US20160130567A1 - Messenger una molecules and uses thereof - Google Patents
Messenger una molecules and uses thereof Download PDFInfo
- Publication number
- US20160130567A1 US20160130567A1 US14/929,366 US201514929366A US2016130567A1 US 20160130567 A1 US20160130567 A1 US 20160130567A1 US 201514929366 A US201514929366 A US 201514929366A US 2016130567 A1 US2016130567 A1 US 2016130567A1
- Authority
- US
- United States
- Prior art keywords
- tilde over
- molecule
- muna
- human
- over
- 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
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 300
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 192
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 171
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000001727 in vivo Methods 0.000 claims abstract description 27
- 229920001184 polypeptide Polymers 0.000 claims abstract description 25
- 238000000338 in vitro Methods 0.000 claims abstract description 16
- 208000035977 Rare disease Diseases 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 230000003053 immunization Effects 0.000 claims abstract description 8
- 238000002649 immunization Methods 0.000 claims abstract description 8
- 229940124856 vaccine component Drugs 0.000 claims abstract description 3
- 239000000178 monomer Substances 0.000 claims description 170
- 108020004999 messenger RNA Proteins 0.000 claims description 56
- -1 human Factor IX Proteins 0.000 claims description 52
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 47
- 238000013519 translation Methods 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 32
- 239000002773 nucleotide Substances 0.000 claims description 30
- 201000010099 disease Diseases 0.000 claims description 29
- 230000007812 deficiency Effects 0.000 claims description 24
- 210000004027 cell Anatomy 0.000 claims description 22
- 102000039446 nucleic acids Human genes 0.000 claims description 21
- 108020004707 nucleic acids Proteins 0.000 claims description 21
- 150000007523 nucleic acids Chemical class 0.000 claims description 17
- 229960005486 vaccine Drugs 0.000 claims description 16
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 102000044890 human EPO Human genes 0.000 claims description 14
- 101000823116 Homo sapiens Alpha-1-antitrypsin Proteins 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 102000051631 human SERPINA1 Human genes 0.000 claims description 11
- 208000019423 liver disease Diseases 0.000 claims description 11
- 108091026898 Leader sequence (mRNA) Proteins 0.000 claims description 10
- 108091036066 Three prime untranslated region Proteins 0.000 claims description 10
- 101000907783 Homo sapiens Cystic fibrosis transmembrane conductance regulator Proteins 0.000 claims description 9
- 229960000027 human factor ix Drugs 0.000 claims description 9
- 210000004962 mammalian cell Anatomy 0.000 claims description 8
- 101001138285 Homo sapiens Adenylosuccinate lyase Proteins 0.000 claims description 7
- 101000685154 Homo sapiens Argininosuccinate lyase Proteins 0.000 claims description 7
- 101001021253 Homo sapiens Hepcidin Proteins 0.000 claims description 7
- 101000604901 Homo sapiens Phenylalanine-4-hydroxylase Proteins 0.000 claims description 7
- 230000001086 cytosolic effect Effects 0.000 claims description 7
- 239000003623 enhancer Substances 0.000 claims description 7
- 102000056427 human CFTR Human genes 0.000 claims description 7
- 108010013351 sodium-iodide symporter Proteins 0.000 claims description 7
- 230000002950 deficient Effects 0.000 claims description 6
- 108091026890 Coding region Proteins 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000002502 liposome Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 239000002105 nanoparticle Substances 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000012096 transfection reagent Substances 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 7
- 235000018102 proteins Nutrition 0.000 description 172
- 230000011664 signaling Effects 0.000 description 48
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 45
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 44
- 101001052490 Homo sapiens Mitogen-activated protein kinase 3 Proteins 0.000 description 44
- 102100024192 Mitogen-activated protein kinase 3 Human genes 0.000 description 44
- 125000003729 nucleotide group Chemical group 0.000 description 42
- 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 description 41
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 41
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 40
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 description 40
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 description 39
- 102100030708 GTPase KRas Human genes 0.000 description 39
- 108010068353 MAP Kinase Kinase 2 Proteins 0.000 description 39
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 38
- 101000967216 Homo sapiens Eosinophil cationic protein Proteins 0.000 description 37
- 101000712530 Homo sapiens RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 37
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 37
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 description 34
- 101000595741 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Proteins 0.000 description 34
- 101000798015 Homo sapiens RAC-beta serine/threonine-protein kinase Proteins 0.000 description 34
- 102100026169 Phosphatidylinositol 3-kinase regulatory subunit alpha Human genes 0.000 description 34
- 102100036061 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Human genes 0.000 description 34
- 102100032315 RAC-beta serine/threonine-protein kinase Human genes 0.000 description 34
- 230000014616 translation Effects 0.000 description 34
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 33
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 33
- 101000721642 Homo sapiens Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha Proteins 0.000 description 31
- 102100025058 Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha Human genes 0.000 description 31
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 31
- 230000000694 effects Effects 0.000 description 31
- 101000605630 Homo sapiens Phosphatidylinositol 3-kinase catalytic subunit type 3 Proteins 0.000 description 30
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 30
- 102100038329 Phosphatidylinositol 3-kinase catalytic subunit type 3 Human genes 0.000 description 30
- 101000798007 Homo sapiens RAC-gamma serine/threonine-protein kinase Proteins 0.000 description 29
- 102100032314 RAC-gamma serine/threonine-protein kinase Human genes 0.000 description 29
- 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 description 23
- 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 description 23
- 101001026852 Homo sapiens Protein kinase C epsilon type Proteins 0.000 description 22
- 102100037339 Protein kinase C epsilon type Human genes 0.000 description 22
- 101001051777 Homo sapiens Protein kinase C alpha type Proteins 0.000 description 21
- 101001026854 Homo sapiens Protein kinase C delta type Proteins 0.000 description 21
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 21
- 102100037340 Protein kinase C delta type Human genes 0.000 description 21
- 101000979338 Homo sapiens Nuclear factor NF-kappa-B p100 subunit Proteins 0.000 description 20
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 20
- 102100023059 Nuclear factor NF-kappa-B p100 subunit Human genes 0.000 description 20
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 20
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 20
- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 101100457345 Danio rerio mapk14a gene Proteins 0.000 description 17
- 101100457347 Danio rerio mapk14b gene Proteins 0.000 description 17
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 17
- 101000971468 Homo sapiens Protein kinase C zeta type Proteins 0.000 description 17
- 108700012928 MAPK14 Proteins 0.000 description 17
- 101150003941 Mapk14 gene Proteins 0.000 description 17
- 102000054819 Mitogen-activated protein kinase 14 Human genes 0.000 description 17
- 102100021538 Protein kinase C zeta type Human genes 0.000 description 17
- 102100032057 ETS domain-containing protein Elk-1 Human genes 0.000 description 16
- 101001043764 Homo sapiens Inhibitor of nuclear factor kappa-B kinase subunit alpha Proteins 0.000 description 16
- 101001055092 Homo sapiens Mitogen-activated protein kinase kinase kinase 7 Proteins 0.000 description 16
- 101000973618 Homo sapiens NF-kappa-B essential modulator Proteins 0.000 description 16
- 101000708741 Homo sapiens Transcription factor RelB Proteins 0.000 description 16
- 102000001284 I-kappa-B kinase Human genes 0.000 description 16
- 108060006678 I-kappa-B kinase Proteins 0.000 description 16
- 102100021892 Inhibitor of nuclear factor kappa-B kinase subunit alpha Human genes 0.000 description 16
- 102100026888 Mitogen-activated protein kinase kinase kinase 7 Human genes 0.000 description 16
- 102100022219 NF-kappa-B essential modulator Human genes 0.000 description 16
