AU2016366560A1 - Gene therapy for treating familial hypercholesterolemia - Google Patents
Gene therapy for treating familial hypercholesterolemia Download PDFInfo
- Publication number
- AU2016366560A1 AU2016366560A1 AU2016366560A AU2016366560A AU2016366560A1 AU 2016366560 A1 AU2016366560 A1 AU 2016366560A1 AU 2016366560 A AU2016366560 A AU 2016366560A AU 2016366560 A AU2016366560 A AU 2016366560A AU 2016366560 A1 AU2016366560 A1 AU 2016366560A1
- Authority
- AU
- Australia
- Prior art keywords
- vector
- raav
- aav8
- hldlr
- dose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 title claims description 91
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 title claims description 23
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 title claims description 22
- 201000001386 familial hypercholesterolemia Diseases 0.000 title claims description 22
- 238000001415 gene therapy Methods 0.000 title description 43
- 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 abstract description 98
- 238000000034 method Methods 0.000 claims abstract description 71
- 108010028554 LDL Cholesterol Proteins 0.000 claims abstract description 63
- 241000282414 Homo sapiens Species 0.000 claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 108010007622 LDL Lipoproteins Proteins 0.000 claims abstract description 22
- 230000010076 replication Effects 0.000 claims abstract description 22
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 21
- 239000000725 suspension Substances 0.000 claims abstract description 20
- 238000001802 infusion Methods 0.000 claims abstract description 19
- 101150102415 Apob gene Proteins 0.000 claims abstract description 18
- 210000003462 vein Anatomy 0.000 claims abstract description 17
- 230000002950 deficient Effects 0.000 claims abstract description 14
- 150000003626 triacylglycerols Chemical class 0.000 claims abstract description 14
- 241000702421 Dependoparvovirus Species 0.000 claims abstract description 13
- 230000002093 peripheral effect Effects 0.000 claims abstract description 13
- 102100040202 Apolipoprotein B-100 Human genes 0.000 claims abstract description 11
- 101710095342 Apolipoprotein B Proteins 0.000 claims abstract description 9
- 230000001925 catabolic effect Effects 0.000 claims abstract description 8
- 238000008214 LDL Cholesterol Methods 0.000 claims abstract 3
- 239000013598 vector Substances 0.000 claims description 231
- 101001051093 Homo sapiens Low-density lipoprotein receptor Proteins 0.000 claims description 160
- 208000030673 Homozygous familial hypercholesterolemia Diseases 0.000 claims description 69
- 210000004185 liver Anatomy 0.000 claims description 58
- 210000000234 capsid Anatomy 0.000 claims description 55
- 239000002245 particle Substances 0.000 claims description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 25
- 102000007330 LDL Lipoproteins Human genes 0.000 claims description 21
- 238000010172 mouse model Methods 0.000 claims description 21
- 230000007423 decrease Effects 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 10
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 10
- 239000002953 phosphate buffered saline Substances 0.000 claims description 10
- 229940127355 PCSK9 Inhibitors Drugs 0.000 claims description 9
- 239000012537 formulation buffer Substances 0.000 claims description 9
- 229920000080 bile acid sequestrant Polymers 0.000 claims description 8
- 229940096699 bile acid sequestrants Drugs 0.000 claims description 8
- 229960000815 ezetimibe Drugs 0.000 claims description 8
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims description 8
- 150000007523 nucleic acids Chemical group 0.000 claims description 8
- 230000037396 body weight Effects 0.000 claims description 7
- 229920001993 poloxamer 188 Polymers 0.000 claims description 7
- 229940044519 poloxamer 188 Drugs 0.000 claims description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 5
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229960003512 nicotinic acid Drugs 0.000 claims description 4
- 235000001968 nicotinic acid Nutrition 0.000 claims description 4
- 239000011664 nicotinic acid Substances 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 3
- 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 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 5
- 241001164825 Adeno-associated virus - 8 Species 0.000 claims 4
- 229910019142 PO4 Inorganic materials 0.000 claims 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 3
- 239000010452 phosphate Substances 0.000 claims 3
- 102100021244 Integral membrane protein GPR180 Human genes 0.000 claims 2
- 102000043555 human LDLR Human genes 0.000 description 146
- 102100028709 Thyroxine-binding globulin Human genes 0.000 description 104
- 101000837639 Homo sapiens Thyroxine-binding globulin Proteins 0.000 description 102
- 210000004027 cell Anatomy 0.000 description 83
- 238000011282 treatment Methods 0.000 description 69
- 108090000623 proteins and genes Proteins 0.000 description 67
