CA2805413A1 - Methods and compositions for cns delivery of heparan n-sulfatase - Google Patents

Info

Publication number

CA2805413A1

CA2805413A1 CA2805413A CA2805413A CA2805413A1 CA 2805413 A1 CA2805413 A1 CA 2805413A1 CA 2805413 A CA2805413 A CA 2805413A CA 2805413 A CA2805413 A CA 2805413A CA 2805413 A1 CA2805413 A1 CA 2805413A1

Authority

CA

Canada

Prior art keywords

approximately

formulation

concentration

nmol

hns

Prior art date

2010-06-25

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 239000000203 mixture Substances 0.000 title claims abstract description 316
• 108010089932 heparan sulfate sulfatase Proteins 0.000 title claims abstract description 193
• 238000000034 method Methods 0.000 title claims abstract description 103
• 238000012384 transportation and delivery Methods 0.000 title claims abstract description 84
• 238000009472 formulation Methods 0.000 claims abstract description 270
• 238000007913 intrathecal administration Methods 0.000 claims abstract description 250
• 108090000623 proteins and genes Proteins 0.000 claims abstract description 136
• 102000004169 proteins and genes Human genes 0.000 claims abstract description 131
• 238000011282 treatment Methods 0.000 claims abstract description 70
• 230000002132 lysosomal effect Effects 0.000 claims abstract description 43
• 150000003839 salts Chemical class 0.000 claims abstract description 19
• 239000004094 surface-active agent Substances 0.000 claims abstract description 18
• 229920000136 polysorbate Polymers 0.000 claims abstract description 9
• 229950008882 polysorbate Drugs 0.000 claims abstract description 7
• 210000004556 brain Anatomy 0.000 claims description 217
• 210000001519 tissue Anatomy 0.000 claims description 182
• 229910019142 PO4 Inorganic materials 0.000 claims description 135
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 135
• 239000010452 phosphate Substances 0.000 claims description 134
• 230000000694 effects Effects 0.000 claims description 132
• 210000000278 spinal cord Anatomy 0.000 claims description 75
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 67
• 210000004185 liver Anatomy 0.000 claims description 65
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 62
• 238000001990 intravenous administration Methods 0.000 claims description 56
• 201000010099 disease Diseases 0.000 claims description 50
• 230000001965 increasing effect Effects 0.000 claims description 49
• 229930006000 Sucrose Natural products 0.000 claims description 45
• 239000005720 sucrose Substances 0.000 claims description 45
• 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 claims description 43
• 238000003860 storage Methods 0.000 claims description 39
• 210000004027 cell Anatomy 0.000 claims description 38
• 150000001413 amino acids Chemical group 0.000 claims description 36
• 239000011780 sodium chloride Substances 0.000 claims description 35
• 210000003734 kidney Anatomy 0.000 claims description 32
• 210000002569 neuron Anatomy 0.000 claims description 32
• 210000002216 heart Anatomy 0.000 claims description 31
• 229920001213 Polysorbate 20 Polymers 0.000 claims description 30
• 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 30
• 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 30
• 229940068977 polysorbate 20 Drugs 0.000 claims description 30
• 230000002093 peripheral effect Effects 0.000 claims description 29
• 208000024891 symptom Diseases 0.000 claims description 28
• 230000002255 enzymatic effect Effects 0.000 claims description 27
• 239000003381 stabilizer Substances 0.000 claims description 24
• 230000002829 reductive effect Effects 0.000 claims description 22
• 210000001638 cerebellum Anatomy 0.000 claims description 17
• 230000002411 adverse Effects 0.000 claims description 16
• 210000004705 lumbosacral region Anatomy 0.000 claims description 16
• 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 14
• 210000005013 brain tissue Anatomy 0.000 claims description 13
• 210000002418 meninge Anatomy 0.000 claims description 13
• 208000011580 syndromic disease Diseases 0.000 claims description 13
• 239000008103 glucose Substances 0.000 claims description 12
• 239000006172 buffering agent Substances 0.000 claims description 10
• 210000001259 mesencephalon Anatomy 0.000 claims description 10
• 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 8
• 229930195725 Mannitol Natural products 0.000 claims description 8
• 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 8
• 210000004884 grey matter Anatomy 0.000 claims description 8
• 239000012669 liquid formulation Substances 0.000 claims description 8
• 239000000594 mannitol Substances 0.000 claims description 8
• 235000010355 mannitol Nutrition 0.000 claims description 8
• 210000004885 white matter Anatomy 0.000 claims description 8
• HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 7
• 230000006735 deficit Effects 0.000 claims description 7
• 238000011161 development Methods 0.000 claims description 7
• HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 7
• 210000004498 neuroglial cell Anatomy 0.000 claims description 7
• 210000000449 purkinje cell Anatomy 0.000 claims description 7
• 239000004475 Arginine Substances 0.000 claims description 5
• 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
• 210000001744 T-lymphocyte Anatomy 0.000 claims description 5
• ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 5
• 239000002552 dosage form Substances 0.000 claims description 5
• 208000013403 hyperactivity Diseases 0.000 claims description 5
• 239000002052 molecular layer Substances 0.000 claims description 5
• 229940071643 prefilled syringe Drugs 0.000 claims description 5
• 210000002637 putamen Anatomy 0.000 claims description 5
• 230000009467 reduction Effects 0.000 claims description 5
• 239000000600 sorbitol Substances 0.000 claims description 5
• 235000010356 sorbitol Nutrition 0.000 claims description 5
• 206010011878 Deafness Diseases 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
• 210000003710 cerebral cortex Anatomy 0.000 claims description 4
• 230000003111 delayed effect Effects 0.000 claims description 4
• 230000010370 hearing loss Effects 0.000 claims description 4
• 231100000888 hearing loss Toxicity 0.000 claims description 4
• 208000016354 hearing loss disease Diseases 0.000 claims description 4
• 208000019116 sleep disease Diseases 0.000 claims description 4
• 208000022925 sleep disturbance Diseases 0.000 claims description 4
• 230000003044 adaptive effect Effects 0.000 claims description 3
• 239000003708 ampul Substances 0.000 claims description 3
• 230000004807 localization Effects 0.000 claims description 3
• 210000000478 neocortex Anatomy 0.000 claims description 3
• 210000004786 perivascular cell Anatomy 0.000 claims description 3
• 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
• 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
• 229940068968 polysorbate 80 Drugs 0.000 claims description 3
• 229920000053 polysorbate 80 Polymers 0.000 claims description 3
• 239000000843 powder Substances 0.000 claims description 3
• 206010001488 Aggression Diseases 0.000 claims description 2
• 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
• 208000036626 Mental retardation Diseases 0.000 claims description 2
• 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 2
• 229920001219 Polysorbate 40 Polymers 0.000 claims description 2
• 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
• 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
• 238000002650 immunosuppressive therapy Methods 0.000 claims description 2
• 230000021633 leukocyte mediated immunity Effects 0.000 claims description 2
• 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
• 150000003904 phospholipids Chemical class 0.000 claims description 2
• 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 2
• 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
• 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 2
• 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 2
• 229940101027 polysorbate 40 Drugs 0.000 claims description 2
• 229940113124 polysorbate 60 Drugs 0.000 claims description 2
• 125000000185 sucrose group Chemical group 0.000 claims description 2
