使用のための安定な製剤であって、
(i)前記ASAタンパク質がヒト細胞株由来の組換えASAタンパク質であるか、または
(ii)前記ASAタンパク質がCHO細胞由来の組換えASAタンパク質である、
安定な製剤。 - 前記塩がNaClであり、任意に、前記NaClが、0〜300mMの範囲の濃度で、任意に、137〜154mMの範囲の濃度で、任意に、154mMの濃度で存在する、請求項2〜10のいずれか一項に記載の安定な製剤または使用のための安定な製剤。
- 前記ポリソルベート界面活性剤が、ポリソルベート20、ポリソルベート40、ポリソルベート60、ポリソルベート80、およびこれらの組み合わせからなる群から選択され、任意に、前記ポリソルベート界面活性剤がポリソルベート20であり、そして0〜0.2%の範囲の濃度で、任意に、0.005%の濃度で存在する、請求項2〜11のいずれか一項に記載の安定な製剤または使用のための安定な製剤。
- 前記製剤が、6.0〜6.5、または6.0のpHを有する、請求項1〜12のいずれか一項に記載の安定な製剤または使用のための安定な製剤。
- 前記製剤が、
(i)液状製剤である、または
(ii)凍結乾燥粉末として調合される、
請求項1〜13のいずれか一項に記載の安定な製剤または使用のための安定な製剤。 - 前記製剤が、ポリソルベート界面活性剤を含み、そして安定化剤をさらに含み、任意に、前記安定化剤が、ショ糖、グルコース、マンニトール、ソルビトール、PEG4000、ヒスチジン、アルギニン、リジン、リン脂質、およびこれらの組み合わせからなる群から選択される、請求項1〜14のいずれか一項に記載の安定な製剤または使用のための安定な製剤。
- 請求項7〜15のいずれか一項に記載の安定な製剤の単一剤形を含む容器であって、任意に:
(i)前記容器は、アンプル、バイアル、カートリッジ、レザバー、Lyo−ject、または前充填した注射器から選択され、任意に、前記容器は前充填した注射器であり、そして任意に、シリコーンの焼付コーティングを有するホウケイ酸ガラス注射器、スプレーしたシリコーンを有するホウケイ酸ガラス注射器、または、シリコーンを含まないプラスチック樹脂注射器から選択される、あるいは
(ii)前記安定な製剤が50.0mL未満の体積で存在する、任意に、前記安定な製剤が5.0mL未満の体積で存在する、
容器。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018226358A JP6898909B2 (ja) | 2010-06-25 | 2018-12-03 | アリールスルファターゼaのcns送達の方法および組成物 |
Applications Claiming Priority (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US35885710P | 2010-06-25 | 2010-06-25 | |
US61/358,857 | 2010-06-25 | ||
US36078610P | 2010-07-01 | 2010-07-01 | |
US61/360,786 | 2010-07-01 | ||
US38786210P | 2010-09-29 | 2010-09-29 | |
US61/387,862 | 2010-09-29 | ||
US201161435710P | 2011-01-24 | 2011-01-24 | |
US61/435,710 | 2011-01-24 | ||
US201161442115P | 2011-02-11 | 2011-02-11 | |
US61/442,115 | 2011-02-11 | ||
US201161476210P | 2011-04-15 | 2011-04-15 | |
US61/476,210 | 2011-04-15 | ||
US201161495268P | 2011-06-09 | 2011-06-09 | |
US61/495,268 | 2011-06-09 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015246952A Division JP6346162B2 (ja) | 2010-06-25 | 2015-12-18 | アリールスルファターゼaのcns送達の方法および組成物 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018226358A Division JP6898909B2 (ja) | 2010-06-25 | 2018-12-03 | アリールスルファターゼaのcns送達の方法および組成物 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018002735A JP2018002735A (ja) | 2018-01-11 |
JP2018002735A5 JP2018002735A5 (ja) | 2018-06-14 |
JP6522073B2 true JP6522073B2 (ja) | 2019-05-29 |
Family
ID=45352777
Family Applications (21)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015236539A Active JP6250616B2 (ja) | 2010-06-25 | 2015-12-03 | 治療薬のcns送達 |
JP2015246589A Pending JP2016094451A (ja) | 2010-06-25 | 2015-12-17 | サンフィリポ症候群b型の処置 |
JP2015246258A Withdrawn JP2016040335A (ja) | 2010-06-25 | 2015-12-17 | ヘパランn−スルファターゼのcns送達のための方法および組成物 |
JP2015246244A Active JP6285409B2 (ja) | 2010-06-25 | 2015-12-17 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2015246952A Active JP6346162B2 (ja) | 2010-06-25 | 2015-12-18 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2017177784A Active JP6466538B2 (ja) | 2010-06-25 | 2017-09-15 | 治療薬のcns送達 |
JP2017194508A Active JP6522073B2 (ja) | 2010-06-25 | 2017-10-04 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2017194348A Active JP6522072B2 (ja) | 2010-06-25 | 2017-10-04 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2018192589A Active JP6797876B2 (ja) | 2010-06-25 | 2018-10-11 | 治療薬のcns送達 |
JP2018226358A Active JP6898909B2 (ja) | 2010-06-25 | 2018-12-03 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2018227369A Active JP6938456B2 (ja) | 2010-06-25 | 2018-12-04 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2020000930A Withdrawn JP2020079244A (ja) | 2010-06-25 | 2020-01-07 | 治療薬のcns送達 |