- 241000699670 Mus sp. Species 0.000 description 55
- 230000014509 gene expression Effects 0.000 description 54
- 102000000853 LDL receptors Human genes 0.000 description 52
- 108010001831 LDL receptors Proteins 0.000 description 52
- 239000013612 plasmid Substances 0.000 description 51
- 241001465754 Metazoa Species 0.000 description 44
- 108700019146 Transgenes Proteins 0.000 description 38
- 238000004519 manufacturing process Methods 0.000 description 34
- 230000009467 reduction Effects 0.000 description 30
- 241000699666 Mus <mouse, genus> Species 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 27
- 201000001320 Atherosclerosis Diseases 0.000 description 24
- 108020004414 DNA Proteins 0.000 description 23
- 102000053602 DNA Human genes 0.000 description 23
- 238000003556 assay Methods 0.000 description 23
- 230000035772 mutation Effects 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 20
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 19
- 108010082126 Alanine transaminase Proteins 0.000 description 19
- 238000001990 intravenous administration Methods 0.000 description 19
- 239000000872 buffer Substances 0.000 description 18
- 210000002966 serum Anatomy 0.000 description 18
- 239000000463 material Substances 0.000 description 17
- 238000010361 transduction Methods 0.000 description 17
- 230000026683 transduction Effects 0.000 description 17
- 239000013607 AAV vector Substances 0.000 description 16
- 108010023302 HDL Cholesterol Proteins 0.000 description 16
- 150000001413 amino acids Chemical group 0.000 description 15
- 210000001744 T-lymphocyte Anatomy 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 14
- 230000001052 transient effect Effects 0.000 description 14
- 241000282553 Macaca Species 0.000 description 13
- 241000282560 Macaca mulatta Species 0.000 description 13
- 238000003306 harvesting Methods 0.000 description 13
- 230000007170 pathology Effects 0.000 description 13
- 238000003753 real-time PCR Methods 0.000 description 13
- 231100000419 toxicity Toxicity 0.000 description 13
- 230000001988 toxicity Effects 0.000 description 13
- 230000003612 virological effect Effects 0.000 description 13
- 241000702423 Adeno-associated virus - 2 Species 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 210000000709 aorta Anatomy 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 238000013411 master cell bank Methods 0.000 description 12
- -1 polyoxypropylene Polymers 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 238000009295 crossflow filtration Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 150000002632 lipids Chemical class 0.000 description 11
- 238000004806 packaging method and process Methods 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 10
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 10
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 10
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- 238000002617 apheresis Methods 0.000 description 10
- 230000027455 binding Effects 0.000 description 10
- 230000008859 change Effects 0.000 description 10
- 239000012091 fetal bovine serum Substances 0.000 description 10
- 230000003902 lesion Effects 0.000 description 10
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 10
- 238000012546 transfer Methods 0.000 description 10
- 108091026890 Coding region Proteins 0.000 description 9
- 102000003929 Transaminases Human genes 0.000 description 9
- 108090000340 Transaminases Proteins 0.000 description 9
- 108010069201 VLDL Cholesterol Proteins 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 239000003623 enhancer Substances 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 210000003494 hepatocyte Anatomy 0.000 description 9
- 229960003444 immunosuppressant agent Drugs 0.000 description 9
- 239000003018 immunosuppressive agent Substances 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 230000007774 longterm Effects 0.000 description 9
- 230000008488 polyadenylation Effects 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 238000004448 titration Methods 0.000 description 9
- 231100000041 toxicology testing Toxicity 0.000 description 9
- 101000805768 Banna virus (strain Indonesia/JKT-6423/1980) mRNA (guanine-N(7))-methyltransferase Proteins 0.000 description 8
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 8
- 101000686790 Chaetoceros protobacilladnavirus 2 Replication-associated protein Proteins 0.000 description 8
- 101000864475 Chlamydia phage 1 Internal scaffolding protein VP3 Proteins 0.000 description 8
- 101000803553 Eumenes pomiformis Venom peptide 3 Proteins 0.000 description 8
- 101000583961 Halorubrum pleomorphic virus 1 Matrix protein Proteins 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 230000005867 T cell response Effects 0.000 description 8
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 8
- 239000002299 complementary DNA Substances 0.000 description 8
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 235000009200 high fat diet Nutrition 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 230000003472 neutralizing effect Effects 0.000 description 8