- 101710163352 Potassium voltage-gated channel subfamily H member 4 Proteins 0.000 description 16
- 102100032727 Transcription factor RelB Human genes 0.000 description 16
- 208000035475 disorder Diseases 0.000 description 16
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 15
- 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 description 15
- 108010062302 rac1 GTP Binding Protein Proteins 0.000 description 15
- 102100023580 Cyclic AMP-dependent transcription factor ATF-4 Human genes 0.000 description 14
- 101000905743 Homo sapiens Cyclic AMP-dependent transcription factor ATF-4 Proteins 0.000 description 14
- 101000852483 Homo sapiens Interleukin-1 receptor-associated kinase 1 Proteins 0.000 description 14
- 101000628968 Homo sapiens Mitogen-activated protein kinase 13 Proteins 0.000 description 14
- 101000927796 Homo sapiens Rho guanine nucleotide exchange factor 7 Proteins 0.000 description 14
- 102100036342 Interleukin-1 receptor-associated kinase 1 Human genes 0.000 description 14
- 102100026930 Mitogen-activated protein kinase 13 Human genes 0.000 description 14
- 102100033200 Rho guanine nucleotide exchange factor 7 Human genes 0.000 description 14
- CDAISMWEOUEBRE-UHFFFAOYSA-N inositol Chemical compound OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 14
- 125000005647 linker group Chemical group 0.000 description 14
- 102100021975 CREB-binding protein Human genes 0.000 description 13
- 102100026359 Cyclic AMP-responsive element-binding protein 1 Human genes 0.000 description 13
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 13
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 13
- 101000896987 Homo sapiens CREB-binding protein Proteins 0.000 description 13
- 101000855516 Homo sapiens Cyclic AMP-responsive element-binding protein 1 Proteins 0.000 description 13
- 101001005550 Homo sapiens Mitogen-activated protein kinase kinase kinase 14 Proteins 0.000 description 13
- 108090001005 Interleukin-6 Proteins 0.000 description 13
- 102100025211 Mitogen-activated protein kinase kinase kinase 14 Human genes 0.000 description 13
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 13
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 13
- 206010010356 Congenital anomaly Diseases 0.000 description 12
- 101000945351 Homo sapiens Killer cell immunoglobulin-like receptor 3DL1 Proteins 0.000 description 12
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 12
- 102100033627 Killer cell immunoglobulin-like receptor 3DL1 Human genes 0.000 description 12
- 102100039124 Methyl-CpG-binding protein 2 Human genes 0.000 description 12
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 12
- 102100032543 Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN Human genes 0.000 description 12
- 102100037310 Serine/threonine-protein kinase D1 Human genes 0.000 description 12
- 102000003714 TNF receptor-associated factor 6 Human genes 0.000 description 12
- 108090000009 TNF receptor-associated factor 6 Proteins 0.000 description 12
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 12
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 12
- 101001110283 Canis lupus familiaris Ras-related C3 botulinum toxin substrate 1 Proteins 0.000 description 11
- 102100029375 Crk-like protein Human genes 0.000 description 11
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 11
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 11
- 101000919315 Homo sapiens Crk-like protein Proteins 0.000 description 11
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 11
- 101000926535 Homo sapiens Interferon-induced, double-stranded RNA-activated protein kinase Proteins 0.000 description 11
- 101001076418 Homo sapiens Interleukin-1 receptor type 1 Proteins 0.000 description 11
- 101001110313 Homo sapiens Ras-related C3 botulinum toxin substrate 2 Proteins 0.000 description 11
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 11
- 101001026870 Homo sapiens Serine/threonine-protein kinase D1 Proteins 0.000 description 11
- 101000987315 Homo sapiens Serine/threonine-protein kinase PAK 3 Proteins 0.000 description 11
- 102100034170 Interferon-induced, double-stranded RNA-activated protein kinase Human genes 0.000 description 11
- 102100026016 Interleukin-1 receptor type 1 Human genes 0.000 description 11
- 102100022129 Ras-related C3 botulinum toxin substrate 2 Human genes 0.000 description 11
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 11
- 108090000925 TNF receptor-associated factor 2 Proteins 0.000 description 11
- 102100034779 TRAF family member-associated NF-kappa-B activator Human genes 0.000 description 11
- 229940088598 enzyme Drugs 0.000 description 11
- 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 10
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 10
- 108091012583 BCL2 Proteins 0.000 description 10
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 10
- 101150008012 Bcl2l1 gene Proteins 0.000 description 10
- 102100034357 Casein kinase I isoform alpha Human genes 0.000 description 10
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 10
- 102100025334 Guanine nucleotide-binding protein G(q) subunit alpha Human genes 0.000 description 10
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 10
- 101000824278 Homo sapiens Acyl-[acyl-carrier-protein] hydrolase Proteins 0.000 description 10
- 101000994700 Homo sapiens Casein kinase I isoform alpha Proteins 0.000 description 10
- 101000857888 Homo sapiens Guanine nucleotide-binding protein G(q) subunit alpha Proteins 0.000 description 10
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 10
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 10
- 108700000711 bcl-X Proteins 0.000 description 10
- 102100022528 5'-AMP-activated protein kinase catalytic subunit alpha-1 Human genes 0.000 description 9
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 9
- 102100032187 Androgen receptor Human genes 0.000 description 9
- 108010017009 CD11b Antigen Proteins 0.000 description 9
- 102100026550 Caspase-9 Human genes 0.000 description 9
- 102000011068 Cdc42 Human genes 0.000 description 9
- 108010058546 Cyclin D1 Proteins 0.000 description 9
- 108010016788 Cyclin-Dependent Kinase Inhibitor p21 Proteins 0.000 description 9
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 9
- 102100028554 Dual specificity tyrosine-phosphorylation-regulated kinase 1A Human genes 0.000 description 9
- 101000677993 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-1 Proteins 0.000 description 9
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 9
- 101000983523 Homo sapiens Caspase-9 Proteins 0.000 description 9
- 101000838016 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 1A Proteins 0.000 description 9
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 9
- 101001064870 Homo sapiens Lon protease homolog, mitochondrial Proteins 0.000 description 9
- 101001033726 Homo sapiens Methyl-CpG-binding protein 2 Proteins 0.000 description 9
- 101000582254 Homo sapiens Nuclear receptor corepressor 2 Proteins 0.000 description 9
- 101001003584 Homo sapiens Prelamin-A/C Proteins 0.000 description 9
- 101001093899 Homo sapiens Retinoic acid receptor RXR-alpha Proteins 0.000 description 9
- 101000595531 Homo sapiens Serine/threonine-protein kinase pim-1 Proteins 0.000 description 9
- 102100022338 Integrin alpha-M Human genes 0.000 description 9
- 102100025304 Integrin beta-1 Human genes 0.000 description 9
- 102100030569 Nuclear receptor corepressor 2 Human genes 0.000 description 9
- 102100026531 Prelamin-A/C Human genes 0.000 description 9
- 102100030706 Ras-related protein Rap-1A Human genes 0.000 description 9
- 102100035178 Retinoic acid receptor RXR-alpha Human genes 0.000 description 9
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 9
- 102100036077 Serine/threonine-protein kinase pim-1 Human genes 0.000 description 9
- 108010051348 cdc42 GTP-Binding Protein Proteins 0.000 description 9
- 230000001404 mediated effect Effects 0.000 description 9
- 108010056274 polo-like kinase 1 Proteins 0.000 description 9
- 108010036805 rap1 GTP-Binding Proteins Proteins 0.000 description 9
- 102100026882 Alpha-synuclein Human genes 0.000 description 8
- 102100033093 Calcium/calmodulin-dependent protein kinase type II subunit alpha Human genes 0.000 description 8
- 108090000397 Caspase 3 Proteins 0.000 description 8
- 102100029855 Caspase-3 Human genes 0.000 description 8
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 8
- 102100023686 G protein-coupled receptor kinase 6 Human genes 0.000 description 8
- 101000944249 Homo sapiens Calcium/calmodulin-dependent protein kinase type II subunit alpha Proteins 0.000 description 8
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 8
- 101000829473 Homo sapiens G protein-coupled receptor kinase 6 Proteins 0.000 description 8
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 8
- 101001078158 Homo sapiens Integrin alpha-1 Proteins 0.000 description 8
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 8
- 101000994369 Homo sapiens Integrin alpha-5 Proteins 0.000 description 8
- 101001015004 Homo sapiens Integrin beta-3 Proteins 0.000 description 8