JP2020023620A Pending JP2020079297A (ja) | 2010-06-25 | 2020-02-14 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2020024183A Pending JP2020079298A (ja) | 2010-06-25 | 2020-02-17 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2021115560A Active JP7448507B2 (ja) | 2010-06-25 | 2021-07-13 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2021115564A Active JP7087175B2 (ja) | 2010-06-25 | 2021-07-13 | 治療薬のcns送達 |
JP2021133184A Pending JP2021181489A (ja) | 2010-06-25 | 2021-08-18 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2021196898A Active JP7359827B2 (ja) | 2010-06-25 | 2021-12-03 | 治療薬のcns送達 |
JP2023014814A Pending JP2023052868A (ja) | 2010-06-25 | 2023-02-02 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2023024170A Pending JP2023062114A (ja) | 2010-06-25 | 2023-02-20 | イズロン酸-2-スルファターゼのcns送達のための方法および組成物 |
JP2023078673A Pending JP2023099216A (ja) | 2010-06-25 | 2023-05-11 | 治療薬のcns送達 |
Family Applications Before (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015236539A Active JP6250616B2 (ja) | 2010-06-25 | 2015-12-03 | 治療薬のcns送達 |
JP2015246589A Pending JP2016094451A (ja) | 2010-06-25 | 2015-12-17 | サンフィリポ症候群b型の処置 |
JP2015246258A Withdrawn JP2016040335A (ja) | 2010-06-25 | 2015-12-17 | ヘパランn−スルファターゼのcns送達のための方法および組成物 |
JP2015246244A Active JP6285409B2 (ja) | 2010-06-25 | 2015-12-17 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2015246952A Active JP6346162B2 (ja) | 2010-06-25 | 2015-12-18 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2017177784A Active JP6466538B2 (ja) | 2010-06-25 | 2017-09-15 | 治療薬のcns送達 |
Family Applications After (14)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017194348A Active JP6522072B2 (ja) | 2010-06-25 | 2017-10-04 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2018192589A Active JP6797876B2 (ja) | 2010-06-25 | 2018-10-11 | 治療薬のcns送達 |
JP2018226358A Active JP6898909B2 (ja) | 2010-06-25 | 2018-12-03 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2018227369A Active JP6938456B2 (ja) | 2010-06-25 | 2018-12-04 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2020000930A Withdrawn JP2020079244A (ja) | 2010-06-25 | 2020-01-07 | 治療薬のcns送達 |
JP2020023620A Pending JP2020079297A (ja) | 2010-06-25 | 2020-02-14 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2020024183A Pending JP2020079298A (ja) | 2010-06-25 | 2020-02-17 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2021115560A Active JP7448507B2 (ja) | 2010-06-25 | 2021-07-13 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2021115564A Active JP7087175B2 (ja) | 2010-06-25 | 2021-07-13 | 治療薬のcns送達 |
JP2021133184A Pending JP2021181489A (ja) | 2010-06-25 | 2021-08-18 | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 |
JP2021196898A Active JP7359827B2 (ja) | 2010-06-25 | 2021-12-03 | 治療薬のcns送達 |
JP2023014814A Pending JP2023052868A (ja) | 2010-06-25 | 2023-02-02 | アリールスルファターゼaのcns送達の方法および組成物 |
JP2023024170A Pending JP2023062114A (ja) | 2010-06-25 | 2023-02-20 | イズロン酸-2-スルファターゼのcns送達のための方法および組成物 |
JP2023078673A Pending JP2023099216A (ja) | 2010-06-25 | 2023-05-11 | 治療薬のcns送達 |
Country Status (24)
Country | Link |
---|---|
US (14) | US9814764B2 (ja) |
JP (21) | JP6250616B2 (ja) |
CN (4) | CN105233277B (ja) |
AR (6) | AR082025A1 (ja) |
BR (1) | BR112012033214B1 (ja) |
CA (1) | CA3171308A1 (ja) |
CL (7) | CL2012003654A1 (ja) |
DK (3) | DK3626257T3 (ja) |
ES (3) | ES2895655T3 (ja) |
HK (2) | HK1214149A1 (ja) |
HR (3) | HRP20211660T1 (ja) |
HU (6) | HUE055963T2 (ja) |
LT (3) | LT3103469T (ja) |
MX (1) | MX354776B (ja) |
NZ (2) | NZ702803A (ja) |
PE (8) | PE20170938A1 (ja) |
PL (1) | PL2588130T3 (ja) |
PT (6) | PT2585104T (ja) |
RS (3) | RS62620B1 (ja) |
RU (1) | RU2761342C2 (ja) |
SI (3) | SI3626257T1 (ja) |
SM (1) | SMT201600385B (ja) |
TW (8) | TW201212936A (ja) |
UA (2) | UA125060C2 (ja) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2661042C (en) | 2006-08-18 | 2012-12-11 | Armagen Technologies, Inc. | Agents for blood-brain barrier delivery |
EP2997976A1 (en) | 2007-07-27 | 2016-03-23 | Armagen Technologies, Inc. | Methods and compositions for increasing alpha-l-iduronidase activity in the cns |
HUE044865T2 (hu) | 2009-10-09 | 2019-11-28 | Armagen Inc | Eljárások és készítmények a központi idegrendszerben iduronát-2-szulfatáz-aktivitás növelésére |
ES2650689T3 (es) | 2010-06-25 | 2018-01-19 | Shire Human Genetic Therapies, Inc. | Administración de agentes terapéuticos al sistema nervioso central |
US20220133863A1 (en) * | 2010-06-25 | 2022-05-05 | Shire Human Genetic Therapies, Inc. | Treatment of sanfilippo syndrome type b |
CA2805413A1 (en) | 2010-06-25 | 2011-12-29 | Shire Human Genetic Therapies, Inc. | Methods and compositions for cns delivery of heparan n-sulfatase |
KR102094094B1 (ko) | 2010-06-25 | 2020-03-27 | 샤이어 휴먼 지네틱 테라피즈 인크. | 아릴설파타제 a의 cns 전달을 위한 방법들 및 조성물들 |
HUE055963T2 (hu) | 2010-06-25 | 2022-01-28 | Shire Human Genetic Therapies | Eljárások és kompozíciók iduronát-2-szulfáz központi idegrendszerbe történõ leadásához |
AU2012346448B2 (en) | 2011-12-02 | 2017-09-14 | Armagen, Inc. | Methods and compositions for increasing arylsulfatase A activity in the CNS |
EP2793922B1 (en) | 2011-12-23 | 2019-10-30 | Shire Human Genetic Therapies, Inc. | Stable formulations for cns delivery of arylsulfatase a |
CA2859988A1 (en) * | 2011-12-23 | 2013-06-27 | Shire Human Genetic Therapies, Inc. | Treatment of cognitive impairment of hunter syndrome by intrathecal delivery of iduronate-2-sulfatase |
KR20220119187A (ko) * | 2013-05-15 | 2022-08-26 | 리젠츠 오브 더 유니버시티 오브 미네소타 | 중추 신경계로의 아데노-연관 바이러스 매개 유전자 전달 |
US10538589B2 (en) * | 2015-01-14 | 2020-01-21 | Armagen Inc. | Methods and compositions for increasing N-acetylglucosaminidase (NAGLU) activity in the CNS using a fusion antibody comprising an anti-human insulin receptor antibody and NAGLU |
EP3292206B8 (en) | 2015-05-07 | 2022-02-09 | Takeda Pharmaceutical Company Limited | Glucocerebrosidase gene therapy for parkinson's disease |
UA123704C2 (uk) * | 2015-12-30 | 2021-05-19 | Грін Кросс Корпорейшн | Спосіб лікування синдрому хантера |
KR20180114199A (ko) * | 2016-02-24 | 2018-10-17 | 바이오마린 파머수티컬 인크. | 표적화된 치료적 리소좀 효소 융합 단백질들, 관련 제형들 및 이의 용도들 |
BR112018071156A2 (pt) | 2016-04-15 | 2019-03-12 | The Trustees Of The University Of Pennsylvania | terapia de gene para tratar mucopolissacaridose tipo ii |
EP3684938A1 (en) | 2017-09-22 | 2020-07-29 | The Trustees of the University of Pennsylvania | Gene therapy for treating mucopolysaccharidosis type ii |
EP3760220A4 (en) * | 2018-02-28 | 2022-01-19 | Seikagaku Corporation | PACKAGING AND ITS MANUFACTURING PROCESS |
CN108534695A (zh) * | 2018-05-04 | 2018-09-14 | 无锡恩特卫自动化检测设备有限公司 | 一种基于机器视觉系统的瓶塞漏酒检测方法及装置 |
WO2020004368A1 (ja) | 2018-06-25 | 2020-01-02 | Jcrファーマ株式会社 | 蛋白質含有水性液剤 |
JP7253770B2 (ja) * | 2019-01-18 | 2023-04-07 | 株式会社大一商会 | 遊技機 |