- 239000013608 rAAV vector Substances 0.000 description 8
- 238000001890 transfection Methods 0.000 description 8
- 238000005199 ultracentrifugation Methods 0.000 description 8
- 108700028369 Alleles Proteins 0.000 description 7
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 108010067770 Endopeptidase K Proteins 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 7
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 7
- 102100032859 Protein AMBP Human genes 0.000 description 7
- 230000005856 abnormality Effects 0.000 description 7
- 238000011072 cell harvest Methods 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 7
- 238000011109 contamination Methods 0.000 description 7
- 238000009826 distribution Methods 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 230000002503 metabolic effect Effects 0.000 description 7
- 238000011012 sanitization Methods 0.000 description 7
- 241000701161 unidentified adenovirus Species 0.000 description 7
- 102100040214 Apolipoprotein(a) Human genes 0.000 description 6
- 101710115418 Apolipoprotein(a) Proteins 0.000 description 6
- 101800001691 Inter-alpha-trypsin inhibitor light chain Proteins 0.000 description 6
- 102000004895 Lipoproteins Human genes 0.000 description 6
- 108090001030 Lipoproteins Proteins 0.000 description 6
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 6
- 108010034546 Serratia marcescens nuclease Proteins 0.000 description 6
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 6
- 229960000723 ampicillin Drugs 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000001861 immunosuppressant effect Effects 0.000 description 6
- 230000002458 infectious effect Effects 0.000 description 6
- 229930027917 kanamycin Natural products 0.000 description 6
- 229960000318 kanamycin Drugs 0.000 description 6
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 6
- 229930182823 kanamycin A Natural products 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 239000013647 rAAV8 vector Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 102000003966 Alpha-1-microglobulin Human genes 0.000 description 5
- 101800001761 Alpha-1-microglobulin Proteins 0.000 description 5
- 108010008150 Apolipoprotein B-100 Proteins 0.000 description 5
- 101150044789 Cap gene Proteins 0.000 description 5
- 108090000565 Capsid Proteins Proteins 0.000 description 5
- 101710132601 Capsid protein Proteins 0.000 description 5
- 101710197658 Capsid protein VP1 Proteins 0.000 description 5
- 102100023321 Ceruloplasmin Human genes 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 5
- 241001135569 Human adenovirus 5 Species 0.000 description 5
- 101150013552 LDLR gene Proteins 0.000 description 5
- 101100510727 Mus musculus Ldlr gene Proteins 0.000 description 5
- 238000011887 Necropsy Methods 0.000 description 5
- 101710163270 Nuclease Proteins 0.000 description 5
- 101710118046 RNA-directed RNA polymerase Proteins 0.000 description 5
- 108090000631 Trypsin Proteins 0.000 description 5
- 102000004142 Trypsin Human genes 0.000 description 5
- 101710108545 Viral protein 1 Proteins 0.000 description 5
- 206010048215 Xanthomatosis Diseases 0.000 description 5
- 238000011213 bioburden testing Methods 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 230000010261 cell growth Effects 0.000 description 5
- 239000013592 cell lysate Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000011262 co‐therapy Methods 0.000 description 5
- 238000011026 diafiltration Methods 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 230000002688 persistence Effects 0.000 description 5
- 230000002028 premature Effects 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000012588 trypsin Substances 0.000 description 5
- 239000013603 viral vector Substances 0.000 description 5
- 102000006991 Apolipoprotein B-100 Human genes 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 208000035150 Hypercholesterolemia Diseases 0.000 description 4
- 108010033266 Lipoprotein(a) Proteins 0.000 description 4
- 102000057248 Lipoprotein(a) Human genes 0.000 description 4
- 101710081079 Minor spike protein H Proteins 0.000 description 4
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 230000003143 atherosclerotic effect Effects 0.000 description 4
- 210000000013 bile duct Anatomy 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- TZRFSLHOCZEXCC-HIVFKXHNSA-N chembl2219536 Chemical compound N1([C@H]2C[C@@H]([C@H](O2)COP(O)(=O)S[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)S[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)S[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C(C)=C2)=O)COP(O)(=O)S[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)S[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)S[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2CO)N2C3=C(C(NC(N)=N3)=O)N=C2)OCCOC)N2C(N=C(N)C(C)=C2)=O)OCCOC)N2C(N=C(N)C(C)=C2)=O)OCCOC)N2C(NC(=O)C(C)=C2)=O)OCCOC)N2C(N=C(N)C(C)=C2)=O)OCCOC)SP(O)(=O)OC[C@H]2O[C@H](C[C@@H]2SP(O)(=O)OC[C@H]2O[C@H](C[C@@H]2SP(O)(=O)OC[C@H]2O[C@H](C[C@@H]2SP(O)(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OCCOC)SP(O)(=O)OC[C@H]2[C@@H]([C@@H]([C@H](O2)N2C(N=C(N)C(C)=C2)=O)OCCOC)SP(O)(=O)OC[C@H]2[C@@H]([C@@H]([C@H](O2)N2C3=NC=NC(N)=C3N=C2)OCCOC)SP(O)(=O)OC[C@H]2[C@@H]([C@@H]([C@H](O2)N2C(N=C(N)C(C)=C2)=O)OCCOC)SP(O)(=O)OC[C@H]2[C@H](O)[C@@H]([C@H](O2)N2C(N=C(N)C(C)=C2)=O)OCCOC)N2C(N=C(N)C(C)=C2)=O)N2C(NC(=O)C(C)=C2)=O)N2C(NC(=O)C(C)=C2)=O)C=C(C)C(N)=NC1=O TZRFSLHOCZEXCC-HIVFKXHNSA-N 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 206010020718 hyperplasia Diseases 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 238000002483 medication Methods 0.000 description 4
- 229960004778 mipomersen Drugs 0.000 description 4
- 108091060283 mipomersen Proteins 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 230000010415 tropism Effects 0.000 description 4
- 238000011179 visual inspection Methods 0.000 description 4
- 239000007989 BIS-Tris Propane buffer Substances 0.000 description 3
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 3
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 3
- 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 description 3
- 108010054147 Hemoglobins Proteins 0.000 description 3
- 102000001554 Hemoglobins Human genes 0.000 description 3
- 241000282567 Macaca fascicularis Species 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 241000202347 Porcine circovirus Species 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 108020004682 Single-Stranded DNA Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108010000259 Thyroxine-Binding Globulin Proteins 0.000 description 3
- 108010067390 Viral Proteins Proteins 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000003957 anion exchange resin Substances 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- HHKZCCWKTZRCCL-UHFFFAOYSA-N bis-tris propane Chemical compound OCC(CO)(CO)NCCCNC(CO)(CO)CO HHKZCCWKTZRCCL-UHFFFAOYSA-N 0.000 description 3
- 238000011278 co-treatment Methods 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 238000012937 correction Methods 0.000 description 3
- 239000012538 diafiltration buffer Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000003292 diminished effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 235000020937 fasting conditions Nutrition 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000004727 humoral immunity Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 229960003566 lomitapide Drugs 0.000 description 3
- MBBCVAKAJPKAKM-UHFFFAOYSA-N lomitapide Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1(C(=O)NCC(F)(F)F)CCCCN(CC1)CCC1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 MBBCVAKAJPKAKM-UHFFFAOYSA-N 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000002572 peristaltic effect Effects 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 102000007592 Apolipoproteins Human genes 0.000 description 2
- 108010071619 Apolipoproteins Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 2
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 108091034131 VA RNA Proteins 0.000 description 2
- 206010048214 Xanthoma Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 2
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 2
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 238000013103 analytical ultracentrifugation Methods 0.000 description 2
- 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 description 2
- 108010006025 bovine growth hormone Proteins 0.000 description 2
- 238000004422 calculation algorithm Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 230000001143 conditioned effect Effects 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000011143 downstream manufacturing Methods 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 238000007449 liver function test Methods 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000007491 morphometric analysis Methods 0.000 description 2
- 230000003562 morphometric effect Effects 0.000 description 2
- 238000013425 morphometry Methods 0.000 description 2
- 238000002887 multiple sequence alignment Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 238000013146 percutaneous coronary intervention Methods 0.000 description 2
- 230000007255 peripheral T cell response Effects 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 231100000683 possible toxicity Toxicity 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 101150066583 rep gene Proteins 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000012289 standard assay Methods 0.000 description 2
- 230000007863 steatosis Effects 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- 238000011477 surgical intervention Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 239000002753 trypsin inhibitor Substances 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 210000002845 virion Anatomy 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 1
- ROHFNLRQFUQHCH-SHJFKSRGSA-N 2-amino-2,3,3,4,5,5,5-heptadeuterio-4-(trideuteriomethyl)pentanoic acid Chemical compound [2H]C([2H])([2H])C([2H])(C([2H])([2H])[2H])C([2H])([2H])C([2H])(N)C(O)=O ROHFNLRQFUQHCH-SHJFKSRGSA-N 0.000 description 1
- DGZSVBBLLGZHSF-UHFFFAOYSA-N 4,4-diethylpiperidine Chemical compound CCC1(CC)CCNCC1 DGZSVBBLLGZHSF-UHFFFAOYSA-N 0.000 description 1
- 101150009299 5.1 gene Proteins 0.000 description 1
- 241001164823 Adeno-associated virus - 7 Species 0.000 description 1
- 241000958487 Adeno-associated virus 3B Species 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 101710081722 Antitrypsin Proteins 0.000 description 1
- 108010027006 Apolipoproteins B Proteins 0.000 description 1
- 102000018616 Apolipoproteins B Human genes 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101100284398 Bos taurus BoLA-DQB gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 238000013382 DNA quantification Methods 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 108091029865 Exogenous DNA Proteins 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 208000009139 Gilbert Disease Diseases 0.000 description 1
- 208000022412 Gilbert syndrome Diseases 0.000 description 1
- 108010051815 Glutamyl endopeptidase Proteins 0.000 description 1
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 1
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 1
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 1
- 108010075704 HLA-A Antigens Proteins 0.000 description 1
- 108010058607 HLA-B Antigens Proteins 0.000 description 1
- 108010052199 HLA-C Antigens Proteins 0.000 description 1
- 108010039343 HLA-DRB1 Chains Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000018565 Hemochromatosis Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101500025164 Homo sapiens Alpha-1-microglobulin Proteins 0.000 description 1
- 101000889953 Homo sapiens Apolipoprotein B-100 Proteins 0.000 description 1
- 101000899111 Homo sapiens Hemoglobin subunit beta Proteins 0.000 description 1
- 101500025163 Homo sapiens Inter-alpha-trypsin inhibitor light chain Proteins 0.000 description 1
- 101100181495 Homo sapiens LDLR gene Proteins 0.000 description 1
- 101000923835 Homo sapiens Low density lipoprotein receptor adapter protein 1 Proteins 0.000 description 1
- 101001005139 Homo sapiens Protein limb expression 1 homolog Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108010046315 IDL Lipoproteins Proteins 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
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 101710172072 Kexin Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 102100034389 Low density lipoprotein receptor adapter protein 1 Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 101100491390 Mus musculus Apob gene Proteins 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 101710087110 ORF6 protein Proteins 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 238000002944 PCR assay Methods 0.000 description 1
- 229940122392 PCSK9 inhibitor Drugs 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 241000364051 Pima Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 108010044159 Proprotein Convertases Proteins 0.000 description 1
- 102000006437 Proprotein Convertases Human genes 0.000 description 1
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 description 1
- 101710180553 Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241001068295 Replication defective viruses Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 229920001304 Solutol HS 15 Polymers 0.000 description 1
- 108090000787 Subtilisin Proteins 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 238000010811 Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Methods 0.000 description 1
- 101710095001 Uncharacterized protein in nifU 5'region Proteins 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 208000036981 active tuberculosis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000011256 aggressive treatment Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000001475 anti-trypsic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 208000027119 bilirubin metabolic disease Diseases 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000010364 biochemical engineering Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003822 cell turnover Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002038 chemiluminescence detection Methods 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 239000012539 chromatography resin Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 231100000313 clinical toxicology Toxicity 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007847 digital PCR Methods 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000011304 droplet digital PCR Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000005670 electromagnetic radiation Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000003366 endpoint assay Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229960002027 evolocumab Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000012224 gene deletion Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 230000001553 hepatotropic effect Effects 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 102000048799 human SERPINA7 Human genes 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 208000036796 hyperbilirubinemia Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 230000003116 impacting effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 1
- 229960004359 iodixanol Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012317 liver biopsy Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 239000012092 media component Substances 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000009126 molecular therapy Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 230000037434 nonsense mutation Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008775 paternal effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012429 release testing Methods 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012609 strong anion exchange resin Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- 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
- C12N15/86—Viral vectors
- C12N15/861—Adenoviral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- 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
- C12N15/86—Viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
- A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
- A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0091—Purification or manufacturing processes for gene therapy compositions
-
- 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
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Virology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- Hematology (AREA)
- Toxicology (AREA)
- Dermatology (AREA)
- Manufacturing & Machinery (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2023201657A AU2023201657A1 (en) | 2015-12-11 | 2023-03-16 | Gene Therapy For Treating Familial Hypercholesterolemia |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562266383P | 2015-12-11 | 2015-12-11 | |
| US62/266,383 | 2015-12-11 | ||
| US201562269440P | 2015-12-18 | 2015-12-18 | |
| US62/269,440 | 2015-12-18 | ||
| PCT/US2016/065984 WO2017100682A1 (en) | 2015-12-11 | 2016-12-09 | Gene therapy for treating familial hypercholesterolemia |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2023201657A Division AU2023201657A1 (en) | 2015-12-11 | 2023-03-16 | Gene Therapy For Treating Familial Hypercholesterolemia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2016366560A1 true AU2016366560A1 (en) | 2018-06-28 |
Family
ID=57794341
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2016366560A Abandoned AU2016366560A1 (en) | 2015-12-11 | 2016-12-09 | Gene therapy for treating familial hypercholesterolemia |
| AU2023201657A Abandoned AU2023201657A1 (en) | 2015-12-11 | 2023-03-16 | Gene Therapy For Treating Familial Hypercholesterolemia |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2023201657A Abandoned AU2023201657A1 (en) | 2015-12-11 | 2023-03-16 | Gene Therapy For Treating Familial Hypercholesterolemia |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US10889832B2 (enExample) |
| EP (2) | EP3400304B1 (enExample) |
| JP (2) | JP7328760B2 (enExample) |
| KR (1) | KR20180113990A (enExample) |
| CN (2) | CN115957350A (enExample) |
| AU (2) | AU2016366560A1 (enExample) |
| BR (1) | BR112018011687A2 (enExample) |
| CA (1) | CA3008142A1 (enExample) |
| CO (1) | CO2018007165A2 (enExample) |
| ES (1) | ES2921450T3 (enExample) |
| IL (2) | IL303850A (enExample) |
| MA (1) | MA43570A (enExample) |
| MX (1) | MX2018007080A (enExample) |
| WO (1) | WO2017100682A1 (enExample) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015164778A1 (en) | 2014-04-25 | 2015-10-29 | The Trustees Of The University Of Pennysylvania | Ldlr variants and their use in compositions for reducing cholesterol levels |
| CN115957350A (zh) | 2015-12-11 | 2023-04-14 | 宾夕法尼亚州大学信托人 | 用于治疗家族性高胆固醇血症的基因疗法 |
| WO2018017956A2 (en) | 2016-07-21 | 2018-01-25 | Spark Therapeutics, Inc. | Scalable high recovery methods for producing high yield recombinant adeno-associated viral (raav) vector and recombinant adeno-associated viral (raav) vectors produced thereby |
| WO2018022511A1 (en) | 2016-07-25 | 2018-02-01 | The Trustees Of The University Of Pennsylvania | Compositions comprising a lecithin cholesterol acyltransferase variant and uses thereof |
| US11554147B2 (en) | 2017-02-20 | 2023-01-17 | The Trustees Of The University Of Pennsylvania | Gene therapy for treating familial hypercholesterolemia |
| KR20200104864A (ko) | 2017-11-30 | 2020-09-04 | 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 | 뮤코다당류증 iiib형에 대한 유전자 요법 |
| JP2022518354A (ja) * | 2018-12-20 | 2022-03-15 | ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア | 家族性高コレステロール血症を治療するための遺伝子療法 |
| JP2023503637A (ja) * | 2019-11-28 | 2023-01-31 | リジェネックスバイオ インコーポレイテッド | マイクロジストロフィン遺伝子治療コンストラクト及びその使用 |
| IL297756A (en) * | 2020-04-29 | 2022-12-01 | Saliogen Therapeutics Inc | Compositions and methods for treatment of familial hypercholesterolemia and elevated low-density lipoprotein cholesterol |
| AU2022214429A1 (en) | 2021-02-01 | 2023-09-14 | Tern Therapeutics, Llc | Gene therapy for neuronal ceroid lipofuscinoses |
| CN117887723A (zh) * | 2024-01-08 | 2024-04-16 | 苏州诺洁贝生物技术有限公司 | 密码子优化的ldlr基因及其应用 |
Family Cites Families (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5139941A (en) | 1985-10-31 | 1992-08-18 | University Of Florida Research Foundation, Inc. | AAV transduction vectors |
| US5436146A (en) | 1989-09-07 | 1995-07-25 | The Trustees Of Princeton University | Helper-free stocks of recombinant adeno-associated virus vectors |
| US6268213B1 (en) | 1992-06-03 | 2001-07-31 | Richard Jude Samulski | Adeno-associated virus vector and cis-acting regulatory and promoter elements capable of expressing at least one gene and method of using same for gene therapy |
| US5478745A (en) | 1992-12-04 | 1995-12-26 | University Of Pittsburgh | Recombinant viral vector system |
| US5869305A (en) | 1992-12-04 | 1999-02-09 | The University Of Pittsburgh | Recombinant viral vector system |
| US6204059B1 (en) | 1994-06-30 | 2001-03-20 | University Of Pittsburgh | AAV capsid vehicles for molecular transfer |
| US6093570A (en) | 1995-06-07 | 2000-07-25 | The University Of North Carolina At Chapel Hill | Helper virus-free AAV production |
| US5741683A (en) | 1995-06-07 | 1998-04-21 | The Research Foundation Of State University Of New York | In vitro packaging of adeno-associated virus DNA |
| AU728220B2 (en) | 1997-04-14 | 2001-01-04 | Cell Genesys, Inc. | Methods for increasing the efficiency of recombinant AAV product |
| WO1999061643A1 (en) | 1998-05-27 | 1999-12-02 | University Of Florida | Method of preparing recombinant adeno-associated virus compositions by using an iodixananol gradient |
| DE69941905D1 (de) | 1998-11-10 | 2010-02-25 | Univ North Carolina | Virusvektoren und verfahren für ihre herstellung und verabreichung. |
| JP4827353B2 (ja) | 1999-08-09 | 2011-11-30 | ターゲティッド ジェネティクス コーポレイション | 鎖内塩基対を形成するような配列の設計による、組換えウイルスベクターからの一本鎖の異種ヌクレオチド配列の発現の増大 |
| AU2001268149B2 (en) | 2000-06-01 | 2005-08-18 | University Of North Carolina At Chapel Hill | Methods and compounds for controlled release of recombinant parvovirus vectors |
| SG168422A1 (en) | 2001-11-13 | 2011-02-28 | Univ Pennsylvania | A method of detecting and/or identifying adeno-associated virus (aav) sequences and isolating novel sequences identified thereby |
| JP4810062B2 (ja) | 2001-12-17 | 2011-11-09 | ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア | アデノ随伴ウイルス（ａａｖ）血清型８の配列 |
| US20070015238A1 (en) | 2002-06-05 | 2007-01-18 | Snyder Richard O | Production of pseudotyped recombinant AAV virions |
| CN1780910A (zh) * | 2003-01-28 | 2006-05-31 | 拉塞有限公司 | 对与家族性高胆固醇血症有关的分离的低密度脂蛋白受体(ldl－r)的基因序列中的突变进行检测的方法和装置 |
| EP3910063A1 (en) | 2003-09-30 | 2021-11-17 | The Trustees of The University of Pennsylvania | Adeno-associated virus (aav) clades, sequences, vectors containing same, and uses therefor |
| EP3409296A1 (en) | 2005-04-07 | 2018-12-05 | The Trustees of the University of Pennsylvania | Method of increasing the function of an aav vector |
| JP4495210B2 (ja) | 2005-06-09 | 2010-06-30 | パナソニック株式会社 | 振幅誤差補償装置及び直交度誤差補償装置 |
| EP1986737A1 (en) | 2006-02-24 | 2008-11-05 | Kenergy Inc | Class-e radio frequency amplifier for use with an implantable medical device |
| EP2007795B1 (en) | 2006-03-30 | 2016-11-16 | The Board Of Trustees Of The Leland Stanford Junior University | Aav capsid proteins |
| KR101010352B1 (ko) | 2008-05-30 | 2011-01-25 | 삼성중공업 주식회사 | 전력 제어 장치 및 방법 |
| EP2391388A1 (en) * | 2009-01-29 | 2011-12-07 | University of California-San Francisco | Methods for distributing high levels of therapeutic agent throughout the cortex to treat neurological disorders |
| US20120252877A1 (en) * | 2009-08-14 | 2012-10-04 | Theramind Research, Llc | Methods and compositions for treatment of tuberous sclerosis complex |
| WO2011094198A1 (en) * | 2010-01-28 | 2011-08-04 | The Children's Hospital Of Philadelphia Research Institute, Abramson Research Center | A scalable manufacturing platform for viral vector purification and viral vectors so purified for use in gene therapy |
| WO2011126808A2 (en) | 2010-03-29 | 2011-10-13 | The Trustees Of The University Of Pennsylvania | Pharmacologically induced transgene ablation system |
| US9315825B2 (en) | 2010-03-29 | 2016-04-19 | The Trustees Of The University Of Pennsylvania | Pharmacologically induced transgene ablation system |
| BR112013032667A2 (pt) | 2011-06-20 | 2017-12-12 | Genentech Inc | polipeptídeo de ligação a pcsk9, ácido nucleico isolado, vetor, célula hospedeira, método para produzir o polipeptídeo, composição farmacêutica, método de redução do nível de colesterol ldl em um sujeito, método de tratamento de disfunção relacionada ao colesterol em um sujeito, método de tratamento de hipercolesterolemia em um sujeito, método de inibição da ligação de pcsk9 a ldlr e método de detecção da proteína pcsk9 em uma amostra |
| FR2977562B1 (fr) | 2011-07-06 | 2016-12-23 | Gaztransport Et Technigaz | Cuve etanche et thermiquement isolante integree dans une structure porteuse |
| EP2748185A1 (en) | 2011-08-24 | 2014-07-02 | The Board of Trustees of The Leland Stanford Junior University | New aav capsid proteins for nucleic acid transfer |
| PL4252857T3 (pl) | 2011-09-16 | 2025-03-03 | Regeneron Pharmaceuticals, Inc. | Sposoby redukowania poziomów lipoproteiny(a) poprzez podawanie inhibitora proproteinowej konwertazy subtylizyny keksyny-9 (pcsk9) |
| CN104520428B (zh) * | 2012-02-17 | 2018-09-21 | 费城儿童医院 | 将基因转移到细胞、器官和组织的aav载体组合物和方法 |
| DK2954051T3 (da) | 2013-02-08 | 2019-07-08 | Univ Pennsylvania | Modificeret kapsid til genoverførsel til behandling af nethinden |
| WO2014127196A1 (en) | 2013-02-15 | 2014-08-21 | The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services | Aav8 retinoschisin expression vector for treating x-linked retinoschisis |
| US8980864B2 (en) * | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
| JP6591956B2 (ja) * | 2013-03-15 | 2019-10-16 | ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア | Ｍｐｓ１を治療するための組成物および方法 |
| US9719106B2 (en) | 2013-04-29 | 2017-08-01 | The Trustees Of The University Of Pennsylvania | Tissue preferential codon modified expression cassettes, vectors containing same, and uses thereof |
| US10323076B2 (en) | 2013-10-03 | 2019-06-18 | Modernatx, Inc. | Polynucleotides encoding low density lipoprotein receptor |
| WO2015164778A1 (en) * | 2014-04-25 | 2015-10-29 | The Trustees Of The University Of Pennysylvania | Ldlr variants and their use in compositions for reducing cholesterol levels |
| ES2833230T3 (es) * | 2014-05-13 | 2021-06-14 | Univ Pennsylvania | Composiciones que comprenden AVV que expresan construcciones y usos de doble anticuerpo del mismo |
| CN115957350A (zh) | 2015-12-11 | 2023-04-14 | 宾夕法尼亚州大学信托人 | 用于治疗家族性高胆固醇血症的基因疗法 |
| EP3387117B1 (en) | 2015-12-11 | 2022-11-23 | The Trustees Of The University Of Pennsylvania | Scalable purification method for aav8 |
| US11554147B2 (en) | 2017-02-20 | 2023-01-17 | The Trustees Of The University Of Pennsylvania | Gene therapy for treating familial hypercholesterolemia |
-
2016
- 2016-12-09 CN CN202211286244.1A patent/CN115957350A/zh active Pending
- 2016-12-09 AU AU2016366560A patent/AU2016366560A1/en not_active Abandoned
- 2016-12-09 MA MA043570A patent/MA43570A/fr unknown
- 2016-12-09 EP EP16825936.4A patent/EP3400304B1/en active Active
- 2016-12-09 BR BR112018011687A patent/BR112018011687A2/pt not_active IP Right Cessation
- 2016-12-09 ES ES16825936T patent/ES2921450T3/es active Active
- 2016-12-09 EP EP22165782.8A patent/EP4085934A1/en not_active Withdrawn
- 2016-12-09 CN CN201680081580.9A patent/CN109121421B/zh active Active
- 2016-12-09 IL IL303850A patent/IL303850A/en unknown
- 2016-12-09 MX MX2018007080A patent/MX2018007080A/es unknown
- 2016-12-09 JP JP2018530566A patent/JP7328760B2/ja active Active
- 2016-12-09 IL IL259850A patent/IL259850B2/en unknown
- 2016-12-09 KR KR1020187019657A patent/KR20180113990A/ko not_active Ceased
- 2016-12-09 CA CA3008142A patent/CA3008142A1/en active Pending
- 2016-12-09 WO PCT/US2016/065984 patent/WO2017100682A1/en not_active Ceased
- 2016-12-09 US US16/060,409 patent/US10889832B2/en active Active
-
2018
- 2018-07-09 CO CONC2018/0007165A patent/CO2018007165A2/es unknown
-
2020
- 2020-11-17 US US16/950,272 patent/US20210285013A1/en not_active Abandoned
-
2022
- 2022-01-11 JP JP2022002190A patent/JP2022050575A/ja active Pending
-
2023
- 2023-03-16 AU AU2023201657A patent/AU2023201657A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR20180113990A (ko) | 2018-10-17 |
| US20210285013A1 (en) | 2021-09-16 |
| EP3400304A1 (en) | 2018-11-14 |
| ES2921450T3 (es) | 2022-08-25 |
| MX2018007080A (es) | 2018-11-12 |
| IL259850B2 (en) | 2023-11-01 |
| JP2022050575A (ja) | 2022-03-30 |
| EP4085934A1 (en) | 2022-11-09 |
| MA43570A (fr) | 2018-11-14 |
| CN109121421A (zh) | 2019-01-01 |
| CN115957350A (zh) | 2023-04-14 |
| IL259850B1 (en) | 2023-07-01 |
| US20190002917A1 (en) | 2019-01-03 |
| IL303850A (en) | 2023-08-01 |
| AU2023201657A1 (en) | 2023-06-15 |
| WO2017100682A1 (en) | 2017-06-15 |
| BR112018011687A2 (pt) | 2018-12-04 |
| CO2018007165A2 (es) | 2018-07-19 |
| US10889832B2 (en) | 2021-01-12 |
| JP2019504003A (ja) | 2019-02-14 |
| JP7328760B2 (ja) | 2023-08-17 |
| EP3400304B1 (en) | 2022-04-06 |
| IL259850A (en) | 2018-07-31 |
| CA3008142A1 (en) | 2017-06-15 |
| CN109121421B (zh) | 2022-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210285013A1 (en) | Gene therapy for treating familial hypercholesterolemia | |
| US20240000974A1 (en) | Gene therapy for treating hemophilia a | |
| US20230190837A1 (en) | Gene therapy for treating familial hypercholesterolemia | |
| US20220040332A1 (en) | Gene therapy for treating familial hypercholesterolemia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |