JP2019516351A5 - - Google Patents

Info

Publication number

JP2019516351A5

JP2019516351A5 JP2018551306A JP2018551306A JP2019516351A5 JP 2019516351 A5 JP2019516351 A5 JP 2019516351A5 JP 2018551306 A JP2018551306 A JP 2018551306A JP 2018551306 A JP2018551306 A JP 2018551306A JP 2019516351 A5 JP2019516351 A5 JP 2019516351A5

Authority

JP

Japan

Prior art keywords

lipid

lipids

lnp

composition

guide rna

Prior art date

2017-03-30

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.)

Granted

Links

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• 150000002632 lipids Chemical class 0.000 claims description 148
• 239000000203 mixture Substances 0.000 claims description 133
• 238000000034 method Methods 0.000 claims description 112
• 108020005004 Guide RNA Proteins 0.000 claims description 65
• 108020004999 messenger RNA Proteins 0.000 claims description 52
• 210000005229 liver cell Anatomy 0.000 claims description 45
• 101710163270 Nuclease Proteins 0.000 claims description 41
• 230000007935 neutral effect Effects 0.000 claims description 30
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 28
• 238000010362 genome editing Methods 0.000 claims description 20
• 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 15
• NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 14
• 235000012000 cholesterol Nutrition 0.000 claims description 14
• -1 (3-(diethylamino)propoxy)carbonyl Chemical group 0.000 claims description 10
• GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 claims description 10
• 108091033409 CRISPR Proteins 0.000 claims description 9
• 210000004027 cell Anatomy 0.000 claims description 8
• 239000002105 nanoparticle Substances 0.000 claims description 8
• BBGNINPPDHJETF-UHFFFAOYSA-N 5-heptadecylresorcinol Chemical compound CCCCCCCCCCCCCCCCCC1=CC(O)=CC(O)=C1 BBGNINPPDHJETF-UHFFFAOYSA-N 0.000 claims description 6
• 210000003494 hepatocyte Anatomy 0.000 claims description 6
• 239000002245 particle Substances 0.000 claims description 6
• 210000004185 liver Anatomy 0.000 claims description 5
• WLNARFZDISHUGS-MIXBDBMTSA-N cholesteryl hemisuccinate Chemical compound C1C=C2C[C@@H](OC(=O)CCC(O)=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 WLNARFZDISHUGS-MIXBDBMTSA-N 0.000 claims description 4
• 238000005538 encapsulation Methods 0.000 claims description 3
• 108090000623 proteins and genes Proteins 0.000 claims description 3
• 102000013918 Apolipoproteins E Human genes 0.000 claims description 2
• 108010025628 Apolipoproteins E Proteins 0.000 claims description 2
• 210000000130 stem cell Anatomy 0.000 claims description 2
• OYHQOLUKZRVURQ-UHFFFAOYSA-N 9,12-Octadecadienoic Acid Chemical compound CCCCCC=CCC=CCCCCCCCC(O)=O OYHQOLUKZRVURQ-UHFFFAOYSA-N 0.000 claims 2
• GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims 2
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
• 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
• AJAMRCUNWLZBDF-UHFFFAOYSA-N propyl octadeca-9,12-dienoate Chemical compound CCCCCC=CCC=CCCCCCCCC(=O)OCCC AJAMRCUNWLZBDF-UHFFFAOYSA-N 0.000 claims 2
• PVLLBTVAVZLTBH-UHFFFAOYSA-N tridecyl 3-octylundecanoate Chemical compound C(CCCCCCC)C(CC(=O)OCCCCCCCCCCCCC)CCCCCCCC PVLLBTVAVZLTBH-UHFFFAOYSA-N 0.000 claims 2
• 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims 2
• CTXSJTVPXXODHB-UHFFFAOYSA-N 2-heptadecylbenzene-1,3-diol Chemical compound C(CCCCCCCCCCCCCCCC)C1=C(O)C=CC=C1O CTXSJTVPXXODHB-UHFFFAOYSA-N 0.000 claims 1
• 108091027544 Subgenomic mRNA Proteins 0.000 claims 1
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
• 230000004048 modification Effects 0.000 description 8
• 238000012986 modification Methods 0.000 description 8
• 239000000872 buffer Substances 0.000 description 6
• 229930006000 Sucrose Natural products 0.000 description 5
• 239000005720 sucrose Substances 0.000 description 5
• 229910019142 PO4 Inorganic materials 0.000 description 4
• 239000007983 Tris buffer Substances 0.000 description 4
• 239000002577 cryoprotective agent Substances 0.000 description 4
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
• 239000010452 phosphate Substances 0.000 description 4
• 239000011780 sodium chloride Substances 0.000 description 4
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
• 230000008836 DNA modification Effects 0.000 description 3
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
• 125000000185 sucrose group Chemical group 0.000 description 3
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
• 230000001105 regulatory effect Effects 0.000 description 2
• HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
• 108020004705 Codon Proteins 0.000 description 1
• 102000001851 Low Density Lipoprotein Receptor-Related Protein-1 Human genes 0.000 description 1
• 108010015340 Low Density Lipoprotein Receptor-Related Protein-1 Proteins 0.000 description 1
• HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
• HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
• 239000007979 citrate buffer Substances 0.000 description 1
• 230000000959 cryoprotective effect Effects 0.000 description 1
• 238000009472 formulation Methods 0.000 description 1
• 238000003209 gene knockout Methods 0.000 description 1
• 239000008363 phosphate buffer Substances 0.000 description 1
• 239000000126 substance Substances 0.000 description 1
• 230000002459 sustained effect Effects 0.000 description 1