JP7253771B2 (ja) * | 2019-01-18 | 2023-04-07 | 株式会社大一商会 | 遊技機 |
CN116916947A (zh) | 2020-10-14 | 2023-10-20 | 戴纳立制药公司 | 包含磺基葡糖胺磺基水解酶的融合蛋白和其方法 |
CN113283465B (zh) * | 2021-04-02 | 2022-04-29 | 电子科技大学 | 一种弥散张量成像数据分析方法及装置 |
CN115116623A (zh) * | 2022-06-28 | 2022-09-27 | 深圳市儿童医院 | 一种基于icd疾病编码的抗菌药物使用指标评价方法、终端 |
Family Cites Families (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3133001A (en) * | 1959-11-26 | 1964-05-12 | Muset Pedro Puig | Stabilization of enzymes |
US4743265A (en) | 1986-04-23 | 1988-05-10 | Dij Catheter Corp | Articulated catheter placement device |
US5222982A (en) | 1991-02-11 | 1993-06-29 | Ommaya Ayub K | Spinal fluid driven artificial organ |
ATE206308T1 (de) * | 1993-02-02 | 2001-10-15 | Xoma Technology Ltd | Arzneizusammensetzungen enthaltend ein bakterizides permeabilität erhöhendes protein und ein tensid |
US5863782A (en) | 1995-04-19 | 1999-01-26 | Women's And Children's Hospital | Synthetic mammalian sulphamidase and genetic sequences encoding same |
US6118045A (en) | 1995-08-02 | 2000-09-12 | Pharming B.V. | Lysosomal proteins produced in the milk of transgenic animals |
AUPN674895A0 (en) | 1995-11-23 | 1995-12-14 | Women's And Children's Hospital | Synthetic mammalian alpha-N-acetylglucosaminidase and genetic sequences encoding same |
DE69808402T2 (de) | 1997-08-22 | 2003-07-03 | Seikagaku Kogyo Co Ltd | Arzneimittel zur Behandlung von durch Hernie gestörter intervertebraler Bandscheibe |
ES2677343T3 (es) | 1998-12-07 | 2018-08-01 | Genzyme Corporation | Tratamiento de la enfermedad de Pompe |
US6217552B1 (en) | 1999-03-01 | 2001-04-17 | Coaxia, Inc. | Medical device for selective intrathecal spinal cooling in aortic surgery and spinal trauma |
US6368315B1 (en) | 1999-06-23 | 2002-04-09 | Durect Corporation | Composite drug delivery catheter |
US20020052311A1 (en) | 1999-09-03 | 2002-05-02 | Beka Solomon | Methods and compostions for the treatment and/or diagnosis of neurological diseases and disorders |
US6534300B1 (en) | 1999-09-14 | 2003-03-18 | Genzyme Glycobiology Research Institute, Inc. | Methods for producing highly phosphorylated lysosomal hydrolases |
US20020099025A1 (en) * | 1999-12-30 | 2002-07-25 | Heywood James A. | Treatment of neurological disorders |
US6866844B2 (en) * | 2002-11-07 | 2005-03-15 | Biomarin Pharmaceutical Inc. | Precursor N-acetylgalactosamine-4-sulfatase, methods of treatment using said enzyme and methods for producing and purifying said enzyme |
US7560424B2 (en) | 2001-04-30 | 2009-07-14 | Zystor Therapeutics, Inc. | Targeted therapeutic proteins |
ATE384736T1 (de) | 2001-04-30 | 2008-02-15 | Zystor Therapeutics Inc | Subzelluläres targeting von therapeutischen proteinen |
US20040005309A1 (en) | 2002-05-29 | 2004-01-08 | Symbiontics, Inc. | Targeted therapeutic proteins |
US7629309B2 (en) | 2002-05-29 | 2009-12-08 | Zystor Therapeutics, Inc. | Targeted therapeutic proteins |
WO2003032727A1 (en) | 2001-10-16 | 2003-04-24 | Symbiontics Inc. | Methods and compositions for targeting underglycosylated proteins across the blood brain barrier |
US20030072761A1 (en) | 2001-10-16 | 2003-04-17 | Lebowitz Jonathan | Methods and compositions for targeting proteins across the blood brain barrier |
WO2003068159A2 (en) | 2002-02-11 | 2003-08-21 | Wake Forest University | Compositions and methods for treating pain using cyclooxygenase-1 inhibitors |
ES2367257T3 (es) * | 2002-04-25 | 2011-10-31 | Shire Human Genetic Therapies, Inc. | Tratamiento de deficit de alfa-galactosidasa a. |
CA2487815A1 (en) | 2002-05-29 | 2003-12-11 | Symbiontics, Inc. | Targeted therapeutic proteins |
US20040248262A1 (en) | 2003-01-22 | 2004-12-09 | Koeberl Dwight D. | Constructs for expressing lysomal polypeptides |
PT2444102E (pt) | 2003-01-31 | 2015-09-17 | Sinai School Medicine | Terapia combinada para o tratamento de distúrbios de deficiência proteica |
CN1788017B (zh) * | 2003-02-10 | 2013-04-24 | to-BBB控股股份有限公司 | 炎症状态下在血脑屏障中差异表达的核酸 |
JP5036302B2 (ja) | 2003-02-10 | 2012-09-26 | ティオー − ビービービー ホールディング ベスローテン フェンノートシャップ | 炎症状態下に血液脳関門で示差的(differentially)に発現される核酸 |
JP5624256B2 (ja) | 2003-06-20 | 2014-11-12 | ラプター・ファーマシューティカル・インコーポレイテッド | 脳および他の組織への治療化合物の送達 |
US20050026823A1 (en) | 2003-06-20 | 2005-02-03 | Biomarin Pharmaceutical Inc. | Use of the chaperone receptor-associated protein (RAP) for the delivery of therapeutic compounds to the brain and other tissues |
US7442372B2 (en) | 2003-08-29 | 2008-10-28 | Biomarin Pharmaceutical Inc. | Delivery of therapeutic compounds to the brain and other tissues |
NZ576986A (en) * | 2004-01-30 | 2010-12-24 | Shire Pharmaceuticals Ireland Ltd | Production and purification of recombinant arylsulfatase A |
WO2005074888A2 (en) | 2004-02-03 | 2005-08-18 | Biodelivery Sciences International, Inc. | Replacement enzyme cochleates |
WO2005077093A2 (en) | 2004-02-06 | 2005-08-25 | Biomarin Pharmaceutical Inc. | Manufacture of highly phosphorylated lysosomal enzymes and uses thereof |
JP4914224B2 (ja) | 2004-02-10 | 2012-04-11 | バイオマリン ファーマシューティカル インコーポレイテッド | 酸性αグルコシダーゼおよびそのフラグメント |
US20050208090A1 (en) * | 2004-03-18 | 2005-09-22 | Medtronic, Inc. | Methods and systems for treatment of neurological diseases of the central nervous system |
BRPI0510271A (pt) * | 2004-06-15 | 2007-10-30 | Baxter Int | aplicações ex-vivo agentes terapêuticos microparticulados |
JP2008516190A (ja) * | 2004-08-11 | 2008-05-15 | チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド | 酵素に基づく時間・温度インジケーター |
IL165334A0 (en) * | 2004-11-22 | 2006-01-15 | Mediwound Ltd | Debriding composition from bromelain and methods of producing same |
JPWO2006121199A1 (ja) * | 2005-05-11 | 2008-12-18 | 日本ケミカルリサーチ株式会社 | 脂質小胞体組成物 |
US7964617B2 (en) | 2005-06-08 | 2011-06-21 | Amicus Therapeutics, Inc. | Methods for treating parkinsons disease and parkinsonism |
AR059089A1 (es) * | 2006-01-20 | 2008-03-12 | Genzyme Corp | Administracion intraventricular de una enzima para enfermedades de almacenamiento lisosomal |
MX361816B (es) | 2006-02-09 | 2018-12-17 | Genzyme Corp | Suministro intraventricular lento. |
CN101410408A (zh) * | 2006-04-04 | 2009-04-15 | 希尔制药爱尔兰有限责任公司 | 用于浓缩多肽的方法 |
PL2631242T3 (pl) | 2006-04-04 | 2023-03-20 | Takeda Pharmaceutical Company Limited | Sposób zatężania polipeptydu |
GB0611463D0 (en) | 2006-06-09 | 2006-07-19 | Novartis Ag | Organic compounds |
WO2008070769A1 (en) * | 2006-12-06 | 2008-06-12 | Medtronic, Inc. | Intrathecal catheter |
CA2680189A1 (en) | 2007-03-06 | 2008-09-12 | Saint Louis University | Modified enzyme and treatment method |
WO2009017005A1 (ja) | 2007-07-27 | 2009-02-05 | Sharp Kabushiki Kaisha | 移動局装置、基地局装置、通信システム及びプログラム |
KR20100058541A (ko) | 2007-08-15 | 2010-06-03 | 아뮤닉스 인코포레이티드 | 생물학적 활성 폴리펩티드의 특성을 변경하기 위한 조성물 및 방법 |
EP2223934B1 (en) * | 2007-11-14 | 2012-10-03 | Institute Of Microbiology, Chinese Academy Of Sciences | Polypeptides for inhibiting influenza virus infection |
SG10201604258YA (en) | 2007-11-30 | 2016-07-28 | Abbvie Biotechnology Ltd | Anti-tnf antibody formulations |
US7722865B2 (en) * | 2008-01-18 | 2010-05-25 | Biomarin Pharmaceutical Inc. | Manufacture of active highly phosphorylated human lysosomal sulfatase enzymes and uses thereof |
TW200936156A (en) * | 2008-01-28 | 2009-09-01 | Novartis Ag | Methods and compositions using Klotho-FGF fusion polypeptides |
WO2009131698A2 (en) | 2008-04-23 | 2009-10-29 | Iowa State University Research Foundation, Inc. | PHOSPHORYLATED RECOMBINANT N-ACETYL-alpha-D- GLUCOSAMINIDASE (NaGlu) AND USES THEREOF |
AU2009244148B2 (en) | 2008-05-07 | 2014-10-09 | Biomarin Pharmaceutical Inc. | Lysosomal targeting peptides and uses thereof |
US8436489B2 (en) | 2009-06-29 | 2013-05-07 | Lightsail Energy, Inc. | Compressed air energy storage system utilizing two-phase flow to facilitate heat exchange |
HUE055963T2 (hu) | 2010-06-25 | 2022-01-28 | Shire Human Genetic Therapies | Eljárások és kompozíciók iduronát-2-szulfáz központi idegrendszerbe történõ leadásához |
CA2805413A1 (en) | 2010-06-25 | 2011-12-29 | Shire Human Genetic Therapies, Inc. | Methods and compositions for cns delivery of heparan n-sulfatase |
MX2013000324A (es) | 2010-06-25 | 2013-02-01 | Shire Human Genetic Therapies | Tratamiento del sindrome de sanfilippo tipo b. |
MX2020001395A (es) | 2010-06-25 | 2022-03-24 | Shire Human Genetic Therapies | Composiciones y su uso para suministro de iduronato-2-sulfatasa al sistema nervioso central. |
US20110318324A1 (en) | 2010-06-25 | 2011-12-29 | Shire Human Genetic Therapies, Inc. | Methods and compositions for cns delivery of b-galactocerebrosidase |
ES2650689T3 (es) * | 2010-06-25 | 2018-01-19 | Shire Human Genetic Therapies, Inc. | Administración de agentes terapéuticos al sistema nervioso central |
KR102094094B1 (ko) | 2010-06-25 | 2020-03-27 | 샤이어 휴먼 지네틱 테라피즈 인크. | 아릴설파타제 a의 cns 전달을 위한 방법들 및 조성물들 |
JP2012062312A (ja) | 2010-08-19 | 2012-03-29 | Yoshikatsu Eto | ハンター症候群の治療剤 |
US8580922B2 (en) * | 2011-03-04 | 2013-11-12 | Shire Human Genetic Therapies, Inc. | Peptide linkers for polypeptide compositions and methods for using same |
EP2793922B1 (en) * | 2011-12-23 | 2019-10-30 | Shire Human Genetic Therapies, Inc. | Stable formulations for cns delivery of arylsulfatase a |
-
2011
- 2011-06-25 HU HUE19192679A patent/HUE055963T2/hu unknown
- 2011-06-25 PT PT117990374T patent/PT2585104T/pt unknown
- 2011-06-25 PE PE2017000503A patent/PE20170938A1/es unknown
- 2011-06-25 RS RS20211359A patent/RS62620B1/sr unknown
- 2011-06-25 MX MX2013000321A patent/MX354776B/es active IP Right Grant
- 2011-06-25 SI SI201132014T patent/SI3626257T1/sl unknown
- 2011-06-25 PE PE2012002474A patent/PE20130578A1/es not_active Application Discontinuation
- 2011-06-25 LT LTEP16179150.4T patent/LT3103469T/lt unknown
- 2011-06-25 PE PE2012002476A patent/PE20130589A1/es not_active Application Discontinuation
- 2011-06-25 PE PE2012002498A patent/PE20130648A1/es not_active Application Discontinuation
- 2011-06-25 ES ES19192679T patent/ES2895655T3/es active Active
- 2011-06-25 PT PT191925080T patent/PT3626257T/pt unknown
- 2011-06-25 RS RS20211191A patent/RS62520B1/sr unknown
- 2011-06-25 PT PT117990358T patent/PT2588130T/pt unknown
- 2011-06-25 LT LTEP19192679.9T patent/LT3626258T/lt unknown
- 2011-06-25 CN CN201510512218.XA patent/CN105233277B/zh active Active
- 2011-06-25 PT PT161791504T patent/PT3103469T/pt unknown
- 2011-06-25 DK DK19192508.0T patent/DK3626257T3/da active
- 2011-06-25 HR HRP20211660TT patent/HRP20211660T1/hr unknown
- 2011-06-25 PE PE2012002475A patent/PE20130579A1/es active IP Right Grant
- 2011-06-25 NZ NZ702803A patent/NZ702803A/en unknown
- 2011-06-25 RU RU2017125281A patent/RU2761342C2/ru active
- 2011-06-25 LT LTEP19192508.0T patent/LT3626257T/lt unknown
- 2011-06-25 BR BR112012033214-7A patent/BR112012033214B1/pt active IP Right Grant
- 2011-06-25 CN CN201610569581.XA patent/CN106139133B/zh active Active
- 2011-06-25 DK DK16179150.4T patent/DK3103469T3/da active
- 2011-06-25 SI SI201131959T patent/SI3103469T1/sl unknown
- 2011-06-25 HU HUE11799035A patent/HUE031036T2/en unknown
- 2011-06-25 PL PL11799035T patent/PL2588130T3/pl unknown
- 2011-06-25 CN CN201610086722.2A patent/CN105664142A/zh active Pending
- 2011-06-25 UA UAA201507719A patent/UA125060C2/uk unknown
- 2011-06-25 CA CA3171308A patent/CA3171308A1/en active Pending
- 2011-06-25 NZ NZ702800A patent/NZ702800A/en not_active IP Right Cessation
- 2011-06-25 RS RS20210291A patent/RS61683B1/sr unknown
- 2011-06-25 UA UAA201507529A patent/UA125743C2/uk unknown
- 2011-06-25 PE PE2017001612A patent/PE20180130A1/es unknown
- 2011-06-25 HU HUE16179150A patent/HUE052944T2/hu unknown
- 2011-06-25 ES ES16179150T patent/ES2858726T3/es active Active
- 2011-06-25 ES ES19192508T patent/ES2896060T3/es active Active
- 2011-06-25 CN CN201510172262.0A patent/CN104857504A/zh active Pending
- 2011-06-25 HR HRP20211520TT patent/HRP20211520T1/hr unknown
- 2011-06-25 SI SI201132007T patent/SI3626258T1/sl unknown
- 2011-06-25 HU HUE11799036A patent/HUE046856T2/hu unknown
- 2011-06-25 PE PE2018000183A patent/PE20180801A1/es unknown
- 2011-06-25 PT PT191926799T patent/PT3626258T/pt unknown
- 2011-06-25 HU HUE19192508A patent/HUE056884T2/hu unknown
- 2011-06-25 HU HUE11799037A patent/HUE046409T2/hu unknown
- 2011-06-25 PE PE2012002479A patent/PE20130637A1/es not_active Application Discontinuation
- 2011-06-25 DK DK19192679.9T patent/DK3626258T3/da active
- 2011-06-25 PT PT117990366T patent/PT2593131T/pt unknown
- 2011-06-27 TW TW100122529A patent/TW201212936A/zh unknown
- 2011-06-27 AR ARP110102246A patent/AR082025A1/es not_active Application Discontinuation
- 2011-06-27 AR ARP110102242A patent/AR081678A1/es not_active Application Discontinuation
- 2011-06-27 TW TW109118555A patent/TWI790444B/zh active
- 2011-06-27 TW TW100122534A patent/TWI602573B/zh active
- 2011-06-27 AR ARP110102241A patent/AR081677A1/es not_active Application Discontinuation
- 2011-06-27 TW TW106127273A patent/TWI698252B/zh active
- 2011-06-27 AR ARP110102245A patent/AR081681A1/es unknown
- 2011-06-27 AR ARP110102243A patent/AR081679A1/es unknown
- 2011-06-27 TW TW105115109A patent/TW201701899A/zh unknown
- 2011-06-27 TW TW106108970A patent/TWI609694B/zh active
- 2011-06-27 TW TW106135183A patent/TWI669128B/zh active
- 2011-06-27 AR ARP110102244A patent/AR081680A1/es unknown
- 2011-06-27 TW TW112102995A patent/TW202337489A/zh unknown
-
2012
- 2012-12-21 CL CL2012003654A patent/CL2012003654A1/es unknown
- 2012-12-21 CL CL2012003655A patent/CL2012003655A1/es unknown
- 2012-12-21 CL CL2012003656A patent/CL2012003656A1/es unknown
- 2012-12-21 CL CL2012003657A patent/CL2012003657A1/es unknown
-
2013
- 2013-05-10 US US13/892,076 patent/US9814764B2/en active Active
- 2013-08-23 US US13/974,457 patent/US9220677B2/en active Active
-
2015
- 2015-11-11 US US14/938,824 patent/US20160158324A1/en not_active Abandoned
- 2015-12-03 JP JP2015236539A patent/JP6250616B2/ja active Active
- 2015-12-17 JP JP2015246589A patent/JP2016094451A/ja active Pending
- 2015-12-17 JP JP2015246258A patent/JP2016040335A/ja not_active Withdrawn
- 2015-12-17 JP JP2015246244A patent/JP6285409B2/ja active Active
- 2015-12-18 JP JP2015246952A patent/JP6346162B2/ja active Active
-
2016
- 2016-02-04 US US15/016,141 patent/US10456454B2/en active Active
- 2016-02-25 HK HK16102145.2A patent/HK1214149A1/zh unknown
- 2016-03-22 US US15/077,046 patent/US20170042977A1/en not_active Abandoned
- 2016-06-13 HK HK16106769.8A patent/HK1218719A1/zh unknown
- 2016-10-27 SM SM201600385T patent/SMT201600385B/it unknown
- 2016-12-07 CL CL2016003159A patent/CL2016003159A1/es unknown
-
2017
- 2017-08-23 US US15/684,568 patent/US10646554B2/en active Active
- 2017-09-15 JP JP2017177784A patent/JP6466538B2/ja active Active
- 2017-09-26 US US15/715,748 patent/US11065307B2/en active Active
- 2017-10-03 CL CL2017002488A patent/CL2017002488A1/es unknown
- 2017-10-04 JP JP2017194508A patent/JP6522073B2/ja active Active
- 2017-10-04 JP JP2017194348A patent/JP6522072B2/ja active Active
-
2018
- 2018-07-16 US US16/036,584 patent/US11065308B2/en active Active
- 2018-10-11 JP JP2018192589A patent/JP6797876B2/ja active Active
- 2018-12-03 JP JP2018226358A patent/JP6898909B2/ja active Active
- 2018-12-04 JP JP2018227369A patent/JP6938456B2/ja active Active
-
2019
- 2019-07-18 US US16/515,568 patent/US11260112B2/en active Active
- 2019-09-17 US US16/573,557 patent/US11471516B2/en active Active
-
2020
- 2020-01-07 JP JP2020000930A patent/JP2020079244A/ja not_active Withdrawn
- 2020-02-14 JP JP2020023620A patent/JP2020079297A/ja active Pending
- 2020-02-17 JP JP2020024183A patent/JP2020079298A/ja active Pending
- 2020-02-26 CL CL2020000468A patent/CL2020000468A1/es unknown
- 2020-03-24 US US16/828,731 patent/US20200405825A1/en active Pending
-
2021
- 2021-02-23 HR HRP20210298TT patent/HRP20210298T1/hr unknown
- 2021-06-17 US US17/350,860 patent/US20220133862A1/en active Pending
- 2021-07-13 JP JP2021115560A patent/JP7448507B2/ja active Active
- 2021-07-13 JP JP2021115564A patent/JP7087175B2/ja active Active
- 2021-08-18 JP JP2021133184A patent/JP2021181489A/ja active Pending
- 2021-12-03 JP JP2021196898A patent/JP7359827B2/ja active Active
-
2022
- 2022-01-18 US US17/578,119 patent/US20230026836A1/en active Pending
- 2022-08-16 US US17/820,155 patent/US20230165942A1/en active Pending
-
2023
- 2023-02-02 JP JP2023014814A patent/JP2023052868A/ja active Pending
- 2023-02-20 JP JP2023024170A patent/JP2023062114A/ja active Pending
- 2023-05-11 JP JP2023078673A patent/JP2023099216A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6522073B2 (ja) | アリールスルファターゼaのcns送達の方法および組成物 | |
JP6045492B2 (ja) | イズロン酸−2−スルファターゼのcns送達のための方法および組成物 | |
JP6045493B2 (ja) | アリールスルファターゼaのcns送達の方法および組成物 | |
JP6073783B2 (ja) | ヘパランn−スルファターゼのcns送達のための方法および組成物 | |
RU2783380C2 (ru) | Способы и композиции для доставки в цнс арилсульфатазы а |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20171004 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180601 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180821 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181203 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190328 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190423 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6522073 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |