WO2023025193A1 - 神经生长因子突变体重组蛋白及其应用 - Google Patents
神经生长因子突变体重组蛋白及其应用 Download PDFInfo
- Publication number
- WO2023025193A1 WO2023025193A1 PCT/CN2022/114516 CN2022114516W WO2023025193A1 WO 2023025193 A1 WO2023025193 A1 WO 2023025193A1 CN 2022114516 W CN2022114516 W CN 2022114516W WO 2023025193 A1 WO2023025193 A1 WO 2023025193A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- recombinant protein
- ngf
- signal peptide
- seq
- composition
- Prior art date
Links
- 108010025020 Nerve Growth Factor Proteins 0.000 title claims abstract description 251
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 title claims abstract description 153
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 title claims abstract description 153
- 229940053128 nerve growth factor Drugs 0.000 title claims abstract description 113
- 102000015336 Nerve Growth Factor Human genes 0.000 title claims abstract 33
- 108010076504 Protein Sorting Signals Proteins 0.000 claims abstract description 274
- 108020004999 messenger RNA Proteins 0.000 claims abstract description 132
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 40
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 35
- 239000013598 vector Substances 0.000 claims abstract description 33
- 208000033808 peripheral neuropathy Diseases 0.000 claims abstract description 30
- 230000008439 repair process Effects 0.000 claims abstract description 13
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 11
- 231100000331 toxic Toxicity 0.000 claims abstract description 9
- 230000002588 toxic effect Effects 0.000 claims abstract description 9
- 230000002503 metabolic effect Effects 0.000 claims abstract description 8
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 111
- 150000002632 lipids Chemical class 0.000 claims description 108
- 239000000203 mixture Substances 0.000 claims description 93
- 150000007523 nucleic acids Chemical class 0.000 claims description 89
- 102000039446 nucleic acids Human genes 0.000 claims description 88
- 108020004707 nucleic acids Proteins 0.000 claims description 88
- 210000004027 cell Anatomy 0.000 claims description 87
- 102000040430 polynucleotide Human genes 0.000 claims description 68
- 108091033319 polynucleotide Proteins 0.000 claims description 68
- 239000002157 polynucleotide Substances 0.000 claims description 68
- 125000003729 nucleotide group Chemical group 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 55
- 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 claims description 54
- 239000002105 nanoparticle Substances 0.000 claims description 54
- 239000002773 nucleotide Substances 0.000 claims description 52
- 239000003981 vehicle Substances 0.000 claims description 47
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 claims description 40
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 claims description 40
- 210000004899 c-terminal region Anatomy 0.000 claims description 36
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 claims description 31
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 claims description 31
- 235000012000 cholesterol Nutrition 0.000 claims description 27
- -1 cationic lipid Chemical class 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 24
- 125000002091 cationic group Chemical group 0.000 claims description 22
- 230000004048 modification Effects 0.000 claims description 21
- 238000012986 modification Methods 0.000 claims description 21
- 108060003951 Immunoglobulin Proteins 0.000 claims description 20
- 102000018358 immunoglobulin Human genes 0.000 claims description 20
- 150000003904 phospholipids Chemical class 0.000 claims description 20
- 208000015114 central nervous system disease Diseases 0.000 claims description 19
- 208000027232 peripheral nervous system disease Diseases 0.000 claims description 19
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 18
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 18
- 102100033857 Neurotrophin-4 Human genes 0.000 claims description 17
- 239000002243 precursor Substances 0.000 claims description 17
- 241000282414 Homo sapiens Species 0.000 claims description 16
- 101000996663 Homo sapiens Neurotrophin-4 Proteins 0.000 claims description 16
- 238000000338 in vitro Methods 0.000 claims description 16
- 230000028327 secretion Effects 0.000 claims description 16
- 108020004414 DNA Proteins 0.000 claims description 15
- 102000007072 Nerve Growth Factors Human genes 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 13
- NRLNQCOGCKAESA-KWXKLSQISA-N [(6z,9z,28z,31z)-heptatriaconta-6,9,28,31-tetraen-19-yl] 4-(dimethylamino)butanoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCC(OC(=O)CCCN(C)C)CCCCCCCC\C=C/C\C=C/CCCCC NRLNQCOGCKAESA-KWXKLSQISA-N 0.000 claims description 13
- 239000003900 neurotrophic factor Substances 0.000 claims description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims description 13
- 208000024827 Alzheimer disease Diseases 0.000 claims description 12
- 210000002569 neuron Anatomy 0.000 claims description 12
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 claims description 11
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 claims description 11
- 239000004698 Polyethylene Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 230000000508 neurotrophic effect Effects 0.000 claims description 10
- 101710111383 Gene 64 protein Proteins 0.000 claims description 9
- 102100029268 Neurotrophin-3 Human genes 0.000 claims description 9
- 108010088751 Albumins Proteins 0.000 claims description 8
- 102000009027 Albumins Human genes 0.000 claims description 8
- 108020004705 Codon Proteins 0.000 claims description 8
- 101001094579 Enterobacteria phage HK97 Crossover junction endodeoxyribonuclease rusA Proteins 0.000 claims description 8
- 101000668235 Mycobacterium phage L5 Gene 67 protein Proteins 0.000 claims description 8
- 108700026244 Open Reading Frames Proteins 0.000 claims description 8
- 102000018968 Salivary Cystatins Human genes 0.000 claims description 8
- 108010026774 Salivary Cystatins Proteins 0.000 claims description 8
- 229920000573 polyethylene Polymers 0.000 claims description 8
- 230000001737 promoting effect Effects 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 108091026898 Leader sequence (mRNA) Proteins 0.000 claims description 7
- 108091036066 Three prime untranslated region Proteins 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000002502 liposome Substances 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- 210000000578 peripheral nerve Anatomy 0.000 claims description 7
- 206010062346 Congenital neuropathy Diseases 0.000 claims description 6
- 108010002350 Interleukin-2 Proteins 0.000 claims description 6
- 108010036176 Melitten Proteins 0.000 claims description 6
- 229930185560 Pseudouridine Natural products 0.000 claims description 6
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 claims description 6
- ULUMTYRKOVZPNM-JXOAFFINSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-(5-methoxy-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(OC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 ULUMTYRKOVZPNM-JXOAFFINSA-N 0.000 claims description 6
- YIJVOACVHQZMKI-JXOAFFINSA-N [[(2r,3s,4r,5r)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 YIJVOACVHQZMKI-JXOAFFINSA-N 0.000 claims description 6
- WGDUUQDYDIIBKT-UHFFFAOYSA-N beta-Pseudouridine Natural products OC1OC(CN2C=CC(=O)NC2=O)C(O)C1O WGDUUQDYDIIBKT-UHFFFAOYSA-N 0.000 claims description 6
- VDXZNPDIRNWWCW-JFTDCZMZSA-N melittin Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(N)=O)CC1=CNC2=CC=CC=C12 VDXZNPDIRNWWCW-JFTDCZMZSA-N 0.000 claims description 6
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 claims description 6
- 239000001226 triphosphate Substances 0.000 claims description 6
- 235000011178 triphosphate Nutrition 0.000 claims description 6
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 6
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000012377 drug delivery Methods 0.000 claims description 5
- 208000014674 injury Diseases 0.000 claims description 5
- 102000015833 Cystatin Human genes 0.000 claims description 4
- 208000012902 Nervous system disease Diseases 0.000 claims description 4
- 208000003435 Optic Neuritis Diseases 0.000 claims description 4
- 206010034620 Peripheral sensory neuropathy Diseases 0.000 claims description 4
- OLRONOIBERDKRE-XUTVFYLZSA-N [[(2r,3s,4r,5s)-3,4-dihydroxy-5-(1-methyl-2,4-dioxopyrimidin-5-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)N(C)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 OLRONOIBERDKRE-XUTVFYLZSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 108050004038 cystatin Proteins 0.000 claims description 4
- 230000004069 differentiation Effects 0.000 claims description 4
- 201000005572 sensory peripheral neuropathy Diseases 0.000 claims description 4
- 230000008733 trauma Effects 0.000 claims description 4
- 230000000472 traumatic effect Effects 0.000 claims description 4
- 108010007337 Azurin Proteins 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 101710154607 Azurocidin Proteins 0.000 claims description 2
- 230000035755 proliferation Effects 0.000 claims description 2
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 claims 7
- 102100030009 Azurocidin Human genes 0.000 claims 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims 1
- 210000005036 nerve Anatomy 0.000 abstract description 8
- 230000008929 regeneration Effects 0.000 abstract description 4
- 238000011069 regeneration method Methods 0.000 abstract description 4
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 208
- 241000699670 Mus sp. Species 0.000 description 42
- 102100037597 Brain-derived neurotrophic factor Human genes 0.000 description 34
- 235000001014 amino acid Nutrition 0.000 description 29
- 150000001413 amino acids Chemical class 0.000 description 27
- 235000018102 proteins Nutrition 0.000 description 27
- 208000002193 Pain Diseases 0.000 description 18
- 230000036407 pain Effects 0.000 description 18
- 102000004196 processed proteins & peptides Human genes 0.000 description 18
- 241000699666 Mus <mouse, genus> Species 0.000 description 17
- 229920001184 polypeptide Polymers 0.000 description 17
- 238000004873 anchoring Methods 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 102000008300 Mutant Proteins Human genes 0.000 description 10
- 108010021466 Mutant Proteins Proteins 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 230000035772 mutation Effects 0.000 description 9
- 208000000114 Pain Threshold Diseases 0.000 description 8
- 230000037040 pain threshold Effects 0.000 description 8
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 210000003169 central nervous system Anatomy 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 210000001428 peripheral nervous system Anatomy 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 238000013518 transcription Methods 0.000 description 7
- 230000035897 transcription Effects 0.000 description 7
- DLZKEQQWXODGGZ-KCJUWKMLSA-N 2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DLZKEQQWXODGGZ-KCJUWKMLSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 102000001708 Protein Isoforms Human genes 0.000 description 6
- 108010029485 Protein Isoforms Proteins 0.000 description 6
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 239000004475 Arginine Substances 0.000 description 5
- 101000739876 Homo sapiens Brain-derived neurotrophic factor Proteins 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- 108091008606 PDGF receptors Proteins 0.000 description 5
- 208000010886 Peripheral nerve injury Diseases 0.000 description 5
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 102000051542 human BDNF Human genes 0.000 description 5
- 229940090044 injection Drugs 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 210000000278 spinal cord Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 125000000129 anionic group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000007385 chemical modification Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 102000015533 trkA Receptor Human genes 0.000 description 4
- 108010064884 trkA Receptor Proteins 0.000 description 4
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 3
- HVLSXIKZNLPZJJ-TXZCQADKSA-N HA peptide Chemical compound C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HVLSXIKZNLPZJJ-TXZCQADKSA-N 0.000 description 3
- 101001111439 Homo sapiens Beta-nerve growth factor Proteins 0.000 description 3
- 101000801254 Homo sapiens Tumor necrosis factor receptor superfamily member 16 Proteins 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 208000037584 hereditary sensory and autonomic neuropathy Diseases 0.000 description 3
- 102000046917 human NGF Human genes 0.000 description 3
- 102000052073 human NGFR Human genes 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000006525 intracellular process Effects 0.000 description 3
- 230000004807 localization Effects 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- 239000002691 unilamellar liposome Substances 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 description 2
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 2
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 description 2
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 description 2
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 2
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 2
- LRFJOIPOPUJUMI-KWXKLSQISA-N 2-[2,2-bis[(9z,12z)-octadeca-9,12-dienyl]-1,3-dioxolan-4-yl]-n,n-dimethylethanamine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCC1(CCCCCCCC\C=C/C\C=C/CCCCC)OCC(CCN(C)C)O1 LRFJOIPOPUJUMI-KWXKLSQISA-N 0.000 description 2
- JQKOHRZNEOQNJE-ZZEZOPTASA-N 2-azaniumylethyl [3-octadecanoyloxy-2-[(z)-octadec-9-enoyl]oxypropyl] phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCC\C=C/CCCCCCCC JQKOHRZNEOQNJE-ZZEZOPTASA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 101710129634 Beta-nerve growth factor Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 101100506090 Caenorhabditis elegans hil-2 gene Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 2
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- XULFJDKZVHTRLG-JDVCJPALSA-N DOSPA trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)CCNC(=O)C(CCCNCCCN)NCCCN)OCCCCCCCC\C=C/CCCCCCCC XULFJDKZVHTRLG-JDVCJPALSA-N 0.000 description 2
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 2
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 2
- 241000963438 Gaussia <copepod> Species 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 108090000099 Neurotrophin-4 Proteins 0.000 description 2
- 108090000095 Neurotrophin-6 Proteins 0.000 description 2
- 101710124239 Poly(A) polymerase Proteins 0.000 description 2
- CZWCKYRVOZZJNM-UHFFFAOYSA-N Prasterone sodium sulfate Natural products C1C(OS(O)(=O)=O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 CZWCKYRVOZZJNM-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 description 2
- NONFBHXKNNVFMO-UHFFFAOYSA-N [2-aminoethoxy(tetradecanoyloxy)phosphoryl] tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OP(=O)(OCCN)OC(=O)CCCCCCCCCCCCC NONFBHXKNNVFMO-UHFFFAOYSA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- CZWCKYRVOZZJNM-USOAJAOKSA-N dehydroepiandrosterone sulfate Chemical compound C1[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 CZWCKYRVOZZJNM-USOAJAOKSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 229940077456 human brain-derived neurotrophic factor Drugs 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- WALUVDCNGPQPOD-UHFFFAOYSA-M 2,3-di(tetradecoxy)propyl-(2-hydroxyethyl)-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCOCC(C[N+](C)(C)CCO)OCCCCCCCCCCCCCC WALUVDCNGPQPOD-UHFFFAOYSA-M 0.000 description 1
- 108020005345 3' Untranslated Regions Proteins 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- 102100023990 60S ribosomal protein L17 Human genes 0.000 description 1
- 108010051457 Acid Phosphatase Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031873 Animal Disease Models Diseases 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- 108090000145 Bacillolysin Proteins 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 102100031673 Corneodesmosin Human genes 0.000 description 1
- 101710139375 Corneodesmosin Proteins 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 101900045614 Escherichia coli Outer membrane protein A Proteins 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000024452 GDNF Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 206010065681 HIV peripheral neuropathy Diseases 0.000 description 1
- 101710111502 Heat-stable enterotoxin ST Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000634196 Homo sapiens Neurotrophin-3 Proteins 0.000 description 1
- 101000848014 Homo sapiens Trypsin-2 Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 241000282596 Hylobatidae Species 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 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 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 235000019687 Lamb Nutrition 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 108050005735 Maltoporin Proteins 0.000 description 1
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101001050268 Mus musculus Kallikrein 1-related peptidase b3 Proteins 0.000 description 1
- 101001050264 Mus musculus Kallikrein 1-related peptidase-like b4 Proteins 0.000 description 1
- 101150111783 NTRK1 gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 102000003683 Neurotrophin-4 Human genes 0.000 description 1
- 102000035092 Neutral proteases Human genes 0.000 description 1
- 108091005507 Neutral proteases Proteins 0.000 description 1
- 108010079246 OMPA outer membrane proteins Proteins 0.000 description 1
- 241001482072 Oikopleura dioica Species 0.000 description 1
- 108700006385 OmpF Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101150023810 PHO1 gene Proteins 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108091093037 Peptide nucleic acid Proteins 0.000 description 1
- 108010090127 Periplasmic Proteins Proteins 0.000 description 1
- 241000282405 Pongo abelii Species 0.000 description 1
- 101710184309 Probable sucrose-6-phosphate hydrolase Proteins 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 101000605527 Rattus norvegicus Kallikrein-1 Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 101100271429 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ATP6 gene Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 101000582398 Staphylococcus aureus Replication initiation protein Proteins 0.000 description 1
- 101710112652 Sucrose-6-phosphate hydrolase Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 101710137500 T7 RNA polymerase Proteins 0.000 description 1
- 101100115751 Trypanosoma brucei brucei dnaaf11 gene Proteins 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- IXKSXJFAGXLQOQ-XISFHERQSA-N WHWLQLKPGQPMY Chemical group C([C@@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CNC=N1 IXKSXJFAGXLQOQ-XISFHERQSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- NYDLOCKCVISJKK-WRBBJXAJSA-N [3-(dimethylamino)-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CN(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC NYDLOCKCVISJKK-WRBBJXAJSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 108010034788 abrineurin Proteins 0.000 description 1
- 229950010081 abrineurin Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical class N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000011558 animal model by disease Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000003012 bilayer membrane Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 201000000887 hereditary sensory and autonomic neuropathy type 5 Diseases 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 102000043635 human AZU1 Human genes 0.000 description 1
- 102000057714 human NTF3 Human genes 0.000 description 1
- 102000043864 human PRSS2 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108010005131 levanase Proteins 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000010859 live-cell imaging Methods 0.000 description 1
- 230000017156 mRNA modification Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000031852 maintenance of location in cell Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- GLGLUQVVDHRLQK-WRBBJXAJSA-N n,n-dimethyl-2,3-bis[(z)-octadec-9-enoxy]propan-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCOCC(CN(C)C)OCCCCCCCC\C=C/CCCCCCCC GLGLUQVVDHRLQK-WRBBJXAJSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002241 neurite Anatomy 0.000 description 1
- 230000003955 neuronal function Effects 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 210000000929 nociceptor Anatomy 0.000 description 1
- 108091008700 nociceptors Proteins 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940108949 paclitaxel injection Drugs 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000002856 peripheral neuron Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 230000005892 protein maturation Effects 0.000 description 1
- 230000029983 protein stabilization Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 229940108461 rennet Drugs 0.000 description 1
- 108010058314 rennet Proteins 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 102000015534 trkB Receptor Human genes 0.000 description 1
- 108010064880 trkB Receptor Proteins 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical group 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/48—Nerve growth factor [NGF]
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- 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
- A61P25/28—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
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0618—Cells of the nervous system
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0684—Cells of the urinary tract or kidneys
- C12N5/0686—Kidney cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- 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
- C12N2510/00—Genetically modified cells
-
- 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
- C12N2800/00—Nucleic acids vectors
- C12N2800/10—Plasmid DNA
- C12N2800/106—Plasmid DNA for vertebrates
- C12N2800/107—Plasmid DNA for vertebrates for mammalian
Abstract
Description
Claims (109)
- 重组蛋白,其包含神经生长因子(NGF)蛋白变体以及与所述NGF蛋白变体连接的异源信号肽,其中,与野生型NGF蛋白相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少50%,与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少50%。
- 根据权利要求1所述的重组蛋白,其中所述野生型NGF蛋白包含SEQ ID NO:32所示的氨基酸序列。
- 根据权利要求1-2中任一项所述的重组蛋白,其中所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
- 根据权利要求1-3中任一项所述的重组蛋白,其中所述异源信号肽能够使得所述NGF蛋白变体的表达量和/或分泌量达到野生型NGF蛋白的50%以上。
- 根据权利要求1-4中任一项所述的重组蛋白,其中所述异源信号肽源自神经营养因子。
- 根据权利要求1-5中任一项所述的重组蛋白,其中所述异源信号肽源自脑源性神经营养因子(BDNF),神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)。
- 根据权利要求1-6中任一项所述的重组蛋白,其中所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白(Albumin,Alb)、IL-2、天青素前蛋白(Azurocidin preproprotein,APP)、小鼠IgK、免疫球蛋白重链(Immunoglobulin heavy chain,HC)和/或胱抑素-S前体(Cystatin-S precursor,Cystatin)。
- 根据权利要求1-7中任一项所述的重组蛋白,其中所述异源信号肽为IgK信号肽和/或BDNF信号肽。
- 根据权利要求1-8中任一项所述的重组蛋白,其中所述异源信号肽包含SEQ ID NO:30-31中任一项所示的氨基酸序列。
- 根据权利要求1-9中任一项所述的重组蛋白,其还包括前导肽。
- 根据权利要求10所述的重组蛋白,其中所述前导肽包含SEQ ID NO:34所示的氨基酸序列。
- 根据权利要求10-11中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述异源信号肽、所述前导肽和所述NGF蛋白变体。
- 根据权利要求10-12中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述IgK信号肽、所述前导肽和所述NGF蛋白变体。
- 根据权利要求1-13中任一项所述的重组蛋白,其包含SEQ ID NO:15-20中任一项所示的氨基酸序列。
- 根据权利要求1-13中任一项所述的重组蛋白,其包含SEQ ID NO:15和19中任一项所示的氨基酸序列。
- 根据权利要求1-15中任一项所述的重组蛋白,其还包括免疫球蛋白的Fc区。
- 根据权利要求16所述的重组蛋白,其中所述Fc区源自人免疫球蛋白和/或小鼠免疫球蛋白。
- 根据权利要求16-17中任一项中所述的重组蛋白,其中所述Fc区为人IgG1的Fc区。
- 根据权利要求16-18中任一项所述的重组蛋白,其中所述Fc区为小鼠IgG的Fc区。
- 根据权利要求16-19中任一项所述的重组蛋白,其中所述Fc区包含SEQ ID NO:56-57中任一项所示的氨基酸序列。
- 根据权利要求16-20中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述异源信号肽、所述前导肽、所述NGF蛋白变体和所述Fc区。
- 根据权利要求16-21中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述IgK信号肽、所述前导肽、所述NGF蛋白变体和所述Fc区。
- 根据权利要求1-22中任一项所述的重组蛋白,其包含SEQ ID NO:54-55中任一项所示的氨基酸序列。
- 分离的核酸分子,其编码权利要求1-23中任一项所述的重组蛋白。
- 根据权利要求24所述的核酸分子,其包括DNA和/或RNA。
- 根据权利要求24-25中任一项所述的核酸分子,其在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
- 根据权利要求24-26中任一项所述的核酸分子,其包含至少一种经修饰的核苷酸。
- 根据权利要求24-27中任一项所述的核酸分子,其包含的经修饰的核苷酸包含一种或多种选自下组的核苷酸:N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP)和5-甲基胞苷三磷酸(5-Methyl-CTP)。
- 根据权利要求24-28中任一项所述的核酸分子,其是密码子优化的。
- 根据权利要求24-29中任一项所述的核酸分子,其包含SEQ ID NO:3-8和46-47中任一项所示的核苷酸序列。
- 根据权利要求24-30中任一项所述的核酸分子,其包含SEQ ID NO:3和7中任一项所示的核苷酸序列。
- 根据权利要求24-31中任一项所述的核酸分子,其包含SEQ ID NO:11-12中任一项所示的核苷酸序列。
- 根据权利要求24-32中任一项所述的核酸分子,其包含SEQ ID NO:23-28和50-51中任一项所示的核苷酸序列。
- 根据权利要求16-21中任一项所述的核酸分子,其包含SEQ ID NO:23和27中任一项所示的核苷酸序列。
- 组合物,其包含(a)mRNA,所述mRNA包含编码神经生长因子(NGF)蛋白或其变体的多核苷酸,和(b)递送载体。
- 根据权利要求35所述的组合物,其中所述NGF蛋白包含SEQ ID NO:32所示的氨基酸序列。
- 根据权利要求35-36中任一项所述的组合物,其中与SEQ ID NO:32所示的氨基酸序列相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少50%。
- 根据权利要求35-37中任一项所述的组合物,其中所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
- 根据权利要求35-38中任一项所述的组合物,其中所述mRNA包含编码异源信号肽的多核苷酸,与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少50%。
- 根据权利要求39所述的组合物,其中所述异源信号肽能够使得所述NGF蛋白变体的表达量和/或分泌量达到野生型NGF蛋白的50%以上。
- 根据权利要求39-40中任一项所述的组合物,其中所述异源信号肽源自神经营养因子。
- 根据权利要求39-41中任一项所述的组合物,其中所述异源信号肽源自脑源性神经营养因子(BDNF),神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)。
- 根据权利要求39-42中任一项所述的组合物,其中所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白、IL-2、天青素前蛋白、小鼠IgK、免疫球蛋白重链和/或胱抑素-S前体。
- 根据权利要求39-43中任一项所述的组合物,其中所述异源信号肽为IgK信号肽和/或BDNF信号肽。
- 根据权利要求39-44中任一项所述的组合物,其中所述异源信号肽包含SEQ ID NO:30-31中任一项所示的氨基酸序列。
- 根据权利要求35-45中任一项所述的组合物,其中所述mRNA还包括编码前导肽的多核 苷酸。
- 根据权利要求46所述的组合物,其中所述前导肽包含SEQ ID NO:34所示的氨基酸序列。
- 根据权利要求46-47中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸和所述编码NGF蛋白或其变体的多核苷酸。
- 根据权利要求46-48中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
- 根据权利要求46-48中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括编码所述BDNF信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
- 根据权利要求35-50中任一项所述的组合物,其中所述mRNA编码包含如SEQ ID NO:14-20中任一项所示的氨基酸序列。
- 根据权利要求35-50中任一项所述的组合物,其中所述mRNA编码包含如SEQ ID NO:15和19中任一项所示的氨基酸序列。
- 根据权利要求35-52中任一项所述的组合物,其中所述mRNA还包含编码免疫球蛋白的Fc区的多核苷酸。
- 根据权利要求53所述的组合物,其中所述Fc区源自人免疫球蛋白和/或小鼠免疫球蛋白。
- 根据权利要求53-54中任一项中所述的组合物,其中所述Fc区为人IgG1的Fc区。
- 根据权利要求53-55中任一项所述的组合物,其中所述Fc区为小鼠IgG的Fc区。
- 根据权利要求53-56中任一项所述的组合物,其中所述Fc区包含SEQ ID NO:56-57中任一项所示的氨基酸序列。
- 根据权利要求53-57中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸、所述编码NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
- 根据权利要求53-58中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸、编码所述NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
- 根据权利要求35-59中任一项所述的组合物,其中所述mRNA编码包含SEQ ID NO:54-55中任一项所示的氨基酸序列。
- 根据权利要求35-60中任一项所述的组合物,其中所述mRNA在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
- 根据权利要求35-61中任一项所述的组合物,其中所述mRNA包含至少一种经修饰的核苷酸。
- 根据权利要求35-62中任一项所述的组合物,其中所述mRNA包含的经修饰的核苷酸包含一种或多种选自下组的核苷酸:N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP)和5-甲基胞苷三磷酸(5-Methyl-CTP)。
- 根据权利要求35-63中任一项所述的组合物,其中所述mRNA是密码子优化的。
- 根据权利要求35-64中任一项所述的组合物,其中所述mRNA包含如SEQ ID NO:22-28和50-51中任一项所示的核苷酸序列。
- 根据权利要求35-65中任一项所述的组合物,其中所述mRNA包含如SEQ ID NO:23和27中任一项所示的核苷酸序列。
- 根据权利要求35-66中任一项所述的组合物,其中所述递送载体包括脂质体。
- 根据权利要求35-67中任一项所述的组合物,其中所述递送载体包括脂质纳米颗粒(LNP)。
- 根据权利要求35-68中任一项所述的组合物,其中所述递送载体包括阳离子脂质。
- 根据权利要求69所述的组合物,在所述递送载体中,其中所述阳离子脂质的摩尔比为约45%至约55%。
- 根据权利要求69-70中任一项所述的组合物,其中所述阳离子脂质为SM102和DLin-MC3-DMA。
- 根据权利要求35-71中任一项所述的组合物,其中所述递送载体包括非阳离子脂质。
- 根据权利要求72所述的组合物,其中所述非阳离子脂质包括磷脂和/或脂质缀合物。
- 根据权利要求73所述的组合物,在所述递送载体中,其中所述磷脂的摩尔比为约35%至约40%。
- 根据权利要求73-74中任一项所述的组合物,其中所述磷脂包括二硬脂酰基磷脂酰胆碱(DSPC)。
- 根据权利要求73-75中任一项所述的组合物,其中所述脂质缀合物包括聚乙二醇修饰的脂 分子。
- 根据权利要求73-76中任一项所述的组合物,在所述递送载体中,其中所述脂质缀合物的摩尔比为约1%至约2%。
- 根据权利要求76-77中任一项所述的组合物,其中所述聚乙二醇修饰的脂分子包括PEG2000-DMG。
- 根据权利要求35-78中任一项所述的组合物,其中所述递送载体包括胆固醇。
- 根据权利要求79所述的组合物,在所述递送载体中,其中所述胆固醇的摩尔比为约8%至约12%。
- 根据权利要求35-80中任一项所述的组合物,其中所述递送载体包含阳离子脂质、胆固醇、磷脂和脂质缀合物,且所述阳离子脂质、胆固醇、磷脂和脂质缀合物的质量比为50:10:38.5:1.5。
- 根据权利要求35-81中任一项所述的组合物,其中所述递送载体包含DLin-MC3-DMA、胆固醇、DSPC和PEG2000-DMPE,且所述DLin-MC3-DMA、胆固醇、DSPC和PEG2000-DMPE的质量比为50:10:38.5:1.5。
- 根据权利要求35-82中任一项所述的组合物,其中所述递送载体的直径为约60nm至约500nm。
- 根据权利要求35-83中任一项所述的组合物,其中所述递送载体的直径为约80nm至约200nm。
- 根据权利要求35-84中任一项所述的组合物,其中所述mRNA包载在所述递送载体中。
- 载体,其包含权利要求24-34中任一项所述的核酸分子。
- 细胞,其包含权利要求24-34中任一项所述的核酸分子,和/或权利要求86所述的载体,或其表达权利要求1-23中任一项所述的重组蛋白。
- 制备权利要求1-23中任一项所述的重组蛋白的方法,所述方法包括在使得权利要求1-23中任一项所述的重组蛋白表达的条件下,培养根据权利要求87所述的细胞。
- 药物组合物,其包含权利要求1-23中任一项所述的重组蛋白、权利要求24-34中任一项所述的核酸分子、权利要求35-85中任一项所述的组合物、权利要求86所述的载体和/或权利要求87所述的细胞,以及任选地药学上可接受的载体。
- 试剂盒或给药装置,其包含权利要求1-23中任一项所述的重组蛋白、权利要求24-34中任一项所述的核酸分子、权利要求35-85中任一项所述的组合物、权利要求86所述的载体、权利要求87所述的细胞,和/或权利要求89所述的药物组合物。
- 缓解、预防和/或治疗中枢和/或周围神经系统疾病的方法,其包括向有需要的受试者施用权利要求1-23中任一项所述的重组蛋白、权利要求24-34中任一项所述的核酸分子、权利要求35-85中任一项所述的组合物、权利要求86所述的载体、权利要求87所述的细胞,和/或权利要求89所述的药物组合物。
- 根据权利要求91所述的方法,其中所述中枢和/或周围神经系统疾病包括神经退行性疾病。
- 根据权利要求91所述的方法,其中所述中枢和/或周围神经系统疾病包括周围神经病变。
- 根据权利要求93所述的方法,其中所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。
- 根据权利要求91所述的方法,其中所述中枢和/或周围神经系统疾病包括糖尿病周围神经病变、药物相关性周围神经病变、遗传性运动感觉神经病、周围神经外伤后修复、外伤性视神经炎和/或阿尔茨海默症。
- 权利要求1-23中任一项所述的重组蛋白、权利要求24-34中任一项所述的核酸分子、权利要求35-85中任一项所述的组合物、权利要求86所述的载体、权利要求87所述的细胞,和/或权利要求89所述的药物组合物在制备药物中的用途,所述药物用于缓解、预防和/或治疗中枢和/或周围神经系统疾病。
- 根据权利要求96所述的用途,其中所述中枢和/或周围神经系统疾病包括神经退行性疾病。
- 根据权利要求96所述的用途,其中所述中枢和/或周围神经系统疾病包括周围神经病变。
- 根据权利要求98所述的用途,其中所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。
- 根据权利要求96所述的用途,其中所述中枢和/或周围神经系统疾病包括糖尿病周围神经病变、药物相关性周围神经病变、遗传性运动感觉神经病、周围神经外伤后修复、外伤性视神经炎和/或阿尔茨海默症。
- 促进神经生长因子(NGF)蛋白分泌和/或表达的方法,其包括使用权利要求1-23中任一项所述的重组蛋白、权利要求24-34中任一项所述的核酸分子、权利要求35-85中任一项所述的组合物、权利要求86所述的载体、权利要求87所述的细胞,和/或权利要求89所述的药物组合物。
- 根据权利要求101所述的方法,其为非治疗目的的方法。
- 根据权利要求101所述的方法,其为体外的和/或离体的方法。
- 促进神经细胞增殖和/或分化的方法,其包括使用权利要求1-23中任一项所述的重组蛋白、权利要求24-34中任一项所述的核酸分子、权利要求35-85中任一项所述的组合物、权利要求86所述的载体、权利要求87所述的细胞,和/或权利要求89所述的药物组合物。
- 根据权利要求104所述的方法,其为非治疗目的的方法。
- 根据权利要求104所述的方法,其为体外的和/或离体的方法。
- 修复损伤的神经细胞的方法,其包括使用权利要求1-23中任一项所述的重组蛋白、权利要求24-34中任一项所述的核酸分子、权利要求35-85中任一项所述的组合物、权利要求86所述的载体、权利要求87所述的细胞,和/或权利要求89所述的药物组合物。
- 根据权利要求107所述的方法,其为非治疗目的的方法。
- 根据权利要求107所述的方法,其为体外的和/或离体的方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110981721 | 2021-08-25 | ||
CN202110981721.5 | 2021-08-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023025193A1 true WO2023025193A1 (zh) | 2023-03-02 |
Family
ID=82862610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/114516 WO2023025193A1 (zh) | 2021-08-25 | 2022-08-24 | 神经生长因子突变体重组蛋白及其应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN114933657B (zh) |
WO (1) | WO2023025193A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114933657B (zh) * | 2021-08-25 | 2024-02-02 | 上海交通大学医学院 | 神经生长因子突变体重组蛋白及其应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080286323A1 (en) * | 2004-01-19 | 2008-11-20 | Nsgene A/S | Human Therapeutic Cells Secreting Nerve Growth Factor |
WO2012170452A2 (en) * | 2011-06-06 | 2012-12-13 | The Regents Of The University Of California | Compositions and methods for treating neurodegenerative diseases |
CN106008722A (zh) * | 2016-05-13 | 2016-10-12 | 未名生物医药有限公司 | 一种重组β-hNGF-Fc融合蛋白、制备方法及用途 |
CN110809476A (zh) * | 2017-04-05 | 2020-02-18 | 奎西拉有限公司 | 用于神经退行性病症或中风的治疗的基因构建体 |
CN110869386A (zh) * | 2017-02-10 | 2020-03-06 | 维维巴巴公司 | 重组神经生长因子的组合物和方法 |
CN114933657A (zh) * | 2021-08-25 | 2022-08-23 | 上海交通大学医学院 | 神经生长因子突变体重组蛋白及其应用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009150470A2 (en) * | 2008-06-12 | 2009-12-17 | Syntaxin Limited | Suppression of cancers |
AU2010206374B2 (en) * | 2009-01-23 | 2013-01-17 | Gloriana Therapeutics Sarl | Improved cell lines and their use in encapsulated cell biodelivery |
CN108178798B (zh) * | 2016-12-08 | 2021-03-30 | 苏州方德门达新药开发有限公司 | pH工程化的NGF抗体及其医药用途 |
CN108314723A (zh) * | 2018-01-11 | 2018-07-24 | 温州医科大学 | 一种人源突变型神经生长因子及其制备方法和应用 |
CN108610398B (zh) * | 2018-01-15 | 2020-08-11 | 武汉海特生物制药股份有限公司 | 一段功能序列及在分泌蛋白表达中的应用 |
-
2022
- 2022-02-17 CN CN202210147754.4A patent/CN114933657B/zh active Active
- 2022-08-24 WO PCT/CN2022/114516 patent/WO2023025193A1/zh active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080286323A1 (en) * | 2004-01-19 | 2008-11-20 | Nsgene A/S | Human Therapeutic Cells Secreting Nerve Growth Factor |
WO2012170452A2 (en) * | 2011-06-06 | 2012-12-13 | The Regents Of The University Of California | Compositions and methods for treating neurodegenerative diseases |
CN106008722A (zh) * | 2016-05-13 | 2016-10-12 | 未名生物医药有限公司 | 一种重组β-hNGF-Fc融合蛋白、制备方法及用途 |
CN110869386A (zh) * | 2017-02-10 | 2020-03-06 | 维维巴巴公司 | 重组神经生长因子的组合物和方法 |
CN110809476A (zh) * | 2017-04-05 | 2020-02-18 | 奎西拉有限公司 | 用于神经退行性病症或中风的治疗的基因构建体 |
CN114933657A (zh) * | 2021-08-25 | 2022-08-23 | 上海交通大学医学院 | 神经生长因子突变体重组蛋白及其应用 |
Non-Patent Citations (4)
Title |
---|
"Genbank", Database accession no. NP_002497.2 |
"UniProtKB", Database accession no. P34130 |
WANG, QIAN; WANG, QIAN; WANG, ZHI-PING; XU, QIN; BAO, NAN: "Effects of Ganglioside 1 and Nerve Growth Factor on the Proliferation of Neural Stem Cells In Vitro", ZHONGGUO DANGDAI ERKE ZAZHI - CHINESE JOURNAL OF CONTEMPORARYPEDIATRICS, ZHONGNAN DAXUE,, CN, vol. 11, no. 10, 11 December 2009 (2009-12-11), CN , pages 841 - 845, XP009543863, ISSN: 1008-8830 * |
YANG WANLIN, SUNG KIJUNG, ZHOU FENGLI, XU WEI, RISSMAN ROBERT A., DING JIANQING, WU CHENGBIAO: "Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System", FRONTIERS IN AGING NEUROSCIENCE, vol. 10, XP093039573, DOI: 10.3389/fnagi.2018.00373 * |
Also Published As
Publication number | Publication date |
---|---|
CN114933657B (zh) | 2024-02-02 |
CN114933657A (zh) | 2022-08-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7240675B2 (ja) | オトフェルリンを発現させるための組成物および方法 | |
Leone et al. | Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease | |
US20210024907A1 (en) | Nucleic acid-based therapeutics | |
CN100475846C (zh) | 增加的神经胚素分泌 | |
Puras et al. | Protamine/DNA/niosome ternary nonviral vectors for gene delivery to the retina: the role of protamine | |
CN103906527A (zh) | Mrna递送的脂质纳米颗粒组合物和方法 | |
WO2023025193A1 (zh) | 神经生长因子突变体重组蛋白及其应用 | |
WO2021233346A1 (zh) | 一种被靶向修饰且装载有药物的外泌体及其制备方法和应用 | |
KR20010093804A (ko) | 심근증 유전자 치료 | |
WO2005120548A1 (en) | Method of treating parkinson’s disease in humans by direct infusion of glial cell-line derived neurotrophic factor into the zona incerta | |
Zhang et al. | Lipofectin-facilitated transfer of cholecystokinin gene corrects behavioral abnormalities of rats with audiogenic seizures | |
BR112020024377A2 (pt) | vetores de vírus adeno-associados para o tratamento de mucopolissacaridose tipo iv a | |
CN111909246B (zh) | 高效感染支持细胞的aav突变体 | |
JP2023508504A (ja) | Gdnfを分泌する哺乳動物細胞およびそれらの治療的使用 | |
US20210222167A1 (en) | Slc2a1 lncrna as a biologic and related treatments and methods | |
KR20110009084A (ko) | 눈-관련된 장애의 치료방법 | |
Canver | Evaluation of the Clinical Success of Ex Vivo and In Vivo Gene Therapy | |
US11793890B2 (en) | ELOVL2 constructs for human gene therapy | |
US20240002818A1 (en) | Mammalian mobile element compositions, systems and therapeutic applications | |
US20230078498A1 (en) | Targeted Translation of RNA with CRISPR-Cas13 to Enhance Protein Synthesis | |
WO2024068898A1 (en) | Therapy by trans-splicing of opa1 pre-messenger rnas for the treatment of diseases associated with opa1 gene mutations | |
JP2011084569A (ja) | プロサポシン受容体活性を刺激する方法 | |
JP2002524468A (ja) | プロサポシン受容体活性を刺激する方法 | |
KR20240019244A (ko) | Apoe 및 apob 변형 지질 나노입자 조성물, 및 이의 용도 | |
WO2022011099A1 (en) | Modified hexosaminidase and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22860539 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 22860539.0 Country of ref document: EP Ref document number: 2022860539 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2022860539 Country of ref document: EP Effective date: 20240221 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |