WO2020106772A1 - Agents thérapeutiques de type exosomes chargés pour le traitement de la stéatohépatite non alcoolique, du diabète sucré de type 1 et de type 2, de l'athérosclérose et de la déficience en alpha-1 antitrypsine - Google Patents
Agents thérapeutiques de type exosomes chargés pour le traitement de la stéatohépatite non alcoolique, du diabète sucré de type 1 et de type 2, de l'athérosclérose et de la déficience en alpha-1 antitrypsineInfo
- Publication number
- WO2020106772A1 WO2020106772A1 PCT/US2019/062293 US2019062293W WO2020106772A1 WO 2020106772 A1 WO2020106772 A1 WO 2020106772A1 US 2019062293 W US2019062293 W US 2019062293W WO 2020106772 A1 WO2020106772 A1 WO 2020106772A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- exosome
- cargo
- exosomes
- human
- combination
- Prior art date
Links
- 210000001808 exosome Anatomy 0.000 title claims abstract description 433
- 201000001320 Atherosclerosis Diseases 0.000 title claims abstract description 35
- 206010003210 Arteriosclerosis Diseases 0.000 title claims abstract description 34
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 title claims abstract description 32
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 25
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 title abstract description 33
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 title abstract description 17
- 238000011282 treatment Methods 0.000 title description 64
- 239000003814 drug Substances 0.000 title description 26
- 210000004027 cell Anatomy 0.000 claims abstract description 55
- 239000000203 mixture Substances 0.000 claims abstract description 35
- 210000000805 cytoplasm Anatomy 0.000 claims abstract 4
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 claims abstract 2
- 239000013612 plasmid Substances 0.000 claims description 173
- 108090000623 proteins and genes Proteins 0.000 claims description 65
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 claims description 47
- 101000824278 Homo sapiens Acyl-[acyl-carrier-protein] hydrolase Proteins 0.000 claims description 46
- 230000008685 targeting Effects 0.000 claims description 40
- 230000003472 neutralizing effect Effects 0.000 claims description 39
- 102100040200 Mitochondrial uncoupling protein 2 Human genes 0.000 claims description 29
- 101710112393 Mitochondrial uncoupling protein 2 Proteins 0.000 claims description 29
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 claims description 29
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 claims description 27
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 108091030071 RNAI Proteins 0.000 claims description 23
- 230000009368 gene silencing by RNA Effects 0.000 claims description 23
- 102000004169 proteins and genes Human genes 0.000 claims description 23
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 20
- 239000011701 zinc Substances 0.000 claims description 20
- 229910052725 zinc Inorganic materials 0.000 claims description 20
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 claims description 19
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 claims description 19
- 239000003446 ligand Substances 0.000 claims description 19
- 239000003642 reactive oxygen metabolite Substances 0.000 claims description 18
- 102000005962 receptors Human genes 0.000 claims description 18
- 108020003175 receptors Proteins 0.000 claims description 18
- 102100026882 Alpha-synuclein Human genes 0.000 claims description 16
- 102000051325 Glucagon Human genes 0.000 claims description 16
- 108060003199 Glucagon Proteins 0.000 claims description 16
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 claims description 16
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 16
- 229960004666 glucagon Drugs 0.000 claims description 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 16
- -1 hrlnsulin/GF-l Proteins 0.000 claims description 15
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 claims description 14
- 241001430294 unidentified retrovirus Species 0.000 claims description 13
- 101000930020 Homo sapiens Diacylglycerol O-acyltransferase 2 Proteins 0.000 claims description 10
- 102000058038 human DGAT2 Human genes 0.000 claims description 10
- 102000047715 human FAS Human genes 0.000 claims description 10
- 102000004877 Insulin Human genes 0.000 claims description 8
- 108090001061 Insulin Proteins 0.000 claims description 8
- 229940125396 insulin Drugs 0.000 claims description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- 108010078791 Carrier Proteins Proteins 0.000 claims description 5
- 108010039731 Fatty Acid Synthases Proteins 0.000 claims description 5
- 102000047000 human FGF19 Human genes 0.000 claims description 5
- 241000702421 Dependoparvovirus Species 0.000 claims description 4
- 102000001902 CC Chemokines Human genes 0.000 claims description 2
- 108010040471 CC Chemokines Proteins 0.000 claims description 2
- 102000002148 Diacylglycerol O-acyltransferase Human genes 0.000 claims description 2
- 108010001348 Diacylglycerol O-acyltransferase Proteins 0.000 claims description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 2
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 claims description 2
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 claims description 2
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 claims description 2
- 102000003802 alpha-Synuclein Human genes 0.000 claims description 2
- 108090000185 alpha-Synuclein Proteins 0.000 claims description 2
- 239000003102 growth factor Substances 0.000 claims description 2
- 210000001685 thyroid gland Anatomy 0.000 claims description 2
- 102000015303 Fatty Acid Synthases Human genes 0.000 claims 4
- 108020004459 Small interfering RNA Proteins 0.000 claims 4
- 239000004055 small Interfering RNA Substances 0.000 claims 4
- 102000057234 Acyl transferases Human genes 0.000 claims 1
- 108700016155 Acyl transferases Proteins 0.000 claims 1
- 101500028774 Homo sapiens Glucagon-like peptide 1 Proteins 0.000 claims 1
- 229940126864 fibroblast growth factor Drugs 0.000 claims 1
- 201000000083 maturity-onset diabetes of the young type 1 Diseases 0.000 claims 1
- 102100022712 Alpha-1-antitrypsin Human genes 0.000 abstract description 31
- 101000823116 Homo sapiens Alpha-1-antitrypsin Proteins 0.000 abstract description 15
- 230000035772 mutation Effects 0.000 abstract description 14
- 108020004414 DNA Proteins 0.000 description 164
- 238000000034 method Methods 0.000 description 107
- 238000011018 current good manufacturing practice Methods 0.000 description 48
- 238000004519 manufacturing process Methods 0.000 description 36
- 230000037361 pathway Effects 0.000 description 36
- 230000014509 gene expression Effects 0.000 description 34
- 238000005516 engineering process Methods 0.000 description 33
- 210000001124 body fluid Anatomy 0.000 description 32
- 239000010839 body fluid Substances 0.000 description 32
- 238000010362 genome editing Methods 0.000 description 30
- 101710163270 Nuclease Proteins 0.000 description 29
- 206010007558 Cardiac failure chronic Diseases 0.000 description 28
- 108091006277 SLC5A1 Proteins 0.000 description 28
- 108091006269 SLC5A2 Proteins 0.000 description 28
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 28
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 28
- 238000011068 loading method Methods 0.000 description 28
- 230000001225 therapeutic effect Effects 0.000 description 28
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 21
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 21
- 238000002560 therapeutic procedure Methods 0.000 description 21
- 230000005923 long-lasting effect Effects 0.000 description 19
- 102000013814 Wnt Human genes 0.000 description 18
- 108050003627 Wnt Proteins 0.000 description 18
- 230000002018 overexpression Effects 0.000 description 18
- 230000011664 signaling Effects 0.000 description 18
- 108091033409 CRISPR Proteins 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 17
- 238000010459 TALEN Methods 0.000 description 17
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 description 17
- 229960000723 ampicillin Drugs 0.000 description 17
- 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 17
- 229960003722 doxycycline Drugs 0.000 description 17
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 17
- 229930027917 kanamycin Natural products 0.000 description 17
- 229960000318 kanamycin Drugs 0.000 description 17
- 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 17
- 229930182823 kanamycin A Natural products 0.000 description 17
- 239000002245 particle Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 16
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 16
- 241000282412 Homo Species 0.000 description 16
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 16
- 238000013459 approach Methods 0.000 description 16
- 230000001684 chronic effect Effects 0.000 description 16
- 239000005090 green fluorescent protein Substances 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 16
- 206010067482 No adverse event Diseases 0.000 description 15
- 230000008867 communication pathway Effects 0.000 description 15
- 239000000556 agonist Substances 0.000 description 14
- 238000011278 co-treatment Methods 0.000 description 14
- 238000002955 isolation Methods 0.000 description 14
- 108700028369 Alleles Proteins 0.000 description 13
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 13
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 13
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 13
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 13
- 210000004185 liver Anatomy 0.000 description 13
- 241000701022 Cytomegalovirus Species 0.000 description 12
- 108010029485 Protein Isoforms Proteins 0.000 description 12
- 102000001708 Protein Isoforms Human genes 0.000 description 12
- 238000001727 in vivo Methods 0.000 description 12
- 238000009097 single-agent therapy Methods 0.000 description 12
- 230000008569 process Effects 0.000 description 11
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000013598 vector Substances 0.000 description 10
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 description 9
- 238000004113 cell culture Methods 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 230000003248 secreting effect Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 241000713666 Lentivirus Species 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 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 7
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 208000019425 cirrhosis of liver Diseases 0.000 description 7
- 230000007812 deficiency Effects 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 238000002743 insertional mutagenesis Methods 0.000 description 7
- 239000003550 marker Substances 0.000 description 7
- 210000005259 peripheral blood Anatomy 0.000 description 7
- 239000011886 peripheral blood Substances 0.000 description 7
- 208000007056 sickle cell anemia Diseases 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 208000024172 Cardiovascular disease Diseases 0.000 description 6
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 6
- 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 6
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 6
- 208000008589 Obesity Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000002526 effect on cardiovascular system Effects 0.000 description 6
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 6
- 238000000275 quality assurance Methods 0.000 description 6
- 230000009863 secondary prevention Effects 0.000 description 6
- 150000003384 small molecules Chemical class 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 206010016654 Fibrosis Diseases 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- 101150069374 Serpina1 gene Proteins 0.000 description 5
- 239000012190 activator Substances 0.000 description 5
- 230000001476 alcoholic effect Effects 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 230000007882 cirrhosis Effects 0.000 description 5
- 238000012937 correction Methods 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- 230000009862 primary prevention Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 108700001624 vesicular stomatitis virus G Proteins 0.000 description 5
- 239000013607 AAV vector Substances 0.000 description 4
- 229930024421 Adenine Natural products 0.000 description 4
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 4
- 229960000643 adenine Drugs 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000030279 gene silencing Effects 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000036542 oxidative stress Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 206010009208 Cirrhosis alcoholic Diseases 0.000 description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 3
- 208000008960 Diabetic foot Diseases 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- 206010014561 Emphysema Diseases 0.000 description 3
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 3
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 description 3
- 208000001280 Prediabetic State Diseases 0.000 description 3
- 208000010002 alcoholic liver cirrhosis Diseases 0.000 description 3
- 239000000074 antisense oligonucleotide Substances 0.000 description 3
- 238000012230 antisense oligonucleotides Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000006143 cell culture medium Substances 0.000 description 3
- 208000033679 diabetic kidney disease Diseases 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 238000012226 gene silencing method Methods 0.000 description 3
- 208000004104 gestational diabetes Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 238000001050 pharmacotherapy Methods 0.000 description 3
- 201000009104 prediabetes syndrome Diseases 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000009103 reabsorption Effects 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 230000007863 steatosis Effects 0.000 description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 description 3
- 102000004217 thyroid hormone receptors Human genes 0.000 description 3
- 108090000721 thyroid hormone receptors Proteins 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 description 2
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 2
- 101100337060 Caenorhabditis elegans glp-1 gene Proteins 0.000 description 2
- 241000450599 DNA viruses Species 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- 102000004533 Endonucleases Human genes 0.000 description 2
- 206010048554 Endothelial dysfunction Diseases 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- 108020005004 Guide RNA Proteins 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 2
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- 208000036741 Pruritus generalised Diseases 0.000 description 2
- 208000033626 Renal failure acute Diseases 0.000 description 2
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 2
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 2
- YAJCHEVQCOHZDC-QMMNLEPNSA-N actrapid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@H](C)CC)[C@H](C)CC)[C@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C(N)=O)C1=CNC=N1 YAJCHEVQCOHZDC-QMMNLEPNSA-N 0.000 description 2
- 201000011040 acute kidney failure Diseases 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 210000002806 clathrin-coated vesicle Anatomy 0.000 description 2
- 230000006395 clathrin-mediated endocytosis Effects 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000012202 endocytosis Effects 0.000 description 2
- 230000008694 endothelial dysfunction Effects 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229950004152 insulin human Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 230000000771 oncological effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940113082 thymine Drugs 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 200000000007 Arterial disease Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 101150003888 FASN gene Proteins 0.000 description 1
- 101150051399 FGF19 gene Proteins 0.000 description 1
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000000857 Hepatic Insufficiency Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 101100120063 Homo sapiens FGF21 gene Proteins 0.000 description 1
- 101001033249 Homo sapiens Interleukin-1 beta Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- 101150088952 IGF1 gene Proteins 0.000 description 1
- 102100039065 Interleukin-1 beta Human genes 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- LTYOQGRJFJAKNA-KKIMTKSISA-N Malonyl CoA Natural products S(C(=O)CC(=O)O)CCNC(=O)CCNC(=O)[C@@H](O)C(CO[P@](=O)(O[P@](=O)(OC[C@H]1[C@@H](OP(=O)(O)O)[C@@H](O)[C@@H](n2c3ncnc(N)c3nc2)O1)O)O)(C)C LTYOQGRJFJAKNA-KKIMTKSISA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 102100029820 Mitochondrial brown fat uncoupling protein 1 Human genes 0.000 description 1
- 108050002686 Mitochondrial brown fat uncoupling protein 1 Proteins 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- 206010054107 Nodule Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 108020004566 Transfer RNA Proteins 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 102000007238 Transferrin Receptors Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002404 acyltransferase inhibitor Substances 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000011948 assay development Methods 0.000 description 1
- 238000007681 bariatric surgery Methods 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 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 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 229960001713 canagliflozin Drugs 0.000 description 1
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000012696 congenital leptin deficiency Diseases 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940096118 ella Drugs 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 108010052621 fas Receptor Proteins 0.000 description 1
- 102000018823 fas Receptor Human genes 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 230000003352 fibrogenic effect Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010363 gene targeting Methods 0.000 description 1
- 230000007614 genetic variation Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000036252 glycation Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000011194 good manufacturing practice Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000038002 heart failure with reduced ejection fraction Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000037456 inflammatory mechanism Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000001871 ion mobility spectroscopy Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000003520 lipogenic effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- LTYOQGRJFJAKNA-DVVLENMVSA-N malonyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-DVVLENMVSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 208000001022 morbid obesity Diseases 0.000 description 1
- 210000000885 nephron Anatomy 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5176—Compounds of unknown constitution, e.g. material from plants or animals
- A61K9/5184—Virus capsids or envelopes enclosing drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
Abstract
L'invention concerne une composition qui permet d'administrer une charge au cytoplasme d'une cellule, la charge étant capable de traiter la stéatohépatite non alcoolique, la stéatose hépatique non alcoolique, le diabète sucré de type 1 et de type 2, l'athérosclérose et la déficience en alpha-1 antitrypsine. Dans un autre mode de réalisation, la composition comprend : un exosome; une charge située à l'intérieur de l'exosome, la charge comprenant un petit ARN interférent (ARNsi) qui épuise les sites actifs des protéines de transport glucose-sodium. Dans un autre mode de réalisation, la composition comprend : un exosome; un emplacement pour une charge à l'intérieur de l'exosome, la charge étant capable de corriger la mutation antisens SERPINA1 de 'Z' à 'M'.
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862769123P | 2018-11-19 | 2018-11-19 | |
| US62/769,123 | 2018-11-19 | ||
| US201862769744P | 2018-11-20 | 2018-11-20 | |
| US201862769711P | 2018-11-20 | 2018-11-20 | |
| US62/769,744 | 2018-11-20 | ||
| US62/769,711 | 2018-11-20 | ||
| US201862770640P | 2018-11-21 | 2018-11-21 | |
| US62/770,640 | 2018-11-21 | ||
| US16/591,502 US20200102563A1 (en) | 2018-10-02 | 2019-10-02 | Exosome loaded therapeutics for treating sickle cell disease |
| US16/591,502 | 2019-10-02 | ||
| US16/591,483 US20200101016A1 (en) | 2018-10-02 | 2019-10-02 | Compositions and methods for producing exosome loaded therapeutics for treating cardiovascular disease |
| US16/591,483 | 2019-10-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2020106772A1 true WO2020106772A1 (fr) | 2020-05-28 |
| WO2020106772A9 WO2020106772A9 (fr) | 2020-07-16 |
Family
ID=70773180
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2019/062293 WO2020106772A1 (fr) | 2018-11-19 | 2019-11-19 | Agents thérapeutiques de type exosomes chargés pour le traitement de la stéatohépatite non alcoolique, du diabète sucré de type 1 et de type 2, de l'athérosclérose et de la déficience en alpha-1 antitrypsine |
| PCT/US2019/062291 WO2020106771A1 (fr) | 2018-11-19 | 2019-11-19 | Compositions et procédés de production d'agents thérapeutiques chargés d'exosomes pour le traitement de multiples troubles oncologiques |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2019/062291 WO2020106771A1 (fr) | 2018-11-19 | 2019-11-19 | Compositions et procédés de production d'agents thérapeutiques chargés d'exosomes pour le traitement de multiples troubles oncologiques |
Country Status (1)
| Country | Link |
|---|---|
| WO (2) | WO2020106772A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114940976A (zh) * | 2022-07-26 | 2022-08-26 | 深圳市茵冠生物科技有限公司 | 一种过表达融合蛋白ptgfrn-glp-1工程化外泌体的制备方法及其应用 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022206738A1 (fr) * | 2021-03-29 | 2022-10-06 | 南京大学 | Système d'administration d'arn plasmidique et son application |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040018191A1 (en) * | 2002-05-24 | 2004-01-29 | Schering Corporation | Neutralizing human anti-IGFR antibody |
| US20090304693A1 (en) * | 2008-06-03 | 2009-12-10 | Abbott Laboratories | Dual Variable Domain Immunoglobulins and Uses Thereof |
| WO2015089465A1 (fr) * | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Relargage, utilisation et applications thérapeutiques de systèmes crispr-cas et compositions pour maladies et troubles viraux et attribuables au vhb |
| WO2016205613A1 (fr) * | 2015-06-18 | 2016-12-22 | The Broad Institute Inc. | Mutations d'enzyme crispr qui réduisent les effets non ciblés |
| US20180193270A1 (en) * | 2016-11-29 | 2018-07-12 | PureTech Health LLC | Exosomes for delivery of therapeutic agents |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016187717A1 (fr) * | 2015-05-26 | 2016-12-01 | Exerkine Corporation | Exosomes utiles pour l'édition génomique |
| US11458097B2 (en) * | 2016-03-30 | 2022-10-04 | The University Of North Carolina At Chapel Hill | Biological agent-exosome compositions and uses thereof |
| CN111479557A (zh) * | 2017-12-15 | 2020-07-31 | 得克萨斯州大学系统董事会 | 用于使用外排体相关基因编辑来治疗癌症的方法和组合物 |
| EA202091486A1 (ru) * | 2018-02-12 | 2021-02-08 | Кодиак Байосайенсес, Инк. | Способы и композиции для поляризации макрофагов |
| GB201804291D0 (en) * | 2018-03-16 | 2018-05-02 | Evox Therapeutics Ltd | Cell-mediated exosome delivery |
-
2019
- 2019-11-19 WO PCT/US2019/062293 patent/WO2020106772A1/fr active Application Filing
- 2019-11-19 WO PCT/US2019/062291 patent/WO2020106771A1/fr active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040018191A1 (en) * | 2002-05-24 | 2004-01-29 | Schering Corporation | Neutralizing human anti-IGFR antibody |
| US20090304693A1 (en) * | 2008-06-03 | 2009-12-10 | Abbott Laboratories | Dual Variable Domain Immunoglobulins and Uses Thereof |
| WO2015089465A1 (fr) * | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Relargage, utilisation et applications thérapeutiques de systèmes crispr-cas et compositions pour maladies et troubles viraux et attribuables au vhb |
| WO2016205613A1 (fr) * | 2015-06-18 | 2016-12-22 | The Broad Institute Inc. | Mutations d'enzyme crispr qui réduisent les effets non ciblés |
| US20180193270A1 (en) * | 2016-11-29 | 2018-07-12 | PureTech Health LLC | Exosomes for delivery of therapeutic agents |
Non-Patent Citations (1)
| Title |
|---|
| BUNGGULAWA ET AL.: "Recent Advancements in the Use of Exosomes as Drug Delivery Systems", JOURNAL OF NANOBIOTECHNOLOGY, vol. 16, no. 81, 16 October 2018 (2018-10-16), pages 1 - 13, XP055709554 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114940976A (zh) * | 2022-07-26 | 2022-08-26 | 深圳市茵冠生物科技有限公司 | 一种过表达融合蛋白ptgfrn-glp-1工程化外泌体的制备方法及其应用 |
| CN114940976B (zh) * | 2022-07-26 | 2022-11-11 | 深圳市茵冠生物科技有限公司 | 一种过表达融合蛋白ptgfrn-glp-1工程化外泌体的制备方法及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020106771A1 (fr) | 2020-05-28 |
| WO2020106772A9 (fr) | 2020-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tombácz et al. | Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs | |
| JP6946399B2 (ja) | Ｃ／ＥＢＰα低分子活性化ＲＮＡ | |
| JP7395355B2 (ja) | 膜融合を促進するための組成物およびその使用 | |
| US20240100100A1 (en) | FGF21 and GLP1 DOUBLE GENE-MODIFIED MESENCHYMAL STEM CELL AND USE IN TREATING A METABOLIC DISEASE | |
| JP6290270B2 (ja) | 遺伝子操作した樹状細胞および癌の治療のための使用 | |
| KR102121086B1 (ko) | 세포에서 단백질을 발현시키는 방법들과 생성물들 | |
| CN111655292A (zh) | 细胞生物制品及其治疗用途 | |
| CN111989108A (zh) | 利用rna去稳定元件协调基因表达 | |
| KR20080036015A (ko) | 글루코오스 유도성 인슐린 발현 및 당뇨병 치료 방법 | |
| US11519008B2 (en) | Exosome delivery system | |
| WO2018083259A1 (fr) | Adénovirus oncolytique codant pour des transgènes | |
| WO2018083258A1 (fr) | Adénovirus oncolytique codant pour au moins trois transgènes | |
| KR20220070433A (ko) | Stat6을 표적으로 하는 세포외 소포-aso 작제물 | |
| WO2020106772A9 (fr) | Agents thérapeutiques de type exosomes chargés pour le traitement de la stéatohépatite non alcoolique, du diabète sucré de type 1 et de type 2, de l'athérosclérose et de la déficience en alpha-1 antitrypsine | |
| CN114786686A (zh) | Gold控制的转基因的联合疗法 | |
| Chu et al. | Lipopolysaccharides improve mesenchymal stem cell-mediated cardioprotection by MyD88 and stat3 signaling in a mouse model of cardiac ischemia/reperfusion injury | |
| Aubert et al. | Cytotoxic immune response blunts long-term transgene expression after efficient retroviral-mediated hepatic gene transfer in rat | |
| US20220040257A1 (en) | Methods and compositions for preventing and treating atherosclerosis and related diseases | |
| TW202102529A (zh) | 用於多肽表現之多核苷酸、組合物及方法 | |
| EP0702518B1 (fr) | Traitement des maladies vasculaires degeneratives par modulation de l'activite ou de la production d'oxyde nitrique endogene | |
| US20200215114A1 (en) | Compositions and methods for producing exosome loaded therapeutics for the treatment of multiple oncological disorders | |
| Unzu et al. | Helper-dependent adenoviral liver gene therapy protects against induced attacks and corrects protein folding stress in acute intermittent porphyria mice | |
| US20200157541A1 (en) | Exosome loaded therapeutics for the treatment of non-alcoholic steatohepatitis, diabetes mellitus type 1 and type 2, atherosclerotic cardiovascular disease, and alpha 1 antitrypsin deficiency | |
| US5925564A (en) | Expression vector systems and method of use | |
| Sjeklocha et al. | β‐globin matrix attachment region improves stable genomic expression of the Sleeping beauty transposon |
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: 19888185 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 19888185 Country of ref document: EP Kind code of ref document: A1 |