• 238000012385 systemic delivery Methods 0.000 claims description 2
• 102000004190 Enzymes Human genes 0.000 abstract description 189
• 108090000790 Enzymes Proteins 0.000 abstract description 189
• 208000015439 Lysosomal storage disease Diseases 0.000 abstract description 43
• 208000025816 Sanfilippo syndrome type A Diseases 0.000 abstract description 19
• 208000012226 mucopolysaccharidosis type IIIA Diseases 0.000 abstract description 19
• 208000036710 mucopolysaccharidosis type 3A Diseases 0.000 abstract description 16
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 138
• 235000021317 phosphate Nutrition 0.000 description 127
• 235000018102 proteins Nutrition 0.000 description 126
• 239000003814 drug Substances 0.000 description 110
• 210000001175 cerebrospinal fluid Anatomy 0.000 description 108
• 229940124597 therapeutic agent Drugs 0.000 description 96
• 108091006629 SLC13A2 Proteins 0.000 description 92
• 210000003169 central nervous system Anatomy 0.000 description 81
• 241000282693 Cercopithecidae Species 0.000 description 78
• 230000001225 therapeutic effect Effects 0.000 description 60
• 239000007924 injection Substances 0.000 description 39
• 238000002347 injection Methods 0.000 description 39
• 238000011084 recovery Methods 0.000 description 38
• 238000004108 freeze drying Methods 0.000 description 31
• 238000011887 Necropsy Methods 0.000 description 30
• 239000008194 pharmaceutical composition Substances 0.000 description 28
• 241001465754 Metazoa Species 0.000 description 26
• 238000004458 analytical method Methods 0.000 description 26
• 210000000056 organ Anatomy 0.000 description 26
• 239000000872 buffer Substances 0.000 description 24
• 239000000243 solution Substances 0.000 description 24
• 210000003712 lysosome Anatomy 0.000 description 23
• 230000001868 lysosomic effect Effects 0.000 description 23
• 210000003491 skin Anatomy 0.000 description 23
• 229920002683 Glycosaminoglycan Polymers 0.000 description 22
• 235000001014 amino acid Nutrition 0.000 description 22
• 208000005340 mucopolysaccharidosis III Diseases 0.000 description 22
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
• 210000002966 serum Anatomy 0.000 description 21
• 239000000047 product Substances 0.000 description 20
• 230000037396 body weight Effects 0.000 description 18
• 239000003085 diluting agent Substances 0.000 description 18
• 238000001035 drying Methods 0.000 description 18
• 239000000499 gel Substances 0.000 description 18
• 239000000126 substance Substances 0.000 description 18
• 238000012360 testing method Methods 0.000 description 18
• 230000008030 elimination Effects 0.000 description 17
• 238000003379 elimination reaction Methods 0.000 description 17
• 210000003128 head Anatomy 0.000 description 17
• 210000004720 cerebrum Anatomy 0.000 description 16
• 238000001542 size-exclusion chromatography Methods 0.000 description 16
• 229920002971 Heparan sulfate Polymers 0.000 description 15
• 239000000463 material Substances 0.000 description 15
• 108090000765 processed proteins & peptides Proteins 0.000 description 15
• 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 15
• 239000003981 vehicle Substances 0.000 description 15
• 230000000875 corresponding effect Effects 0.000 description 14
• 238000009826 distribution Methods 0.000 description 14
• 238000012377 drug delivery Methods 0.000 description 14
• 230000000366 juvenile effect Effects 0.000 description 14
• 239000007787 solid Substances 0.000 description 14
• -1 Fucosyl Oligosaccharides Chemical class 0.000 description 13
• 230000007812 deficiency Effects 0.000 description 13
• 239000002245 particle Substances 0.000 description 13
• 208000008955 Mucolipidoses Diseases 0.000 description 12
• 230000003247 decreasing effect Effects 0.000 description 12
• 239000000539 dimer Substances 0.000 description 12
• 208000035475 disorder Diseases 0.000 description 12
• 230000006870 function Effects 0.000 description 12
• 238000001802 infusion Methods 0.000 description 12
• 230000003442 weekly effect Effects 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
• 238000003556 assay Methods 0.000 description 11
• 210000004369 blood Anatomy 0.000 description 11
• 239000008280 blood Substances 0.000 description 11
• 230000008499 blood brain barrier function Effects 0.000 description 11
• 210000001218 blood-brain barrier Anatomy 0.000 description 11
• 239000004067 bulking agent Substances 0.000 description 11
• 239000003795 chemical substances by application Substances 0.000 description 11
• 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 11
• 238000013467 fragmentation Methods 0.000 description 11
• 238000006062 fragmentation reaction Methods 0.000 description 11
• 230000008014 freezing Effects 0.000 description 11
• 238000007710 freezing Methods 0.000 description 11
• 239000003018 immunosuppressive agent Substances 0.000 description 11
• 208000011045 mucopolysaccharidosis type 3 Diseases 0.000 description 11
• 239000002953 phosphate buffered saline Substances 0.000 description 11
• 102000004196 processed proteins & peptides Human genes 0.000 description 11
• 230000008685 targeting Effects 0.000 description 11
• 238000002560 therapeutic procedure Methods 0.000 description 11
• 241000700159 Rattus Species 0.000 description 10
• 238000009825 accumulation Methods 0.000 description 10
• 230000015556 catabolic process Effects 0.000 description 10
• 230000002490 cerebral effect Effects 0.000 description 10
• 210000003703 cisterna magna Anatomy 0.000 description 10
• 230000002950 deficient Effects 0.000 description 10
• 238000002641 enzyme replacement therapy Methods 0.000 description 10
• 238000002474 experimental method Methods 0.000 description 10
• 229920001184 polypeptide Polymers 0.000 description 10
• 239000001488 sodium phosphate Substances 0.000 description 10
• 235000011008 sodium phosphates Nutrition 0.000 description 10
• RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 10
• 238000013103 analytical ultracentrifugation Methods 0.000 description 9
• 230000004071 biological effect Effects 0.000 description 9
• 210000000133 brain stem Anatomy 0.000 description 9
• 230000001413 cellular effect Effects 0.000 description 9
• 238000000113 differential scanning calorimetry Methods 0.000 description 9
• 229940079593 drug Drugs 0.000 description 9
• 229960003444 immunosuppressant agent Drugs 0.000 description 9
• 239000012931 lyophilized formulation Substances 0.000 description 9
• 229920001542 oligosaccharide Polymers 0.000 description 9
• 230000007170 pathology Effects 0.000 description 9
• 230000008569 process Effects 0.000 description 9
• 229910000162 sodium phosphate Inorganic materials 0.000 description 9
• 231100000041 toxicology testing Toxicity 0.000 description 9
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
• 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 8
• 241000282567 Macaca fascicularis Species 0.000 description 8
• 238000000137 annealing Methods 0.000 description 8
• 230000008859 change Effects 0.000 description 8
• 238000006731 degradation reaction Methods 0.000 description 8
• 238000009792 diffusion process Methods 0.000 description 8
• 238000011156 evaluation Methods 0.000 description 8
• 230000028993 immune response Effects 0.000 description 8
• 238000005259 measurement Methods 0.000 description 8
• 150000007523 nucleic acids Chemical class 0.000 description 8
• 150000002482 oligosaccharides Chemical class 0.000 description 8
• 230000003068 static effect Effects 0.000 description 8
• 235000000346 sugar Nutrition 0.000 description 8
• 238000001356 surgical procedure Methods 0.000 description 8
• 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 7
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 7
• 238000006243 chemical reaction Methods 0.000 description 7
• 230000007850 degeneration Effects 0.000 description 7
• 210000003979 eosinophil Anatomy 0.000 description 7
• 239000012530 fluid Substances 0.000 description 7
• 210000000265 leukocyte Anatomy 0.000 description 7
• 210000004072 lung Anatomy 0.000 description 7
• 238000002844 melting Methods 0.000 description 7
• 230000008018 melting Effects 0.000 description 7
• 239000008363 phosphate buffer Substances 0.000 description 7
• 239000003755 preservative agent Substances 0.000 description 7
• 210000003594 spinal ganglia Anatomy 0.000 description 7
• 210000000273 spinal nerve root Anatomy 0.000 description 7
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• 239000011521 glass Substances 0.000 description 6
• 238000003384 imaging method Methods 0.000 description 6
• 230000001861 immunosuppressant effect Effects 0.000 description 6
• 238000003780 insertion Methods 0.000 description 6
• 230000037431 insertion Effects 0.000 description 6
• 238000004519 manufacturing process Methods 0.000 description 6
• 208000022018 mucopolysaccharidosis type 2 Diseases 0.000 description 6
• 238000002600 positron emission tomography Methods 0.000 description 6
• 239000002243 precursor Substances 0.000 description 6
• 238000002203 pretreatment Methods 0.000 description 6
• 108020003175 receptors Proteins 0.000 description 6
• 102000005962 receptors Human genes 0.000 description 6
• 230000000717 retained effect Effects 0.000 description 6
• 238000010186 staining Methods 0.000 description 6
• 239000000758 substrate Substances 0.000 description 6
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
• 206010067484 Adverse reaction Diseases 0.000 description 5
• 229920000045 Dermatan sulfate Polymers 0.000 description 5
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
• 241000282412 Homo Species 0.000 description 5
• 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 5
• 102000048143 Insulin-Like Growth Factor II Human genes 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
• 230000006838 adverse reaction Effects 0.000 description 5
• 230000002776 aggregation Effects 0.000 description 5
• 238000004220 aggregation Methods 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
• SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• 159000000007 calcium salts Chemical class 0.000 description 5
• 239000007979 citrate buffer Substances 0.000 description 5
• 150000001875 compounds Chemical class 0.000 description 5
• 230000002327 eosinophilic effect Effects 0.000 description 5
• 238000001914 filtration Methods 0.000 description 5
• 238000003364 immunohistochemistry Methods 0.000 description 5
• 239000000644 isotonic solution Substances 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 230000007774 longterm Effects 0.000 description 5
• 229920002521 macromolecule Polymers 0.000 description 5
• 230000007246 mechanism Effects 0.000 description 5
• 238000012008 microflow imaging Methods 0.000 description 5
• 201000002273 mucopolysaccharidosis II Diseases 0.000 description 5
• 230000001537 neural effect Effects 0.000 description 5
• 238000010606 normalization Methods 0.000 description 5
• 230000035515 penetration Effects 0.000 description 5
• 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 5
• 239000000546 pharmaceutical excipient Substances 0.000 description 5
• 238000002360 preparation method Methods 0.000 description 5
• 230000002335 preservative effect Effects 0.000 description 5
• 230000000750 progressive effect Effects 0.000 description 5
• 238000004007 reversed phase HPLC Methods 0.000 description 5
• SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 5
• 230000000392 somatic effect Effects 0.000 description 5
• 238000007619 statistical method Methods 0.000 description 5
• 230000004083 survival effect Effects 0.000 description 5
• 230000002459 sustained effect Effects 0.000 description 5
• 238000012546 transfer Methods 0.000 description 5
• 230000001052 transient effect Effects 0.000 description 5
• 230000032258 transport Effects 0.000 description 5
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
• 102100022548 Beta-hexosaminidase subunit alpha Human genes 0.000 description 4
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
• 208000010055 Globoid Cell Leukodystrophy Diseases 0.000 description 4
• 239000004471 Glycine Substances 0.000 description 4
• 206010053185 Glycogen storage disease type II Diseases 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
• 208000028226 Krabbe disease Diseases 0.000 description 4
• 208000027933 Mannosidase Deficiency disease Diseases 0.000 description 4
• 201000011442 Metachromatic leukodystrophy Diseases 0.000 description 4
• 206010072927 Mucolipidosis type I Diseases 0.000 description 4
• 206010028095 Mucopolysaccharidosis IV Diseases 0.000 description 4
• 208000008457 Neurologic Manifestations Diseases 0.000 description 4
• BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 4
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
• 230000009471 action Effects 0.000 description 4
• 239000013543 active substance Substances 0.000 description 4
• 238000013459 approach Methods 0.000 description 4
• 239000008228 bacteriostatic water for injection Substances 0.000 description 4
• 230000006399 behavior Effects 0.000 description 4
• 239000005388 borosilicate glass Substances 0.000 description 4
• 210000004289 cerebral ventricle Anatomy 0.000 description 4
• 230000007547 defect Effects 0.000 description 4
• 238000001514 detection method Methods 0.000 description 4
• 239000012634 fragment Substances 0.000 description 4
• 102000037865 fusion proteins Human genes 0.000 description 4
• 108020001507 fusion proteins Proteins 0.000 description 4
• 230000036541 health Effects 0.000 description 4
• 230000003118 histopathologic effect Effects 0.000 description 4
• 210000003016 hypothalamus Anatomy 0.000 description 4
• 230000006058 immune tolerance Effects 0.000 description 4
• 210000003292 kidney cell Anatomy 0.000 description 4
• 238000009593 lumbar puncture Methods 0.000 description 4
• 230000007388 microgliosis Effects 0.000 description 4
• 208000025919 mucopolysaccharidosis type 7 Diseases 0.000 description 4
• 210000004126 nerve fiber Anatomy 0.000 description 4
• 210000000653 nervous system Anatomy 0.000 description 4
• 108020004707 nucleic acids Proteins 0.000 description 4
• 102000039446 nucleic acids Human genes 0.000 description 4
• 239000012188 paraffin wax Substances 0.000 description 4
• 210000000578 peripheral nerve Anatomy 0.000 description 4
• 239000008177 pharmaceutical agent Substances 0.000 description 4
• 229920001296 polysiloxane Polymers 0.000 description 4
• 230000004952 protein activity Effects 0.000 description 4
• 230000011514 reflex Effects 0.000 description 4
• 229910052709 silver Inorganic materials 0.000 description 4
• 239000004332 silver Substances 0.000 description 4
• 239000011734 sodium Substances 0.000 description 4
• 210000000952 spleen Anatomy 0.000 description 4
• 238000006467 substitution reaction Methods 0.000 description 4
• 210000001103 thalamus Anatomy 0.000 description 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
• 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
• 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
• 108010036949 Cyclosporine Proteins 0.000 description 3
• 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 3
• 206010012559 Developmental delay Diseases 0.000 description 3
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
• 208000001948 Farber Lipogranulomatosis Diseases 0.000 description 3
• 208000033149 Farber disease Diseases 0.000 description 3
• 208000001905 GM2 Gangliosidoses Diseases 0.000 description 3
• 201000008905 GM2 gangliosidosis Diseases 0.000 description 3
• 208000017462 Galactosialidosis Diseases 0.000 description 3
• 208000015872 Gaucher disease Diseases 0.000 description 3
• 208000028782 Hereditary disease 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
• 208000026350 Inborn Genetic disease Diseases 0.000 description 3
• YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-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
• 208000024556 Mendelian disease Diseases 0.000 description 3
• 206010056886 Mucopolysaccharidosis I Diseases 0.000 description 3
• 206010056893 Mucopolysaccharidosis VII Diseases 0.000 description 3
• 102100027661 N-sulphoglucosamine sulphohydrolase Human genes 0.000 description 3
• 208000012902 Nervous system disease Diseases 0.000 description 3
• 241000288906 Primates Species 0.000 description 3
• 208000025820 Sanfilippo syndrome type B Diseases 0.000 description 3
• 210000004227 basal ganglia Anatomy 0.000 description 3
• 230000008901 benefit Effects 0.000 description 3
• 210000001185 bone marrow Anatomy 0.000 description 3
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 3
• 230000001684 chronic effect Effects 0.000 description 3
• 229960001265 ciclosporin Drugs 0.000 description 3
• 230000003930 cognitive ability Effects 0.000 description 3
• 208000010877 cognitive disease Diseases 0.000 description 3
• 230000001054 cortical effect Effects 0.000 description 3
• 230000001419 dependent effect Effects 0.000 description 3
• 238000013461 design Methods 0.000 description 3
• 235000005911 diet Nutrition 0.000 description 3
• 230000037213 diet Effects 0.000 description 3
• 230000004064 dysfunction Effects 0.000 description 3
• 238000002565 electrocardiography Methods 0.000 description 3
• 238000005516 engineering process Methods 0.000 description 3
• 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 3
• 235000012631 food intake Nutrition 0.000 description 3
• GIVLTTJNORAZON-HDBOBKCLSA-N ganglioside GM2 (18:0) Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 GIVLTTJNORAZON-HDBOBKCLSA-N 0.000 description 3
• 208000016361 genetic disease Diseases 0.000 description 3
• 201000004502 glycogen storage disease II Diseases 0.000 description 3
• 201000008977 glycoproteinosis Diseases 0.000 description 3
• 239000008187 granular material Substances 0.000 description 3
• 230000002440 hepatic effect Effects 0.000 description 3
• 229940050526 hydroxyethylstarch Drugs 0.000 description 3
• 238000002991 immunohistochemical analysis Methods 0.000 description 3
• 230000001976 improved effect Effects 0.000 description 3
• 230000008595 infiltration Effects 0.000 description 3
• 238000001764 infiltration Methods 0.000 description 3
• 230000028709 inflammatory response Effects 0.000 description 3
• 230000000977 initiatory effect Effects 0.000 description 3
• 238000007917 intracranial administration Methods 0.000 description 3
• 229960003299 ketamine Drugs 0.000 description 3
• 239000008101 lactose Substances 0.000 description 3
• 230000000670 limiting effect Effects 0.000 description 3
• 210000001165 lymph node Anatomy 0.000 description 3
• 230000014759 maintenance of location Effects 0.000 description 3
• 210000004962 mammalian cell Anatomy 0.000 description 3
• 239000003550 marker Substances 0.000 description 3
• 239000011159 matrix material Substances 0.000 description 3
• 230000002503 metabolic effect Effects 0.000 description 3
• 238000002156 mixing Methods 0.000 description 3
• 239000000178 monomer Substances 0.000 description 3
• 230000004660 morphological change Effects 0.000 description 3
• 201000007769 mucolipidosis Diseases 0.000 description 3
• 208000020468 mucolipidosis III alpha/beta Diseases 0.000 description 3
• 208000010978 mucopolysaccharidosis type 4 Diseases 0.000 description 3
• 208000012227 mucopolysaccharidosis type IIIB Diseases 0.000 description 3
• 230000017074 necrotic cell death Effects 0.000 description 3
• 210000003463 organelle Anatomy 0.000 description 3
• 229920001983 poloxamer Polymers 0.000 description 3
• 230000002265 prevention Effects 0.000 description 3
• 230000004044 response 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
• 229910052708 sodium Inorganic materials 0.000 description 3
• 239000002904 solvent Substances 0.000 description 3
• 241000894007 species Species 0.000 description 3
• 229910001220 stainless steel Inorganic materials 0.000 description 3
• 239000010935 stainless steel Substances 0.000 description 3
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
• 150000008163 sugars Chemical class 0.000 description 3
• 210000000115 thoracic cavity Anatomy 0.000 description 3
• 238000002054 transplantation Methods 0.000 description 3
• 210000002700 urine Anatomy 0.000 description 3
• 210000003462 vein Anatomy 0.000 description 3
• 230000002861 ventricular Effects 0.000 description 3
• OEANUJAFZLQYOD-CXAZCLJRSA-N (2r,3s,4r,5r,6r)-6-[(2r,3r,4r,5r,6r)-5-acetamido-3-hydroxy-2-(hydroxymethyl)-6-methoxyoxan-4-yl]oxy-4,5-dihydroxy-3-methoxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](OC)O[C@H](CO)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](OC)[C@H](C(O)=O)O1 OEANUJAFZLQYOD-CXAZCLJRSA-N 0.000 description 2
• 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 2
• 108010088751 Albumins Proteins 0.000 description 2
• 102000009027 Albumins Human genes 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
• 208000029602 Alpha-N-acetylgalactosaminidase deficiency Diseases 0.000 description 2
• 102100022146 Arylsulfatase A Human genes 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
• 206010068220 Aspartylglucosaminuria Diseases 0.000 description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
• 108010036867 Cerebroside-Sulfatase Proteins 0.000 description 2
• 102100037364 Craniofacial development protein 1 Human genes 0.000 description 2
• 229930105110 Cyclosporin A Natural products 0.000 description 2
• 206010011777 Cystinosis Diseases 0.000 description 2
• 206010012289 Dementia Diseases 0.000 description 2
• 229920002307 Dextran Polymers 0.000 description 2
• 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 2
• 101710190709 Eukaryotic translation initiation factor 4 gamma 2 Proteins 0.000 description 2
• 208000024720 Fabry Disease Diseases 0.000 description 2
• 206010016654 Fibrosis Diseases 0.000 description 2
• IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
• 206010018341 Gliosis Diseases 0.000 description 2
• 208000032007 Glycogen storage disease due to acid maltase deficiency 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
• 206010061218 Inflammation Diseases 0.000 description 2
• 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
• 102000004218 Insulin-Like Growth Factor I Human genes 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
• LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-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
• 102100033448 Lysosomal alpha-glucosidase Human genes 0.000 description 2
• 208000033868 Lysosomal disease Diseases 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
• 208000037490 Medically Unexplained Symptoms Diseases 0.000 description 2
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
• 206010072929 Mucolipidosis type III Diseases 0.000 description 2
• 208000002678 Mucopolysaccharidoses Diseases 0.000 description 2
• 208000035032 Multiple sulfatase deficiency Diseases 0.000 description 2
• 108010006140 N-sulfoglucosamine sulfohydrolase Proteins 0.000 description 2
• 206010060860 Neurological symptom Diseases 0.000 description 2
• 208000002537 Neuronal Ceroid-Lipofuscinoses Diseases 0.000 description 2
• 208000014060 Niemann-Pick disease Diseases 0.000 description 2
• 108091028043 Nucleic acid sequence Proteins 0.000 description 2
• 241000283973 Oryctolagus cuniculus Species 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
• 208000021811 Sandhoff disease Diseases 0.000 description 2
• 208000017460 Sialidosis type 2 Diseases 0.000 description 2
• 201000001828 Sly syndrome Diseases 0.000 description 2
• 208000022292 Tay-Sachs disease Diseases 0.000 description 2
• 101710132062 Transitional endoplasmic reticulum ATPase Proteins 0.000 description 2
• 108700001567 Type I Schindler Disease Proteins 0.000 description 2
• 208000026589 Wolman disease Diseases 0.000 description 2
• 230000005856 abnormality Effects 0.000 description 2
• 239000002253 acid Substances 0.000 description 2
• 239000000654 additive Substances 0.000 description 2
• IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 2
• VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
• 230000005875 antibody response Effects 0.000 description 2
• 239000013011 aqueous formulation Substances 0.000 description 2
• 230000001174 ascending effect Effects 0.000 description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
• 210000003050 axon Anatomy 0.000 description 2
• 230000004888 barrier function Effects 0.000 description 2
• 238000002869 basic local alignment search tool Methods 0.000 description 2
• 238000003766 bioinformatics method Methods 0.000 description 2
• 239000000090 biomarker Substances 0.000 description 2
• 210000004204 blood vessel Anatomy 0.000 description 2
• 230000036760 body temperature Effects 0.000 description 2
• 238000009835 boiling Methods 0.000 description 2
• 210000000988 bone and bone Anatomy 0.000 description 2
• 210000004958 brain cell Anatomy 0.000 description 2
• 239000008366 buffered solution Substances 0.000 description 2
• 238000011088 calibration curve Methods 0.000 description 2
• 238000005251 capillar electrophoresis Methods 0.000 description 2
• 235000011089 carbon dioxide Nutrition 0.000 description 2
• 238000005277 cation exchange chromatography Methods 0.000 description 2
• 238000012512 characterization method Methods 0.000 description 2
• 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
• 230000006999 cognitive decline Effects 0.000 description 2
• 238000004590 computer program Methods 0.000 description 2
• 230000003750 conditioning effect Effects 0.000 description 2
• 230000001276 controlling effect Effects 0.000 description 2
• 230000002596 correlated effect Effects 0.000 description 2
• 239000013078 crystal Substances 0.000 description 2
• 229960003067 cystine Drugs 0.000 description 2
• 230000006378 damage Effects 0.000 description 2
• 230000034994 death Effects 0.000 description 2
• 231100000517 death Toxicity 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
• 238000000502 dialysis Methods 0.000 description 2
• 210000002451 diencephalon Anatomy 0.000 description 2
• 238000010790 dilution Methods 0.000 description 2
• 239000012895 dilution Substances 0.000 description 2
• 231100000673 dose–response relationship Toxicity 0.000 description 2
• 230000009977 dual effect Effects 0.000 description 2
• 238000010828 elution Methods 0.000 description 2
• 210000002889 endothelial cell Anatomy 0.000 description 2
• 230000029142 excretion Effects 0.000 description 2
• 210000003754 fetus Anatomy 0.000 description 2
• 230000004761 fibrosis Effects 0.000 description 2
• 239000013022 formulation composition Substances 0.000 description 2
• 201000008049 fucosidosis Diseases 0.000 description 2
• 150000002270 gangliosides Chemical class 0.000 description 2
• 230000002068 genetic effect Effects 0.000 description 2
• 230000007387 gliosis Effects 0.000 description 2
• 229940097043 glucuronic acid Drugs 0.000 description 2
• 235000011187 glycerol Nutrition 0.000 description 2
• KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
• 210000003494 hepatocyte Anatomy 0.000 description 2
• 210000001320 hippocampus Anatomy 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
• 238000012744 immunostaining Methods 0.000 description 2
• 229940125721 immunosuppressive agent Drugs 0.000 description 2
• 230000001771 impaired effect Effects 0.000 description 2
• 238000001727 in vivo Methods 0.000 description 2
• 208000016245 inborn errors of metabolism Diseases 0.000 description 2
• 230000006698 induction Effects 0.000 description 2
• 230000001939 inductive effect Effects 0.000 description 2
• 230000004054 inflammatory process Effects 0.000 description 2
• 238000007918 intramuscular administration Methods 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
• 210000001865 kupffer cell Anatomy 0.000 description 2
• 210000005229 liver cell Anatomy 0.000 description 2
• 238000012792 lyophilization process Methods 0.000 description 2
• 239000012528 membrane Substances 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
• 230000004060 metabolic process Effects 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
• 238000007431 microscopic evaluation Methods 0.000 description 2
• 238000001565 modulated differential scanning calorimetry Methods 0.000 description 2
• 230000007659 motor function Effects 0.000 description 2
• 206010028093 mucopolysaccharidosis Diseases 0.000 description 2
• 208000036709 mucopolysaccharidosis type 3B Diseases 0.000 description 2
• 208000027333 mucopolysaccharidosis type IIID Diseases 0.000 description 2
• 208000012091 mucopolysaccharidosis type IVB Diseases 0.000 description 2
• 238000000569 multi-angle light scattering Methods 0.000 description 2
• 230000003472 neutralizing effect Effects 0.000 description 2
• 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 2
• 231100000252 nontoxic Toxicity 0.000 description 2
• 230000003000 nontoxic effect Effects 0.000 description 2
• 230000003204 osmotic effect Effects 0.000 description 2
• 239000001301 oxygen Substances 0.000 description 2
• 229910052760 oxygen Inorganic materials 0.000 description 2
• 230000036961 partial effect Effects 0.000 description 2
• 229960001412 pentobarbital Drugs 0.000 description 2
• WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
• 239000004033 plastic Substances 0.000 description 2
• 229920003023 plastic Polymers 0.000 description 2
• 239000000088 plastic resin Substances 0.000 description 2
• 229920001223 polyethylene glycol Polymers 0.000 description 2
• 229940068965 polysorbates Drugs 0.000 description 2
• 230000002028 premature Effects 0.000 description 2
• 238000011002 quantification Methods 0.000 description 2
• 238000010188 recombinant method Methods 0.000 description 2
• 238000012552 review Methods 0.000 description 2
• 238000012216 screening Methods 0.000 description 2
• 230000035945 sensitivity Effects 0.000 description 2
• 230000035939 shock Effects 0.000 description 2
• 208000011985 sialidosis Diseases 0.000 description 2
• 239000004447 silicone coating 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
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
• 238000001228 spectrum Methods 0.000 description 2
• 238000013112 stability test Methods 0.000 description 2
• 230000000087 stabilizing effect Effects 0.000 description 2
• 238000010189 synthetic method Methods 0.000 description 2
• 238000007910 systemic administration Methods 0.000 description 2
• 230000009885 systemic effect Effects 0.000 description 2
• 238000012800 visualization Methods 0.000 description 2
• BFCDFTHTSVTWOG-PXNSSMCTSA-N (1r,2s)-2-(octylamino)-1-(4-propan-2-ylsulfanylphenyl)propan-1-ol Chemical compound CCCCCCCCN[C@@H](C)[C@H](O)C1=CC=C(SC(C)C)C=C1 BFCDFTHTSVTWOG-PXNSSMCTSA-N 0.000 description 1
• KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-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
• DIROHOMJLWMERM-UHFFFAOYSA-N 3-[dimethyl(octadecyl)azaniumyl]propane-1-sulfonate Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCS([O-])(=O)=O DIROHOMJLWMERM-UHFFFAOYSA-N 0.000 description 1
• 108010055851 Acetylglucosaminidase Proteins 0.000 description 1
• 102000006772 Acid Ceramidase Human genes 0.000 description 1
• 108020005296 Acid Ceramidase Proteins 0.000 description 1
• 101800000263 Acidic protein Proteins 0.000 description 1
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
• 102100035028 Alpha-L-iduronidase Human genes 0.000 description 1
• 208000031277 Amaurotic familial idiocy Diseases 0.000 description 1
• 206010002091 Anaesthesia Diseases 0.000 description 1
• 240000003291 Armoracia rusticana Species 0.000 description 1
• 102100031491 Arylsulfatase B Human genes 0.000 description 1
• 206010003591 Ataxia Diseases 0.000 description 1
• 108090001008 Avidin Proteins 0.000 description 1
• 238000011725 BALB/c mouse Methods 0.000 description 1
• 241000894006 Bacteria Species 0.000 description 1
• 102000004506 Blood Proteins Human genes 0.000 description 1
• 108010017384 Blood Proteins Proteins 0.000 description 1
• 208000031648 Body Weight Changes Diseases 0.000 description 1
• 206010006187 Breast cancer Diseases 0.000 description 1
• YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
• 241000282465 Canis Species 0.000 description 1
• 241000283707 Capra Species 0.000 description 1
• 102000005572 Cathepsin A Human genes 0.000 description 1
• 108010059081 Cathepsin A Proteins 0.000 description 1
• RFLHUYUQCKHUKS-JUODUXDSSA-M Ceftiofur sodium Chemical compound [Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 RFLHUYUQCKHUKS-JUODUXDSSA-M 0.000 description 1
• 206010051290 Central nervous system lesion Diseases 0.000 description 1
• 241000282552 Chlorocebus aethiops Species 0.000 description 1
• 208000028698 Cognitive impairment Diseases 0.000 description 1
• 208000032170 Congenital Abnormalities Diseases 0.000 description 1
• 208000006069 Corneal Opacity Diseases 0.000 description 1
• 241000699800 Cricetinae Species 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
• 208000011518 Danon disease Diseases 0.000 description 1
• 241000045500 Diseae Species 0.000 description 1
• 238000001061 Dunnett's test Methods 0.000 description 1
• 241001269524 Dura Species 0.000 description 1
• 238000002965 ELISA Methods 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
• VXLCNTLWWUDBSO-UHFFFAOYSA-N Ethiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC)NC2=C1 VXLCNTLWWUDBSO-UHFFFAOYSA-N 0.000 description 1
• CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
• 108700024394 Exon Proteins 0.000 description 1
• 201000008808 Fibrosarcoma Diseases 0.000 description 1
• 201000008892 GM1 Gangliosidosis Diseases 0.000 description 1
• 102100028496 Galactocerebrosidase Human genes 0.000 description 1
• 108010042681 Galactosylceramidase Proteins 0.000 description 1
• 208000003098 Ganglion Cysts Diseases 0.000 description 1
• 208000009796 Gangliosidoses Diseases 0.000 description 1
• 102000004366 Glucosidases Human genes 0.000 description 1
• 108010056771 Glucosidases Proteins 0.000 description 1
• 102000004547 Glucosylceramidase Human genes 0.000 description 1
• 108010017544 Glucosylceramidase Proteins 0.000 description 1
• 229920002527 Glycogen Polymers 0.000 description 1
• 208000001500 Glycogen Storage Disease Type IIb Diseases 0.000 description 1
• 208000035148 Glycogen storage disease due to LAMP-2 deficiency Diseases 0.000 description 1
• 108010000540 Hexosaminidases Proteins 0.000 description 1
• 102000002268 Hexosaminidases Human genes 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
• 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
• 208000015178 Hurler syndrome Diseases 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
• 108010053927 Iduronate Sulfatase Proteins 0.000 description 1
• 108060003951 Immunoglobulin Proteins 0.000 description 1
• XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
• 244000147568 Laurus nobilis Species 0.000 description 1
• 235000017858 Laurus nobilis Nutrition 0.000 description 1
• 102000004882 Lipase Human genes 0.000 description 1
• 108090001060 Lipase Proteins 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• 208000007650 Meningeal Carcinomatosis Diseases 0.000 description 1
• 206010051696 Metastases to meninges Diseases 0.000 description 1
• 206010072928 Mucolipidosis type II 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
• 101000822667 Mus musculus Something about silencing protein 10 Proteins 0.000 description 1
• 108010027520 N-Acetylgalactosamine-4-Sulfatase Proteins 0.000 description 1
• 102100031688 N-acetylgalactosamine-6-sulfatase Human genes 0.000 description 1
• CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
• 201000000785 Niemann-Pick disease type C2 Diseases 0.000 description 1
• 238000012879 PET imaging Methods 0.000 description 1
• 206010057249 Phagocytosis Diseases 0.000 description 1
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
• 108091000080 Phosphotransferase Proteins 0.000 description 1
• 206010035226 Plasma cell myeloma Diseases 0.000 description 1
• 239000004743 Polypropylene Substances 0.000 description 1
• 102100036197 Prosaposin Human genes 0.000 description 1
• 101710152403 Prosaposin Proteins 0.000 description 1
• 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
• 208000008425 Protein deficiency Diseases 0.000 description 1
• 208000003251 Pruritus 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
• 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
• 108010008281 Recombinant Fusion Proteins Proteins 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
• 241001275899 Salta Species 0.000 description 1
• 208000025802 Sanfilippo syndrome type C Diseases 0.000 description 1
• 208000025804 Sanfilippo syndrome type D Diseases 0.000 description 1
• 201000002883 Scheie syndrome Diseases 0.000 description 1
• 206010039897 Sedation Diseases 0.000 description 1
• 208000000828 Sialic Acid Storage Disease Diseases 0.000 description 1
• 102000011971 Sphingomyelin Phosphodiesterase Human genes 0.000 description 1
• 108010061312 Sphingomyelin Phosphodiesterase Proteins 0.000 description 1
• 238000000692 Student's t-test Methods 0.000 description 1
• 239000012505 Superdex™ Substances 0.000 description 1
• 208000005400 Synovial Cyst Diseases 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
• 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
• 102000005488 Thioesterase Human genes 0.000 description 1
• RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
• 206010044565 Tremor Diseases 0.000 description 1
• BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-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
• 244000000188 Vaccinium ovalifolium Species 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
• HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 description 1
• LEBBDRXHHNYZIA-LDUWYPJVSA-N [(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] n-[(z)-1,3-dihydroxyoctadec-4-en-2-yl]carbamate Chemical compound CCCCCCCCCCCCC\C=C/C(O)C(CO)NC(=O)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O LEBBDRXHHNYZIA-LDUWYPJVSA-N 0.000 description 1
• SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
• 230000003187 abdominal effect Effects 0.000 description 1
• 238000010521 absorption reaction Methods 0.000 description 1
• 102000005421 acetyltransferase Human genes 0.000 description 1
• 108020002494 acetyltransferase Proteins 0.000 description 1
• 230000003213 activating effect Effects 0.000 description 1
• 239000012190 activator Substances 0.000 description 1
• 239000011149 active material Substances 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
• 108010028144 alpha-Glucosidases Proteins 0.000 description 1
• 230000004075 alteration Effects 0.000 description 1
• 210000004727 amygdala Anatomy 0.000 description 1
• 230000037005 anaesthesia Effects 0.000 description 1
• 238000010171 animal model Methods 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
• 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
• 235000009582 asparagine Nutrition 0.000 description 1
• 125000000613 asparagine group Chemical class N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
• 208000006673 asthma Diseases 0.000 description 1
• 210000001130 astrocyte Anatomy 0.000 description 1
• 229960002028 atropine sulfate Drugs 0.000 description 1
• 238000002555 auscultation Methods 0.000 description 1
• 230000008335 axon cargo transport 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
• 230000009286 beneficial effect Effects 0.000 description 1
• 235000019445 benzyl alcohol Nutrition 0.000 description 1
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
• 229960003237 betaine Drugs 0.000 description 1
• 229920002988 biodegradable polymer Polymers 0.000 description 1
• 239000004621 biodegradable polymer Substances 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• 235000015895 biscuits Nutrition 0.000 description 1
• 230000017531 blood circulation Effects 0.000 description 1
• 230000004579 body weight change Effects 0.000 description 1
• 239000007975 buffered saline Substances 0.000 description 1
• 230000003139 buffering effect Effects 0.000 description 1
• GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 description 1
• 229960001590 butorphanol tartrate Drugs 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 239000003560 cancer drug Substances 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 210000000845 cartilage Anatomy 0.000 description 1
• 210000003164 cauda equina Anatomy 0.000 description 1
• 229960004467 ceftiofur sodium Drugs 0.000 description 1
• 230000004700 cellular uptake Effects 0.000 description 1
• 229940106189 ceramide Drugs 0.000 description 1
• ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
• 210000003591 cerebellar nuclei Anatomy 0.000 description 1
• 208000019065 cervical carcinoma Diseases 0.000 description 1
• 239000002738 chelating agent Substances 0.000 description 1
• 239000003153 chemical reaction reagent Substances 0.000 description 1
• 239000003638 chemical reducing agent Substances 0.000 description 1
• 235000012000 cholesterol Nutrition 0.000 description 1
• 208000024042 cholesterol ester storage disease Diseases 0.000 description 1
• 208000013760 cholesteryl ester storage disease Diseases 0.000 description 1
• 230000015271 coagulation Effects 0.000 description 1
• 238000005345 coagulation Methods 0.000 description 1
• 230000001149 cognitive effect Effects 0.000 description 1
• 238000002648 combination therapy Methods 0.000 description 1
• 238000004891 communication Methods 0.000 description 1
• 238000007906 compression Methods 0.000 description 1
• 230000006835 compression Effects 0.000 description 1
• 230000036461 convulsion Effects 0.000 description 1
• 229920001577 copolymer Polymers 0.000 description 1
• 230000009260 cross reactivity 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
• 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
• 229960002806 daclizumab Drugs 0.000 description 1
• 238000007405 data analysis Methods 0.000 description 1
• 230000006240 deamidation Effects 0.000 description 1
• 230000007423 decrease Effects 0.000 description 1
• 239000007857 degradation product Substances 0.000 description 1
• 238000002242 deionisation method Methods 0.000 description 1
• 230000001934 delay Effects 0.000 description 1
• 230000002939 deleterious effect Effects 0.000 description 1
• 210000001787 dendrite Anatomy 0.000 description 1
• 238000003745 diagnosis Methods 0.000 description 1
• 238000010586 diagram Methods 0.000 description 1
• 235000014113 dietary fatty acids Nutrition 0.000 description 1
• 238000007865 diluting Methods 0.000 description 1
• 208000037765 diseases and disorders Diseases 0.000 description 1
• 238000004821 distillation Methods 0.000 description 1
• 239000003937 drug carrier Substances 0.000 description 1
• 229960001484 edetic acid Drugs 0.000 description 1
• 239000003792 electrolyte Substances 0.000 description 1
• 230000005670 electromagnetic radiation Effects 0.000 description 1
• 210000003038 endothelium Anatomy 0.000 description 1
• 206010015037 epilepsy Diseases 0.000 description 1
• 210000000647 epithalamus Anatomy 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
• 230000032050 esterification Effects 0.000 description 1
• 238000005886 esterification reaction Methods 0.000 description 1
• 229960000403 etanercept Drugs 0.000 description 1
• AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Natural products CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 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
• 238000013401 experimental design Methods 0.000 description 1
• 239000000284 extract Substances 0.000 description 1
• 230000001815 facial 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
• 230000003619 fibrillary effect Effects 0.000 description 1
• 239000008394 flocculating agent Substances 0.000 description 1
• MGCCHNLNRBULBU-WZTVWXICSA-N flunixin meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O MGCCHNLNRBULBU-WZTVWXICSA-N 0.000 description 1
• 229960000469 flunixin meglumine Drugs 0.000 description 1
• MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
• 238000007421 fluorometric assay Methods 0.000 description 1
• 239000012537 formulation buffer Substances 0.000 description 1
• 230000005021 gait Effects 0.000 description 1
• 210000000232 gallbladder Anatomy 0.000 description 1
• 201000006440 gangliosidosis Diseases 0.000 description 1
• 210000001035 gastrointestinal tract Anatomy 0.000 description 1
• 230000009477 glass transition Effects 0.000 description 1
• 230000002518 glial effect Effects 0.000 description 1
• 230000009688 glial response Effects 0.000 description 1
• 150000002298 globosides Chemical class 0.000 description 1
• 210000001905 globus pallidus Anatomy 0.000 description 1
• 150000008271 glucosaminides Chemical class 0.000 description 1
• 150000002305 glucosylceramides Chemical class 0.000 description 1
• 229940096919 glycogen Drugs 0.000 description 1
• 229930182470 glycoside Natural products 0.000 description 1
• 210000002288 golgi apparatus Anatomy 0.000 description 1
• 230000012010 growth Effects 0.000 description 1
• 229940093915 gynecological organic acid Drugs 0.000 description 1
• 210000001308 heart ventricle Anatomy 0.000 description 1
• 238000002685 hemilaminectomy Methods 0.000 description 1
• 229920000669 heparin Polymers 0.000 description 1
• 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 1
• 229960001008 heparin sodium Drugs 0.000 description 1
• 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
• 206010019847 hepatosplenomegaly Diseases 0.000 description 1
• 102000044162 human IGF1 Human genes 0.000 description 1
• 210000005260 human cell Anatomy 0.000 description 1
• 229920002674 hyaluronan Polymers 0.000 description 1
• 229960003160 hyaluronic acid Drugs 0.000 description 1
• BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 0.000 description 1
• 150000002433 hydrophilic molecules Chemical class 0.000 description 1
• 230000002209 hydrophobic effect Effects 0.000 description 1
• 206010020718 hyperplasia Diseases 0.000 description 1
• 102000018358 immunoglobulin Human genes 0.000 description 1
• 229940027941 immunoglobulin g Drugs 0.000 description 1
• 230000002055 immunohistochemical effect Effects 0.000 description 1
• 238000011532 immunohistochemical staining Methods 0.000 description 1
• 239000007943 implant Substances 0.000 description 1
• 238000002513 implantation Methods 0.000 description 1
• 230000006872 improvement Effects 0.000 description 1
• 208000015181 infectious disease Diseases 0.000 description 1
• 230000002757 inflammatory effect Effects 0.000 description 1
• 239000004615 ingredient Substances 0.000 description 1
• 230000005764 inhibitory process Effects 0.000 description 1
• 230000003834 intracellular effect Effects 0.000 description 1
• 238000007912 intraperitoneal administration Methods 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 1
• 239000007951 isotonicity adjuster Substances 0.000 description 1
• 208000017476 juvenile neuronal ceroid lipofuscinosis Diseases 0.000 description 1
• KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 1
• 210000003127 knee Anatomy 0.000 description 1
• 210000003140 lateral ventricle Anatomy 0.000 description 1
• 230000003902 lesion Effects 0.000 description 1
• 208000036546 leukodystrophy Diseases 0.000 description 1
• 239000003446 ligand Substances 0.000 description 1
• 239000006193 liquid solution Substances 0.000 description 1
• 238000011068 loading method Methods 0.000 description 1
• 238000012153 long-term therapy Methods 0.000 description 1
• 210000005265 lung cell Anatomy 0.000 description 1
• 230000002535 lyotropic effect Effects 0.000 description 1
• 230000002934 lysing effect Effects 0.000 description 1
• 239000012139 lysis buffer Substances 0.000 description 1
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
• 235000019341 magnesium sulphate Nutrition 0.000 description 1
• 150000002704 mannoses Chemical class 0.000 description 1
• 229940127554 medical product Drugs 0.000 description 1
• 210000001767 medulla oblongata Anatomy 0.000 description 1
• 210000001718 meningeal macrophage Anatomy 0.000 description 1
• 230000003458 metachromatic effect Effects 0.000 description 1
• 210000002891 metencephalon Anatomy 0.000 description 1
• 238000001471 micro-filtration Methods 0.000 description 1
• 230000002025 microglial effect Effects 0.000 description 1
• 239000008185 minitablet Substances 0.000 description 1
• 210000003470 mitochondria Anatomy 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 238000012544 monitoring process Methods 0.000 description 1
• 150000002772 monosaccharides Chemical class 0.000 description 1
• LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
• 239000004223 monosodium glutamate Substances 0.000 description 1
• 235000013923 monosodium glutamate Nutrition 0.000 description 1
• 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
• 208000020460 mucolipidosis II alpha/beta Diseases 0.000 description 1
• 208000000690 mucopolysaccharidosis VI Diseases 0.000 description 1
• 208000036707 mucopolysaccharidosis type 3C Diseases 0.000 description 1
• 208000036725 mucopolysaccharidosis type 3D Diseases 0.000 description 1
• 208000020004 mucopolysaccharidosis type 9 Diseases 0.000 description 1
• 208000012224 mucopolysaccharidosis type IIIC Diseases 0.000 description 1
• 210000003205 muscle Anatomy 0.000 description 1
• 201000000050 myeloid neoplasm Diseases 0.000 description 1
• MBLBDJOUHNCFQT-UHFFFAOYSA-N n-(3,4,5,6-tetrahydroxy-1-oxohexan-2-yl)acetamide Chemical compound CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 1
• NZXVYLJKFYSEPO-UHFFFAOYSA-N n-[3-(dimethylamino)propyl]-16-methylheptadecanamide Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)NCCCN(C)C NZXVYLJKFYSEPO-UHFFFAOYSA-N 0.000 description 1
• 238000001728 nano-filtration Methods 0.000 description 1
• 239000013642 negative control Substances 0.000 description 1
• 238000004848 nephelometry Methods 0.000 description 1
• 230000004770 neurodegeneration Effects 0.000 description 1
• 230000001123 neurodevelopmental effect Effects 0.000 description 1
• 210000005044 neurofilament Anatomy 0.000 description 1
• 230000000926 neurological effect Effects 0.000 description 1
• 201000008051 neuronal ceroid lipofuscinosis Diseases 0.000 description 1
• 201000007642 neuronal ceroid lipofuscinosis 1 Diseases 0.000 description 1
• 201000007607 neuronal ceroid lipofuscinosis 3 Diseases 0.000 description 1
• 230000007935 neutral effect Effects 0.000 description 1
• 230000003448 neutrophilic effect Effects 0.000 description 1
• VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
• 239000002736 nonionic surfactant Substances 0.000 description 1
• 210000002589 oculomotor nerve Anatomy 0.000 description 1
• 210000000956 olfactory bulb Anatomy 0.000 description 1
• 210000004248 oligodendroglia Anatomy 0.000 description 1
• 238000001543 one-way ANOVA Methods 0.000 description 1
• 210000001328 optic nerve Anatomy 0.000 description 1
• 210000005112 optic tract 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
• 229910052762 osmium Inorganic materials 0.000 description 1
• SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 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
• 239000006179 pH buffering agent Substances 0.000 description 1
• 238000002559 palpation Methods 0.000 description 1
• 210000004738 parenchymal cell Anatomy 0.000 description 1
• 239000008188 pellet Substances 0.000 description 1
• 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
• 230000003836 peripheral circulation Effects 0.000 description 1
• 210000001428 peripheral nervous system Anatomy 0.000 description 1
• 210000003067 perivascular macrophage Anatomy 0.000 description 1
• 230000035699 permeability Effects 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
• 230000008782 phagocytosis Effects 0.000 description 1
• 238000001050 pharmacotherapy Methods 0.000 description 1
• 102000020233 phosphotransferase Human genes 0.000 description 1
• 210000003446 pia mater Anatomy 0.000 description 1
• 238000011020 pilot scale process Methods 0.000 description 1
• 229920001993 poloxamer 188 Polymers 0.000 description 1
• 229940044519 poloxamer 188 Drugs 0.000 description 1
• 229920000728 polyester Polymers 0.000 description 1
• 229920005862 polyol Polymers 0.000 description 1
• 150000003077 polyols Chemical class 0.000 description 1
• 229920001155 polypropylene Polymers 0.000 description 1
• 229920002635 polyurethane Polymers 0.000 description 1
• 239000004814 polyurethane Substances 0.000 description 1
• 239000011148 porous material Substances 0.000 description 1
• FKKAEMQFOIDZNY-CODXZCKSSA-M prednisolone sodium succinate Chemical compound [Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC([O-])=O)[C@@H]4[C@@H]3CCC2=C1 FKKAEMQFOIDZNY-CODXZCKSSA-M 0.000 description 1
• 229960002176 prednisolone sodium succinate Drugs 0.000 description 1
• 238000012545 processing Methods 0.000 description 1
• 230000000069 prophylactic effect Effects 0.000 description 1
• 230000000272 proprioceptive effect Effects 0.000 description 1
• 230000004845 protein aggregation Effects 0.000 description 1
• 230000006920 protein precipitation Effects 0.000 description 1
• 239000012460 protein solution Substances 0.000 description 1
• 230000010349 pulsation Effects 0.000 description 1
• 230000001179 pupillary effect Effects 0.000 description 1
• 201000010108 pycnodysostosis Diseases 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
• 238000001953 recrystallisation Methods 0.000 description 1
• 210000000463 red nucleus Anatomy 0.000 description 1
• 239000012925 reference material Substances 0.000 description 1
• 230000001850 reproductive effect Effects 0.000 description 1
• 239000011347 resin Substances 0.000 description 1
• 229920005989 resin Polymers 0.000 description 1
• 230000029058 respiratory gaseous exchange Effects 0.000 description 1
• 230000036387 respiratory rate Effects 0.000 description 1
• 238000001223 reverse osmosis Methods 0.000 description 1
• 210000004761 scalp Anatomy 0.000 description 1
• 210000004116 schwann cell Anatomy 0.000 description 1
• 210000003497 sciatic nerve Anatomy 0.000 description 1
• 230000036280 sedation Effects 0.000 description 1
• 230000001953 sensory effect Effects 0.000 description 1
• 210000000717 sertoli cell Anatomy 0.000 description 1
• 229960002930 sirolimus Drugs 0.000 description 1
• 210000002027 skeletal muscle Anatomy 0.000 description 1
• 230000007958 sleep Effects 0.000 description 1
• 235000010288 sodium nitrite Nutrition 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
• 230000003381 solubilizing effect Effects 0.000 description 1
• 125000006850 spacer group Chemical group 0.000 description 1
• 238000013222 sprague-dawley male rat Methods 0.000 description 1
• 239000008223 sterile water Substances 0.000 description 1
• 239000008227 sterile water for injection Substances 0.000 description 1
• 210000002784 stomach Anatomy 0.000 description 1
• 238000007920 subcutaneous administration Methods 0.000 description 1
• 238000000859 sublimation Methods 0.000 description 1
• 230000008022 sublimation Effects 0.000 description 1
• 210000000495 subthalamus Anatomy 0.000 description 1
• 150000005846 sugar alcohols Chemical class 0.000 description 1
• 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
• 238000004781 supercooling Methods 0.000 description 1
• 239000006228 supernatant Substances 0.000 description 1
• 210000001590 sural nerve Anatomy 0.000 description 1
• 238000004114 suspension culture Methods 0.000 description 1
• 238000003786 synthesis reaction Methods 0.000 description 1
• 230000001839 systemic circulation Effects 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
• 108020002982 thioesterase Proteins 0.000 description 1
• 210000002972 tibial nerve Anatomy 0.000 description 1
• 210000001578 tight junction Anatomy 0.000 description 1
• 230000000451 tissue damage Effects 0.000 description 1
• 231100000827 tissue damage Toxicity 0.000 description 1
• 239000010936 titanium Substances 0.000 description 1
• 229910052719 titanium Inorganic materials 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
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 231100000027 toxicology Toxicity 0.000 description 1
• 238000012549 training Methods 0.000 description 1
• 230000005945 translocation Effects 0.000 description 1
• 238000011269 treatment regimen Methods 0.000 description 1
• 210000000427 trigeminal ganglion Anatomy 0.000 description 1
• GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
• 229960004791 tropicamide Drugs 0.000 description 1
• 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
• 238000007039 two-step reaction Methods 0.000 description 1
• 241000701447 unidentified baculovirus Species 0.000 description 1
• 238000002562 urinalysis Methods 0.000 description 1
• 230000002485 urinary effect Effects 0.000 description 1
• 210000003934 vacuole Anatomy 0.000 description 1
• 210000005166 vasculature Anatomy 0.000 description 1
• 210000004785 virchow-robin space Anatomy 0.000 description 1
• 238000005303 weighing Methods 0.000 description 1
• 239000000811 xylitol Substances 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
• 235000010447 xylitol Nutrition 0.000 description 1
• 229960002675 xylitol Drugs 0.000 description 1
• 210000005253 yeast cell Anatomy 0.000 description 1