- 101001015037 Homo sapiens Integrin beta-7 Proteins 0.000 description 8
- 101001043594 Homo sapiens Low-density lipoprotein receptor-related protein 5 Proteins 0.000 description 8
- 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 description 8
- 101000617536 Homo sapiens Presenilin-1 Proteins 0.000 description 8
- 101000971404 Homo sapiens Protein kinase C iota type Proteins 0.000 description 8
- 101000623857 Homo sapiens Serine/threonine-protein kinase mTOR Proteins 0.000 description 8
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 8
- 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 description 8
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 8
- 102100025323 Integrin alpha-1 Human genes 0.000 description 8
- 102100025305 Integrin alpha-2 Human genes 0.000 description 8
- 102100032817 Integrin alpha-5 Human genes 0.000 description 8
- 102100032999 Integrin beta-3 Human genes 0.000 description 8
- 102100033016 Integrin beta-7 Human genes 0.000 description 8
- 102100021926 Low-density lipoprotein receptor-related protein 5 Human genes 0.000 description 8
- 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 description 8
- 102100021557 Protein kinase C iota type Human genes 0.000 description 8
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 8
- 101150063267 STAT5B gene Proteins 0.000 description 8
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 8
- 102100029904 Signal transducer and activator of transcription 1-alpha/beta Human genes 0.000 description 8
- 102100024474 Signal transducer and activator of transcription 5B Human genes 0.000 description 8
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 8
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 8
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 210000000805 cytoplasm Anatomy 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 101100510324 Aplysia californica PRKC1 gene Proteins 0.000 description 7
- 108010009306 Forkhead Box Protein O1 Proteins 0.000 description 7
- 102100035427 Forkhead box protein O1 Human genes 0.000 description 7
- 102100032610 Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Human genes 0.000 description 7
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 description 7
- 101001014590 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Proteins 0.000 description 7
- 101001014594 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms short Proteins 0.000 description 7
- 101000973778 Homo sapiens NAD(P)H dehydrogenase [quinone] 1 Proteins 0.000 description 7
- 101001014610 Homo sapiens Neuroendocrine secretory protein 55 Proteins 0.000 description 7
- 101000797903 Homo sapiens Protein ALEX Proteins 0.000 description 7
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 description 7
- 101001051706 Homo sapiens Ribosomal protein S6 kinase beta-1 Proteins 0.000 description 7
- 101001095368 Homo sapiens Serine/threonine-protein phosphatase PP1-gamma catalytic subunit Proteins 0.000 description 7
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 7
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 7
- 102100023915 Insulin Human genes 0.000 description 7
- 102100036721 Insulin receptor Human genes 0.000 description 7
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 description 7
- 102100022033 Presenilin-1 Human genes 0.000 description 7
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 description 7
- 102100024908 Ribosomal protein S6 kinase beta-1 Human genes 0.000 description 7
- 102100037761 Serine/threonine-protein phosphatase PP1-gamma catalytic subunit Human genes 0.000 description 7
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 7
- 208000037765 diseases and disorders Diseases 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 7
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 7
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 7
- 208000011580 syndromic disease Diseases 0.000 description 7
- 102100040685 14-3-3 protein zeta/delta Human genes 0.000 description 6
- 102100032197 Alpha-crystallin A chain Human genes 0.000 description 6
- 102100034524 Apoptotic protease-activating factor 1 Human genes 0.000 description 6
- 102100026008 Breakpoint cluster region protein Human genes 0.000 description 6
- 102100025399 Breast cancer type 2 susceptibility protein Human genes 0.000 description 6
- 102100026548 Caspase-8 Human genes 0.000 description 6
- 102100028914 Catenin beta-1 Human genes 0.000 description 6
- 206010010904 Convulsion Diseases 0.000 description 6
- 102000000577 Cyclin-Dependent Kinase Inhibitor p27 Human genes 0.000 description 6
- 108010016777 Cyclin-Dependent Kinase Inhibitor p27 Proteins 0.000 description 6
- 102100027417 Cytochrome P450 1B1 Human genes 0.000 description 6
- 102100026234 Cytokine receptor common subunit gamma Human genes 0.000 description 6
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 6
- 102100022207 E3 ubiquitin-protein ligase parkin Human genes 0.000 description 6
- 102100038595 Estrogen receptor Human genes 0.000 description 6
- 102100032191 Guanine nucleotide exchange factor VAV3 Human genes 0.000 description 6
- 101000964898 Homo sapiens 14-3-3 protein zeta/delta Proteins 0.000 description 6
- 101000920937 Homo sapiens Alpha-crystallin A chain Proteins 0.000 description 6
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 6
- 101000924629 Homo sapiens Apoptotic protease-activating factor 1 Proteins 0.000 description 6
- 101000933320 Homo sapiens Breakpoint cluster region protein Proteins 0.000 description 6
- 101000983528 Homo sapiens Caspase-8 Proteins 0.000 description 6
- 101000916173 Homo sapiens Catenin beta-1 Proteins 0.000 description 6
- 101000725164 Homo sapiens Cytochrome P450 1B1 Proteins 0.000 description 6
- 101001055227 Homo sapiens Cytokine receptor common subunit gamma Proteins 0.000 description 6
- 101000775742 Homo sapiens Guanine nucleotide exchange factor VAV3 Proteins 0.000 description 6
- 101000852815 Homo sapiens Insulin receptor Proteins 0.000 description 6
- 101001128156 Homo sapiens Nanos homolog 3 Proteins 0.000 description 6
- 101001124309 Homo sapiens Nitric oxide synthase, endothelial Proteins 0.000 description 6
- 101000741788 Homo sapiens Peroxisome proliferator-activated receptor alpha Proteins 0.000 description 6
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 6
- 101000846198 Homo sapiens Ribitol 5-phosphate transferase FKRP Proteins 0.000 description 6
- 101000987297 Homo sapiens Serine/threonine-protein kinase PAK 4 Proteins 0.000 description 6
- 101000783373 Homo sapiens Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform Proteins 0.000 description 6
- 101000783404 Homo sapiens Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Proteins 0.000 description 6
- 101001068027 Homo sapiens Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform Proteins 0.000 description 6
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 102100031893 Nanos homolog 3 Human genes 0.000 description 6
- 102100033819 Nuclear pore complex protein Nup214 Human genes 0.000 description 6
- 102100037499 Parkinson disease protein 7 Human genes 0.000 description 6
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 description 6
- 102100035832 Phakinin Human genes 0.000 description 6
- 108010032428 Protein Deglycase DJ-1 Proteins 0.000 description 6
- 101150111584 RHOA gene Proteins 0.000 description 6
- 102100025234 Receptor of activated protein C kinase 1 Human genes 0.000 description 6
- 108010044157 Receptors for Activated C Kinase Proteins 0.000 description 6
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 6
- 102100031774 Ribitol 5-phosphate transferase FKRP Human genes 0.000 description 6
- 102100027940 Serine/threonine-protein kinase PAK 4 Human genes 0.000 description 6
- 102100036140 Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform Human genes 0.000 description 6
- 102100036122 Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Human genes 0.000 description 6
- 102100034464 Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform Human genes 0.000 description 6
- 101150045565 Socs1 gene Proteins 0.000 description 6
- 108700027336 Suppressor of Cytokine Signaling 1 Proteins 0.000 description 6
- 102100024779 Suppressor of cytokine signaling 1 Human genes 0.000 description 6
- 102100033456 TGF-beta receptor type-1 Human genes 0.000 description 6
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 6
- 108010011702 Transforming Growth Factor-beta Type I Receptor Proteins 0.000 description 6
- 102100022387 Transforming protein RhoA Human genes 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 239000004019 antithrombin Substances 0.000 description 6
- 206010015037 epilepsy Diseases 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- CDKIEBFIMCSCBB-UHFFFAOYSA-N 1-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-3-(1-methyl-2-phenylpyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one;hydrochloride Chemical compound Cl.C1C=2C=C(OC)C(OC)=CC=2CCN1C(=O)C=CC(C1=CC=CN=C1N1C)=C1C1=CC=CC=C1 CDKIEBFIMCSCBB-UHFFFAOYSA-N 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 5
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 description 5
- 102100030685 Alpha-sarcoglycan Human genes 0.000 description 5
- 102100030907 Aryl hydrocarbon receptor nuclear translocator Human genes 0.000 description 5
- 101000690445 Caenorhabditis elegans Aryl hydrocarbon receptor nuclear translocator homolog Proteins 0.000 description 5
- 102100029398 Calpain small subunit 1 Human genes 0.000 description 5
- 102100025172 Calpain-1 catalytic subunit Human genes 0.000 description 5
- 102100032537 Calpain-2 catalytic subunit Human genes 0.000 description 5
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 5
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 5
- 102000003951 Erythropoietin Human genes 0.000 description 5
- 108090000394 Erythropoietin Proteins 0.000 description 5
- 102100038576 F-box/WD repeat-containing protein 1A Human genes 0.000 description 5
- 102100027581 Forkhead box protein P3 Human genes 0.000 description 5
- 102100033417 Glucocorticoid receptor Human genes 0.000 description 5
- 102100022975 Glycogen synthase kinase-3 alpha Human genes 0.000 description 5
- 101150096895 HSPB1 gene Proteins 0.000 description 5
- 102100039165 Heat shock protein beta-1 Human genes 0.000 description 5
- 101000793115 Homo sapiens Aryl hydrocarbon receptor nuclear translocator Proteins 0.000 description 5
- 101000919194 Homo sapiens Calpain small subunit 1 Proteins 0.000 description 5
- 101000934069 Homo sapiens Calpain-1 catalytic subunit Proteins 0.000 description 5
- 101000867692 Homo sapiens Calpain-2 catalytic subunit Proteins 0.000 description 5
- 101000882584 Homo sapiens Estrogen receptor Proteins 0.000 description 5
- 101001030691 Homo sapiens F-box/WD repeat-containing protein 1A Proteins 0.000 description 5
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 description 5
- 101000903717 Homo sapiens Glycogen synthase kinase-3 alpha Proteins 0.000 description 5
- 101001077604 Homo sapiens Insulin receptor substrate 1 Proteins 0.000 description 5
- 101000974356 Homo sapiens Nuclear receptor coactivator 3 Proteins 0.000 description 5
- 101000992283 Homo sapiens Optineurin Proteins 0.000 description 5
- 101001126417 Homo sapiens Platelet-derived growth factor receptor alpha Proteins 0.000 description 5
- 101000899806 Homo sapiens Retinal guanylyl cyclase 1 Proteins 0.000 description 5
- 101000617285 Homo sapiens Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 description 5
- 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 5
- 101150083522 MECP2 gene Proteins 0.000 description 5
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 5
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 5
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 5
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 description 5
- 108010062309 Nuclear Receptor Interacting Protein 1 Proteins 0.000 description 5
- 102100022883 Nuclear receptor coactivator 3 Human genes 0.000 description 5
- 102100029558 Nuclear receptor-interacting protein 1 Human genes 0.000 description 5
- 102100031822 Optineurin Human genes 0.000 description 5
- 102100031014 Phosphatidylinositol-binding clathrin assembly protein Human genes 0.000 description 5
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 5
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 5
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 5
- 101150104557 Ppargc1a gene Proteins 0.000 description 5
- 102100022663 Retinal guanylyl cyclase 1 Human genes 0.000 description 5
- 108010038912 Retinoid X Receptors Proteins 0.000 description 5
- 101150058731 STAT5A gene Proteins 0.000 description 5
- 102100024481 Signal transducer and activator of transcription 5A Human genes 0.000 description 5
- 102100021657 Tyrosine-protein phosphatase non-receptor type 6 Human genes 0.000 description 5
- 108010080146 androgen receptors Proteins 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 229940105423 erythropoietin Drugs 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 210000003128 head Anatomy 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 102100024378 AF4/FMR2 family member 2 Human genes 0.000 description 4
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 4
- 102100040069 Aldehyde dehydrogenase 1A1 Human genes 0.000 description 4
- 102100032959 Alpha-actinin-4 Human genes 0.000 description 4
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 4
- 102100030343 Antigen peptide transporter 2 Human genes 0.000 description 4
- 108091007065 BIRCs Proteins 0.000 description 4
- 102000036365 BRCA1 Human genes 0.000 description 4
- 108700020463 BRCA1 Proteins 0.000 description 4
- 101150072950 BRCA1 gene Proteins 0.000 description 4
- 108700003785 Baculoviral IAP Repeat-Containing 3 Proteins 0.000 description 4
- 102100021677 Baculoviral IAP repeat-containing protein 2 Human genes 0.000 description 4
- 102100021662 Baculoviral IAP repeat-containing protein 3 Human genes 0.000 description 4
- 201000006935 Becker muscular dystrophy Diseases 0.000 description 4
- 102100029388 Beta-crystallin B2 Human genes 0.000 description 4
- 101150104237 Birc3 gene Proteins 0.000 description 4
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 4
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 4
- 102100034798 CCAAT/enhancer-binding protein beta Human genes 0.000 description 4
- 102100022641 Coagulation factor IX Human genes 0.000 description 4
- 102000004360 Cofilin 1 Human genes 0.000 description 4
- 108090000996 Cofilin 1 Proteins 0.000 description 4
- 102100040496 Collagen alpha-2(VIII) chain Human genes 0.000 description 4
- 101150046567 DAO gene Proteins 0.000 description 4
- 102100038694 DNA-binding protein SMUBP-2 Human genes 0.000 description 4
- 102100037024 E3 ubiquitin-protein ligase XIAP Human genes 0.000 description 4
- 108700041152 Endoplasmic Reticulum Chaperone BiP Proteins 0.000 description 4
- 102100021451 Endoplasmic reticulum chaperone BiP Human genes 0.000 description 4
- 102100031690 Erythroid transcription factor Human genes 0.000 description 4
- 102100027813 Gamma-crystallin C Human genes 0.000 description 4
- 102100027812 Gamma-crystallin D Human genes 0.000 description 4
- 102100021792 Gamma-sarcoglycan Human genes 0.000 description 4
- 102100021223 Glucosidase 2 subunit beta Human genes 0.000 description 4
- 102100030943 Glutathione S-transferase P Human genes 0.000 description 4
- 229920002527 Glycogen Polymers 0.000 description 4
- 102100031150 Growth arrest and DNA damage-inducible protein GADD45 alpha Human genes 0.000 description 4
- 101150112743 HSPA5 gene Proteins 0.000 description 4
- 102100034047 Heat shock factor protein 4 Human genes 0.000 description 4
- 102100022846 Histone acetyltransferase KAT2B Human genes 0.000 description 4
- 102100039999 Histone deacetylase 2 Human genes 0.000 description 4
- 102100021455 Histone deacetylase 3 Human genes 0.000 description 4
- 102100038720 Histone deacetylase 9 Human genes 0.000 description 4
- 101000833172 Homo sapiens AF4/FMR2 family member 2 Proteins 0.000 description 4
- 101000890570 Homo sapiens Aldehyde dehydrogenase 1A1 Proteins 0.000 description 4
- 101000797282 Homo sapiens Alpha-actinin-4 Proteins 0.000 description 4
- 101000703500 Homo sapiens Alpha-sarcoglycan Proteins 0.000 description 4
- 101000823051 Homo sapiens Amyloid-beta precursor protein Proteins 0.000 description 4
- 101000919250 Homo sapiens Beta-crystallin B2 Proteins 0.000 description 4
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 4
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 4
- 101000945963 Homo sapiens CCAAT/enhancer-binding protein beta Proteins 0.000 description 4
- 101000749886 Homo sapiens Collagen alpha-2(VIII) chain Proteins 0.000 description 4
- 101000804865 Homo sapiens E3 ubiquitin-protein ligase XIAP Proteins 0.000 description 4
- 101000859938 Homo sapiens Gamma-crystallin C Proteins 0.000 description 4
- 101000859943 Homo sapiens Gamma-crystallin D Proteins 0.000 description 4
- 101000616435 Homo sapiens Gamma-sarcoglycan Proteins 0.000 description 4
- 101000926939 Homo sapiens Glucocorticoid receptor Proteins 0.000 description 4
- 101001040875 Homo sapiens Glucosidase 2 subunit beta Proteins 0.000 description 4
- 101001010139 Homo sapiens Glutathione S-transferase P Proteins 0.000 description 4
- 101001066158 Homo sapiens Growth arrest and DNA damage-inducible protein GADD45 alpha Proteins 0.000 description 4
- 101001016879 Homo sapiens Heat shock factor protein 4 Proteins 0.000 description 4
- 101001047006 Homo sapiens Histone acetyltransferase KAT2B Proteins 0.000 description 4
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 description 4
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 description 4
- 101001032092 Homo sapiens Histone deacetylase 9 Proteins 0.000 description 4
- 101001030232 Homo sapiens Myosin-9 Proteins 0.000 description 4
- 101001124991 Homo sapiens Nitric oxide synthase, inducible Proteins 0.000 description 4
- 101000996563 Homo sapiens Nuclear pore complex protein Nup214 Proteins 0.000 description 4
- 101000602930 Homo sapiens Nuclear receptor coactivator 2 Proteins 0.000 description 4
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 description 4
- 101000629597 Homo sapiens Sterol regulatory element-binding protein 1 Proteins 0.000 description 4
- 101000617738 Homo sapiens Survival motor neuron protein Proteins 0.000 description 4
- 101000645320 Homo sapiens Titin Proteins 0.000 description 4
- 101000894525 Homo sapiens Transforming growth factor-beta-induced protein ig-h3 Proteins 0.000 description 4
- 101000671676 Homo sapiens U3 small nucleolar RNA-associated protein 4 homolog Proteins 0.000 description 4
- 108090000174 Interleukin-10 Proteins 0.000 description 4
- 102000013691 Interleukin-17 Human genes 0.000 description 4
- 108050003558 Interleukin-17 Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 208000027747 Kennedy disease Diseases 0.000 description 4
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 4
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 4
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 4
- 208000002678 Mucopolysaccharidoses Diseases 0.000 description 4
- 102100038938 Myosin-9 Human genes 0.000 description 4
- 208000012902 Nervous system disease Diseases 0.000 description 4
- 102000048238 Neuregulin-1 Human genes 0.000 description 4
- 108090000556 Neuregulin-1 Proteins 0.000 description 4
- 101710203761 Neurexin-1 Proteins 0.000 description 4
- 102100021582 Neurexin-1-beta Human genes 0.000 description 4
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 4
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 4
- 102100037226 Nuclear receptor coactivator 2 Human genes 0.000 description 4
- 102100029441 Nucleotide-binding oligomerization domain-containing protein 2 Human genes 0.000 description 4
- 102100040375 Peripherin-2 Human genes 0.000 description 4
- 108090000709 Phakinin Proteins 0.000 description 4
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 description 4
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 description 4
- 101100379220 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) API2 gene Proteins 0.000 description 4
- 102100026839 Sterol regulatory element-binding protein 1 Human genes 0.000 description 4
- 102100021947 Survival motor neuron protein Human genes 0.000 description 4
- 102100040296 TATA-box-binding protein Human genes 0.000 description 4
- 102100026260 Titin Human genes 0.000 description 4
- 102100021398 Transforming growth factor-beta-induced protein ig-h3 Human genes 0.000 description 4
- 102100040072 U3 small nucleolar RNA-associated protein 4 homolog Human genes 0.000 description 4
- 108010005656 Ubiquitin Thiolesterase Proteins 0.000 description 4
- 102100025038 Ubiquitin carboxyl-terminal hydrolase isozyme L1 Human genes 0.000 description 4
- 208000023940 X-Linked Combined Immunodeficiency disease Diseases 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 210000004392 genitalia Anatomy 0.000 description 4
- 229940096919 glycogen Drugs 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 102000004311 liver X receptors Human genes 0.000 description 4
- 108090000865 liver X receptors Proteins 0.000 description 4
- 208000002780 macular degeneration Diseases 0.000 description 4
- 206010028093 mucopolysaccharidosis Diseases 0.000 description 4
- 108091008581 nuclear androgen receptors Proteins 0.000 description 4
- 150000004713 phosphodiesters Chemical group 0.000 description 4
- 230000000750 progressive effect Effects 0.000 description 4
- 102100022464 5'-nucleotidase Human genes 0.000 description 3
- 101150092476 ABCA1 gene Proteins 0.000 description 3
- 108091007505 ADAM17 Proteins 0.000 description 3
- 108700005241 ATP Binding Cassette Transporter 1 Proteins 0.000 description 3
- 102100022712 Alpha-1-antitrypsin Human genes 0.000 description 3
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 3
- 102100033715 Apolipoprotein A-I Human genes 0.000 description 3
- 206010003805 Autism Diseases 0.000 description 3
- 108700024832 B-Cell CLL-Lymphoma 10 Proteins 0.000 description 3
- 102100037598 B-cell lymphoma/leukemia 10 Human genes 0.000 description 3
- 101150074953 BCL10 gene Proteins 0.000 description 3
- 108700020462 BRCA2 Proteins 0.000 description 3
- 208000037663 Best vitelliform macular dystrophy Diseases 0.000 description 3
- 101150008921 Brca2 gene Proteins 0.000 description 3
- 102100032937 CD40 ligand Human genes 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- 102100032616 Caspase-2 Human genes 0.000 description 3
- 102100035888 Caveolin-1 Human genes 0.000 description 3
- 102100023804 Coagulation factor VII Human genes 0.000 description 3
- 102100026735 Coagulation factor VIII Human genes 0.000 description 3
- 102100029362 Cone-rod homeobox protein Human genes 0.000 description 3
- 102100032323 Corticosteroid-binding globulin Human genes 0.000 description 3
- 102100033245 Cyclin-dependent kinase 16 Human genes 0.000 description 3
- 102100034746 Cyclin-dependent kinase-like 5 Human genes 0.000 description 3
- 101150077031 DAXX gene Proteins 0.000 description 3
- 102100022204 DNA-dependent protein kinase catalytic subunit Human genes 0.000 description 3
- 102100028559 Death domain-associated protein 6 Human genes 0.000 description 3
- 102100021790 Delta-sarcoglycan Human genes 0.000 description 3
- 206010012559 Developmental delay Diseases 0.000 description 3
- 102100031111 Disintegrin and metalloproteinase domain-containing protein 17 Human genes 0.000 description 3
- 102100029503 E3 ubiquitin-protein ligase TRIM32 Human genes 0.000 description 3
- 102100032053 Elongation of very long chain fatty acids protein 4 Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000005233 Eukaryotic Initiation Factor-4E Human genes 0.000 description 3
- 108060002636 Eukaryotic Initiation Factor-4E Proteins 0.000 description 3
- 102100034174 Eukaryotic translation initiation factor 2-alpha kinase 3 Human genes 0.000 description 3
- 102100022466 Eukaryotic translation initiation factor 4E-binding protein 1 Human genes 0.000 description 3
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 3
- 108010076282 Factor IX Proteins 0.000 description 3
- 108010023321 Factor VII Proteins 0.000 description 3
- 108010014173 Factor X Proteins 0.000 description 3
- 102100027280 Fanconi anemia group A protein Human genes 0.000 description 3
- 102100027285 Fanconi anemia group B protein Human genes 0.000 description 3
- 102100034553 Fanconi anemia group J protein Human genes 0.000 description 3
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 3
- 102100036334 Fragile X mental retardation syndrome-related protein 1 Human genes 0.000 description 3
- 102100036336 Fragile X mental retardation syndrome-related protein 2 Human genes 0.000 description 3
- 208000036357 GUCY2D-related recessive retinopathy Diseases 0.000 description 3
- 102100030526 Gap junction alpha-3 protein Human genes 0.000 description 3
- 102100025283 Gap junction alpha-8 protein Human genes 0.000 description 3
- 102100028685 H(+)/Cl(-) exchange transporter 7 Human genes 0.000 description 3
- 108091005772 HDAC11 Proteins 0.000 description 3
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 3
- 102100022057 Hepatocyte nuclear factor 1-alpha Human genes 0.000 description 3
- 102100039385 Histone deacetylase 11 Human genes 0.000 description 3
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 3
- 102100021453 Histone deacetylase 5 Human genes 0.000 description 3
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 3
- 102100038719 Histone deacetylase 7 Human genes 0.000 description 3
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 3
- 101000733802 Homo sapiens Apolipoprotein A-I Proteins 0.000 description 3
- 101000934858 Homo sapiens Breast cancer type 2 susceptibility protein Proteins 0.000 description 3
- 101000868215 Homo sapiens CD40 ligand Proteins 0.000 description 3
- 101000867612 Homo sapiens Caspase-2 Proteins 0.000 description 3
- 101000715467 Homo sapiens Caveolin-1 Proteins 0.000 description 3
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 3
- 101000919370 Homo sapiens Cone-rod homeobox protein Proteins 0.000 description 3
- 101000868967 Homo sapiens Corticosteroid-binding globulin Proteins 0.000 description 3
- 101000945692 Homo sapiens Cyclin-dependent kinase-like 5 Proteins 0.000 description 3
- 101000665135 Homo sapiens DNA-binding protein SMUBP-2 Proteins 0.000 description 3
- 101000619536 Homo sapiens DNA-dependent protein kinase catalytic subunit Proteins 0.000 description 3
- 101000616408 Homo sapiens Delta-sarcoglycan Proteins 0.000 description 3
- 101000722054 Homo sapiens Dynamin-like 120 kDa protein, mitochondrial Proteins 0.000 description 3
- 101000634982 Homo sapiens E3 ubiquitin-protein ligase TRIM32 Proteins 0.000 description 3
- 101000921354 Homo sapiens Elongation of very long chain fatty acids protein 4 Proteins 0.000 description 3
- 101001066268 Homo sapiens Erythroid transcription factor Proteins 0.000 description 3
- 101000926508 Homo sapiens Eukaryotic translation initiation factor 2-alpha kinase 3 Proteins 0.000 description 3
- 101000678280 Homo sapiens Eukaryotic translation initiation factor 4E-binding protein 1 Proteins 0.000 description 3
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 3
- 101000914679 Homo sapiens Fanconi anemia group B protein Proteins 0.000 description 3
- 101000891683 Homo sapiens Fanconi anemia group D2 protein Proteins 0.000 description 3
- 101000848171 Homo sapiens Fanconi anemia group J protein Proteins 0.000 description 3
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 3
- 101000930945 Homo sapiens Fragile X mental retardation syndrome-related protein 1 Proteins 0.000 description 3
- 101000930952 Homo sapiens Fragile X mental retardation syndrome-related protein 2 Proteins 0.000 description 3
- 101000766971 Homo sapiens H(+)/Cl(-) exchange transporter 7 Proteins 0.000 description 3
- 101001045751 Homo sapiens Hepatocyte nuclear factor 1-alpha Proteins 0.000 description 3
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 3
- 101000899255 Homo sapiens Histone deacetylase 5 Proteins 0.000 description 3
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 3
- 101001032113 Homo sapiens Histone deacetylase 7 Proteins 0.000 description 3
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 3
- 101000599048 Homo sapiens Interleukin-6 receptor subunit alpha Proteins 0.000 description 3
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 description 3
- 101000677891 Homo sapiens Iron-sulfur clusters transporter ABCB7, mitochondrial Proteins 0.000 description 3
- 101000614618 Homo sapiens Junctophilin-3 Proteins 0.000 description 3
- 101000945492 Homo sapiens Killer cell immunoglobulin-like receptor 3DS1 Proteins 0.000 description 3
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 3
- 101000585663 Homo sapiens Myocilin Proteins 0.000 description 3
- 101001109698 Homo sapiens Nuclear receptor subfamily 4 group A member 2 Proteins 0.000 description 3
- 101000610652 Homo sapiens Peripherin-2 Proteins 0.000 description 3
- 101000741790 Homo sapiens Peroxisome proliferator-activated receptor gamma Proteins 0.000 description 3
- 101000583474 Homo sapiens Phosphatidylinositol-binding clathrin assembly protein Proteins 0.000 description 3
- 101000617546 Homo sapiens Presenilin-2 Proteins 0.000 description 3
- 101000876829 Homo sapiens Protein C-ets-1 Proteins 0.000 description 3
- 101000720958 Homo sapiens Protein artemis Proteins 0.000 description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 3
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 3
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 3
- 101000927774 Homo sapiens Rho guanine nucleotide exchange factor 12 Proteins 0.000 description 3
- 101001095783 Homo sapiens Ribonucleoside-diphosphate reductase subunit M2 B Proteins 0.000 description 3
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 3
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 3
- 101000605835 Homo sapiens Serine/threonine-protein kinase PINK1, mitochondrial Proteins 0.000 description 3
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 3
- 101000597193 Homo sapiens Telethonin Proteins 0.000 description 3
- 101000702545 Homo sapiens Transcription activator BRG1 Proteins 0.000 description 3
- 101000904152 Homo sapiens Transcription factor E2F1 Proteins 0.000 description 3
- 101000854875 Homo sapiens V-type proton ATPase 116 kDa subunit a 3 Proteins 0.000 description 3
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 3
- 101000854936 Homo sapiens Visual system homeobox 1 Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 3
- 102000003814 Interleukin-10 Human genes 0.000 description 3
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 3
- 102100021504 Iron-sulfur clusters transporter ABCB7, mitochondrial Human genes 0.000 description 3
- 102100040488 Junctophilin-3 Human genes 0.000 description 3
- 102100034833 Killer cell immunoglobulin-like receptor 3DS1 Human genes 0.000 description 3
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 description 3
- 102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 description 3
- 102100034069 MAP kinase-activated protein kinase 2 Human genes 0.000 description 3
- 108010041955 MAP-kinase-activated kinase 2 Proteins 0.000 description 3
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 3
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 3
- 108091027974 Mature messenger RNA Proteins 0.000 description 3
- 101000987583 Mus musculus Eosinophil peroxidase Proteins 0.000 description 3
- 102100029839 Myocilin Human genes 0.000 description 3
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 3
- 108010071382 NF-E2-Related Factor 2 Proteins 0.000 description 3
- 102000014413 Neuregulin Human genes 0.000 description 3
- 108050003475 Neuregulin Proteins 0.000 description 3
- 102100022676 Nuclear receptor subfamily 4 group A member 2 Human genes 0.000 description 3
- 108090000445 Parathyroid hormone Proteins 0.000 description 3
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 3
- 102100033616 Phospholipid-transporting ATPase ABCA1 Human genes 0.000 description 3
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 3
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 3
- 102100030477 Plectin Human genes 0.000 description 3
- 102100022036 Presenilin-2 Human genes 0.000 description 3
- 102100035251 Protein C-ets-1 Human genes 0.000 description 3
- 102100025918 Protein artemis Human genes 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 3
- 201000000582 Retinoblastoma Diseases 0.000 description 3
- 102100033193 Rho guanine nucleotide exchange factor 12 Human genes 0.000 description 3
- 102100038013 Ribonucleoside-diphosphate reductase subunit M2 B Human genes 0.000 description 3
- 102100023781 Selenoprotein N Human genes 0.000 description 3
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 3
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 3
- 102100038376 Serine/threonine-protein kinase PINK1, mitochondrial Human genes 0.000 description 3
- 208000020221 Short stature Diseases 0.000 description 3
- 102100022433 Single-stranded DNA cytosine deaminase Human genes 0.000 description 3
- 102100032891 Superoxide dismutase [Mn], mitochondrial Human genes 0.000 description 3
- 102100035155 Telethonin Human genes 0.000 description 3
- 102100031027 Transcription activator BRG1 Human genes 0.000 description 3
- 102100024026 Transcription factor E2F1 Human genes 0.000 description 3
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 3
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 description 3
- 108091023045 Untranslated Region Proteins 0.000 description 3
- 102100037111 Uracil-DNA glycosylase Human genes 0.000 description 3
- 102100020738 V-type proton ATPase 116 kDa subunit a 3 Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 3
- 102100021164 Vasodilator-stimulated phosphoprotein Human genes 0.000 description 3
- 102100020673 Visual system homeobox 1 Human genes 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 206010064930 age-related macular degeneration Diseases 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 108091008324 binding proteins Proteins 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 229960004222 factor ix Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 3
- 108010045815 superoxide dismutase 2 Proteins 0.000 description 3
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 3
- 108010054220 vasodilator-stimulated phosphoprotein Proteins 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 208000020938 vitelliform macular dystrophy 2 Diseases 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- 108020005345 3' Untranslated Regions Proteins 0.000 description 2
- 102100033051 40S ribosomal protein S19 Human genes 0.000 description 2
- 102100031020 5-aminolevulinate synthase, erythroid-specific, mitochondrial Human genes 0.000 description 2
- 108091007504 ADAM10 Proteins 0.000 description 2
- 102100028446 ADP-ribosylation factor-like protein 11 Human genes 0.000 description 2
- 108010029988 AICDA (activation-induced cytidine deaminase) Proteins 0.000 description 2
- 208000034431 Adrenal hypoplasia congenita Diseases 0.000 description 2
- 102100022524 Alpha-1-antichymotrypsin Human genes 0.000 description 2
- 102100040743 Alpha-crystallin B chain Human genes 0.000 description 2
- 102100032047 Alsin Human genes 0.000 description 2
- 208000005875 Alternating hemiplegia of childhood Diseases 0.000 description 2
- 102100034452 Alternative prion protein Human genes 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 108700037019 Aminoacylase 1 deficiency Proteins 0.000 description 2
- 102100025981 Aminoacylase-1 Human genes 0.000 description 2
- 101710143180 Aminoacylase-1 Proteins 0.000 description 2
- 102100020895 Ammonium transporter Rh type A Human genes 0.000 description 2
- 102100040894 Amylo-alpha-1,6-glucosidase Human genes 0.000 description 2
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 2
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 2
- 102100036438 Amyloid beta precursor protein binding family B member 2 Human genes 0.000 description 2
- 102100029470 Apolipoprotein E Human genes 0.000 description 2
- 108010071619 Apolipoproteins Proteins 0.000 description 2
- 102000007592 Apolipoproteins Human genes 0.000 description 2
- 102000004888 Aquaporin 1 Human genes 0.000 description 2
- 108090001004 Aquaporin 1 Proteins 0.000 description 2
- 102100024081 Aryl-hydrocarbon-interacting protein-like 1 Human genes 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- 102000007372 Ataxin-1 Human genes 0.000 description 2
- 108010032963 Ataxin-1 Proteins 0.000 description 2
- 102000002785 Ataxin-10 Human genes 0.000 description 2
- 102100021321 Ataxin-3 Human genes 0.000 description 2
- 102000007368 Ataxin-7 Human genes 0.000 description 2
- 108010032953 Ataxin-7 Proteins 0.000 description 2
- 102000007370 Ataxin2 Human genes 0.000 description 2
- 108010032951 Ataxin2 Proteins 0.000 description 2
- 102100020741 Atrophin-1 Human genes 0.000 description 2
- 108090000806 Atrophin-1 Proteins 0.000 description 2
- 101150070808 Atxn10 gene Proteins 0.000 description 2
- 208000020706 Autistic disease Diseases 0.000 description 2
- 102100035682 Axin-1 Human genes 0.000 description 2
- 102100021630 B-cell CLL/lymphoma 7 protein family member A Human genes 0.000 description 2
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 2
- 102100029334 Beta-crystallin A3 Human genes 0.000 description 2
- 102100030686 Beta-sarcoglycan Human genes 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 208000029402 Bulbospinal muscular atrophy Diseases 0.000 description 2
- 108700019257 Butyrylcholinesterase deficiency Proteins 0.000 description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 2
- 102100034808 CCAAT/enhancer-binding protein alpha Human genes 0.000 description 2
- 102100031168 CCN family member 2 Human genes 0.000 description 2
- 101150083327 CCR2 gene Proteins 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 2
- 208000032325 CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome Diseases 0.000 description 2
- 102100032539 Calpain-3 Human genes 0.000 description 2
- 102100035904 Caspase-1 Human genes 0.000 description 2
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 2
- 102100040999 Catechol O-methyltransferase Human genes 0.000 description 2
- 102100037182 Cation-independent mannose-6-phosphate receptor Human genes 0.000 description 2
- 102100032212 Caveolin-3 Human genes 0.000 description 2
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 2
- 108010075016 Ceruloplasmin Proteins 0.000 description 2
- 102100023321 Ceruloplasmin Human genes 0.000 description 2
- 206010008635 Cholestasis Diseases 0.000 description 2
- 102100029117 Coagulation factor X Human genes 0.000 description 2
- 102100029057 Coagulation factor XIII A chain Human genes 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 102100027826 Complexin-1 Human genes 0.000 description 2
- 101710137249 Complexin-1 Proteins 0.000 description 2
- 102000015775 Core Binding Factor Alpha 1 Subunit Human genes 0.000 description 2
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 description 2
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 description 2
- 101150092474 Cplx1 gene Proteins 0.000 description 2
- 102100030299 Cysteine-rich hydrophobic domain-containing protein 2 Human genes 0.000 description 2
- 102100023419 Cystic fibrosis transmembrane conductance regulator Human genes 0.000 description 2
- 102100028717 Cytosolic 5'-nucleotidase 3A Human genes 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- 102100039693 D-amino acid oxidase activator Human genes 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102100024829 DNA polymerase delta catalytic subunit Human genes 0.000 description 2
- 102100037799 DNA-binding protein Ikaros Human genes 0.000 description 2
- 102100020986 DNA-binding protein RFX5 Human genes 0.000 description 2
- 101150110160 DRD1 gene Proteins 0.000 description 2
- 201000008163 Dentatorubral pallidoluysian atrophy Diseases 0.000 description 2
- 102100022317 Dihydropteridine reductase Human genes 0.000 description 2
- 102100039673 Disintegrin and metalloproteinase domain-containing protein 10 Human genes 0.000 description 2
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 2
- 102100025327 Dynamin-like 120 kDa protein, mitochondrial Human genes 0.000 description 2
- 108010045061 Dysbindin Proteins 0.000 description 2
- 102000005611 Dysbindin Human genes 0.000 description 2
- 102100032248 Dysferlin Human genes 0.000 description 2
- 102100034546 E3 ubiquitin-protein ligase FANCL Human genes 0.000 description 2
- 102100031918 E3 ubiquitin-protein ligase NEDD4 Human genes 0.000 description 2
- 102100022554 E3 ubiquitin-protein ligase NHLRC1 Human genes 0.000 description 2
- 102100038631 E3 ubiquitin-protein ligase SMURF1 Human genes 0.000 description 2
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 2
- 208000032274 Encephalopathy Diseases 0.000 description 2
- 102100033902 Endothelin-1 Human genes 0.000 description 2
- 102100021601 Ephrin type-A receptor 8 Human genes 0.000 description 2
- 102100029951 Estrogen receptor beta Human genes 0.000 description 2
- 102100020903 Ezrin Human genes 0.000 description 2
- 201000007176 Factor XII Deficiency Diseases 0.000 description 2
- 108010033305 Fanconi Anemia Complementation Group G protein Proteins 0.000 description 2
- 102100034555 Fanconi anemia group G protein Human genes 0.000 description 2
- 102100034552 Fanconi anemia group M protein Human genes 0.000 description 2
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 2
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 2
- 102100032596 Fibrocystin Human genes 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 208000001914 Fragile X syndrome Diseases 0.000 description 2
- 102000001267 GSK3 Human genes 0.000 description 2
- 108060006662 GSK3 Proteins 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 2
- 102100039684 Glucose-6-phosphate exchanger SLC37A4 Human genes 0.000 description 2
- 102100036589 Glycine-tRNA ligase Human genes 0.000 description 2
- 208000032007 Glycogen storage disease due to acid maltase deficiency Diseases 0.000 description 2
- 206010053185 Glycogen storage disease type II Diseases 0.000 description 2
- 101150087728 Grm5 gene Proteins 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 208000002927 Hamartoma Diseases 0.000 description 2
- 102100027685 Hemoglobin subunit alpha Human genes 0.000 description 2
- 208000009292 Hemophilia A Diseases 0.000 description 2
- 206010019663 Hepatic failure Diseases 0.000 description 2
- 108010000487 High-Molecular-Weight Kininogen Proteins 0.000 description 2
- 102100029235 Histone-lysine N-methyltransferase NSD3 Human genes 0.000 description 2
- 102100021086 Homeobox protein Hox-D4 Human genes 0.000 description 2
- 101000733040 Homo sapiens 40S ribosomal protein S19 Proteins 0.000 description 2
- 101000769457 Homo sapiens ADP-ribosylation factor-like protein 11 Proteins 0.000 description 2
- 101000678026 Homo sapiens Alpha-1-antichymotrypsin Proteins 0.000 description 2
- 101000891982 Homo sapiens Alpha-crystallin B chain Proteins 0.000 description 2
- 101000776160 Homo sapiens Alsin Proteins 0.000 description 2
- 101001075525 Homo sapiens Ammonium transporter Rh type A Proteins 0.000 description 2
- 101000928680 Homo sapiens Amyloid beta precursor protein binding family B member 2 Proteins 0.000 description 2
- 101000652582 Homo sapiens Antigen peptide transporter 2 Proteins 0.000 description 2
- 101000833576 Homo sapiens Aryl-hydrocarbon-interacting protein-like 1 Proteins 0.000 description 2
- 101000895100 Homo sapiens Ataxin-3 Proteins 0.000 description 2
- 101000971230 Homo sapiens B-cell CLL/lymphoma 7 protein family member A Proteins 0.000 description 2
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 2
- 101000919139 Homo sapiens Beta-crystallin A3 Proteins 0.000 description 2
- 101000703495 Homo sapiens Beta-sarcoglycan Proteins 0.000 description 2
- 101000945515 Homo sapiens CCAAT/enhancer-binding protein alpha Proteins 0.000 description 2
- 101000777550 Homo sapiens CCN family member 2 Proteins 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- 101000867715 Homo sapiens Calpain-3 Proteins 0.000 description 2
- 101000715398 Homo sapiens Caspase-1 Proteins 0.000 description 2
- 101001028831 Homo sapiens Cation-independent mannose-6-phosphate receptor Proteins 0.000 description 2
- 101000869042 Homo sapiens Caveolin-3 Proteins 0.000 description 2
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 2
- 101000918352 Homo sapiens Coagulation factor XIII A chain Proteins 0.000 description 2
- 101000944357 Homo sapiens Cyclin-dependent kinase 16 Proteins 0.000 description 2
- 101000991100 Homo sapiens Cysteine-rich hydrophobic domain-containing protein 2 Proteins 0.000 description 2
- 101000915170 Homo sapiens Cytosolic 5'-nucleotidase 3A Proteins 0.000 description 2
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 2
- 101000886242 Homo sapiens D-amino acid oxidase activator Proteins 0.000 description 2
- 101000909198 Homo sapiens DNA polymerase delta catalytic subunit Proteins 0.000 description 2
- 101001075432 Homo sapiens DNA-binding protein RFX5 Proteins 0.000 description 2
- 101001016184 Homo sapiens Dysferlin Proteins 0.000 description 2
- 101000636713 Homo sapiens E3 ubiquitin-protein ligase NEDD4 Proteins 0.000 description 2
- 101000973111 Homo sapiens E3 ubiquitin-protein ligase NHLRC1 Proteins 0.000 description 2
- 101000664993 Homo sapiens E3 ubiquitin-protein ligase SMURF1 Proteins 0.000 description 2
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 2
- 101000925493 Homo sapiens Endothelin-1 Proteins 0.000 description 2
- 101000898676 Homo sapiens Ephrin type-A receptor 8 Proteins 0.000 description 2
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 description 2
- 101001010910 Homo sapiens Estrogen receptor beta Proteins 0.000 description 2
- 101000854648 Homo sapiens Ezrin Proteins 0.000 description 2
- 101100012329 Homo sapiens F9 gene Proteins 0.000 description 2
- 101000848187 Homo sapiens Fanconi anemia group M protein Proteins 0.000 description 2
- 101000730595 Homo sapiens Fibrocystin Proteins 0.000 description 2
- 101000726577 Homo sapiens Gap junction alpha-3 protein Proteins 0.000 description 2
- 101000858024 Homo sapiens Gap junction alpha-8 protein Proteins 0.000 description 2
- 101000930910 Homo sapiens Glucose-6-phosphatase catalytic subunit 1 Proteins 0.000 description 2
- 101001009007 Homo sapiens Hemoglobin subunit alpha Proteins 0.000 description 2
- 101000899111 Homo sapiens Hemoglobin subunit beta Proteins 0.000 description 2
- 101000634046 Homo sapiens Histone-lysine N-methyltransferase NSD3 Proteins 0.000 description 2
- 101001041136 Homo sapiens Homeobox protein Hox-D4 Proteins 0.000 description 2
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 2
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 2
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 2
- 101000599056 Homo sapiens Interleukin-6 receptor subunit beta Proteins 0.000 description 2
- 101001090713 Homo sapiens L-lactate dehydrogenase A chain Proteins 0.000 description 2
- 101000876418 Homo sapiens Laforin Proteins 0.000 description 2
- 101000882389 Homo sapiens Laforin, isoform 9 Proteins 0.000 description 2
- 101000972491 Homo sapiens Laminin subunit alpha-2 Proteins 0.000 description 2
- 101000615657 Homo sapiens MAM domain-containing glycosylphosphatidylinositol anchor protein 2 Proteins 0.000 description 2
- 101000983747 Homo sapiens MHC class II transactivator Proteins 0.000 description 2
- 101001030184 Homo sapiens Myotilin Proteins 0.000 description 2
- 101000996111 Homo sapiens Neuroligin-4, X-linked Proteins 0.000 description 2
- 101001109719 Homo sapiens Nucleophosmin Proteins 0.000 description 2
- 101000979629 Homo sapiens Nucleoside diphosphate kinase A Proteins 0.000 description 2
- 101000979623 Homo sapiens Nucleoside diphosphate kinase B Proteins 0.000 description 2
- 101001125026 Homo sapiens Nucleotide-binding oligomerization domain-containing protein 2 Proteins 0.000 description 2
- 101001098523 Homo sapiens PAX-interacting protein 1 Proteins 0.000 description 2
- 101000987581 Homo sapiens Perforin-1 Proteins 0.000 description 2
- 101000755630 Homo sapiens Peripheral-type benzodiazepine receptor-associated protein 1 Proteins 0.000 description 2
- 101000873719 Homo sapiens Phakinin Proteins 0.000 description 2
- 101000730454 Homo sapiens Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha Proteins 0.000 description 2
- 101001053641 Homo sapiens Plasma serine protease inhibitor Proteins 0.000 description 2
- 101000692464 Homo sapiens Platelet-derived growth factor receptor-like protein Proteins 0.000 description 2
- 101001126471 Homo sapiens Plectin Proteins 0.000 description 2
- 101001074439 Homo sapiens Polycystin-2 Proteins 0.000 description 2
- 101000836337 Homo sapiens Probable helicase senataxin Proteins 0.000 description 2
- 101000718497 Homo sapiens Protein AF-10 Proteins 0.000 description 2
- 101000735417 Homo sapiens Protein PAPPAS Proteins 0.000 description 2
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 2
- 101000716803 Homo sapiens Protein SCO1 homolog, mitochondrial Proteins 0.000 description 2
- 101000781981 Homo sapiens Protein Wnt-11 Proteins 0.000 description 2
- 101000804792 Homo sapiens Protein Wnt-5a Proteins 0.000 description 2
- 101000726148 Homo sapiens Protein crumbs homolog 1 Proteins 0.000 description 2
- 101000666171 Homo sapiens Protein-glutamine gamma-glutamyltransferase 2 Proteins 0.000 description 2
- 101000823100 Homo sapiens Putative alpha-1-antitrypsin-related protein Proteins 0.000 description 2
- 101001091538 Homo sapiens Pyruvate kinase PKM Proteins 0.000 description 2
- 101000729271 Homo sapiens Retinoid isomerohydrolase Proteins 0.000 description 2
- 101000575639 Homo sapiens Ribonucleoside-diphosphate reductase subunit M2 Proteins 0.000 description 2
- 101000945093 Homo sapiens Ribosomal protein S6 kinase alpha-4 Proteins 0.000 description 2
- 101000857677 Homo sapiens Runt-related transcription factor 1 Proteins 0.000 description 2
- 101000939246 Homo sapiens SUMO-conjugating enzyme UBC9 Proteins 0.000 description 2
- 101000898985 Homo sapiens Seipin Proteins 0.000 description 2
- 101000683839 Homo sapiens Selenoprotein N Proteins 0.000 description 2
- 101000665442 Homo sapiens Serine/threonine-protein kinase TBK1 Proteins 0.000 description 2
- 101000631929 Homo sapiens Sodium-dependent serotonin transporter Proteins 0.000 description 2
- 101000663635 Homo sapiens Sphingosine kinase 1 Proteins 0.000 description 2
- 101000651197 Homo sapiens Sphingosine kinase 2 Proteins 0.000 description 2
- 101000946863 Homo sapiens T-cell surface glycoprotein CD3 delta chain Proteins 0.000 description 2
- 101000891092 Homo sapiens TAR DNA-binding protein 43 Proteins 0.000 description 2
- 101000891654 Homo sapiens TATA-box-binding protein Proteins 0.000 description 2
- 101000598025 Homo sapiens Talin-1 Proteins 0.000 description 2
- 101000837639 Homo sapiens Thyroxine-binding globulin Proteins 0.000 description 2
- 101000785523 Homo sapiens Tight junction protein ZO-2 Proteins 0.000 description 2
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 2
- 101000625299 Homo sapiens Transcription initiation factor TFIID subunit 4B Proteins 0.000 description 2
- 101000772194 Homo sapiens Transthyretin Proteins 0.000 description 2
- 101000851865 Homo sapiens Tryptophan 5-hydroxylase 2 Proteins 0.000 description 2
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 2
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 2
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 2
- 101000807668 Homo sapiens Uracil-DNA glycosylase Proteins 0.000 description 2
- 101000638886 Homo sapiens Urokinase-type plasminogen activator Proteins 0.000 description 2
- 101000666934 Homo sapiens Very low-density lipoprotein receptor Proteins 0.000 description 2
- 101000775932 Homo sapiens Vesicle-associated membrane protein-associated protein B/C Proteins 0.000 description 2
- 101001104110 Homo sapiens X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 Proteins 0.000 description 2
- 101000926525 Homo sapiens eIF-2-alpha kinase GCN2 Proteins 0.000 description 2
- 206010020365 Homocystinuria Diseases 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 2
- 201000004029 Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 102100025390 Integrin beta-2 Human genes 0.000 description 2
- 201000006347 Intellectual Disability Diseases 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 102100037795 Interleukin-6 receptor subunit beta Human genes 0.000 description 2
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 2
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 2
- 102100035792 Kininogen-1 Human genes 0.000 description 2
- 102100035878 Krev interaction trapped protein 1 Human genes 0.000 description 2
- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 description 2
- 102100035192 Laforin Human genes 0.000 description 2
- 102100022745 Laminin subunit alpha-2 Human genes 0.000 description 2
- 201000003533 Leber congenital amaurosis Diseases 0.000 description 2
- 102100023487 Lens fiber major intrinsic protein Human genes 0.000 description 2
- 102100026038 Lens fiber membrane intrinsic protein Human genes 0.000 description 2
- 206010024612 Lipoma Diseases 0.000 description 2
- 208000015439 Lysosomal storage disease Diseases 0.000 description 2
- 102100021319 MAM domain-containing glycosylphosphatidylinositol anchor protein 2 Human genes 0.000 description 2
- 102100026371 MHC class II transactivator Human genes 0.000 description 2
- 101150053046 MYD88 gene Proteins 0.000 description 2
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 2
- 102100025744 Mothers against decapentaplegic homolog 1 Human genes 0.000 description 2
- 101100293261 Mus musculus Naa15 gene Proteins 0.000 description 2
- 102100024134 Myeloid differentiation primary response protein MyD88 Human genes 0.000 description 2
- 102100038894 Myotilin Human genes 0.000 description 2
- 206010068871 Myotonic dystrophy Diseases 0.000 description 2
- 108010052185 Myotonin-Protein Kinase Proteins 0.000 description 2
- 102100022437 Myotonin-protein kinase Human genes 0.000 description 2
- 101150082943 NAT1 gene Proteins 0.000 description 2
- 101150019103 NAT2 gene Proteins 0.000 description 2
- 101150043994 NOS1 gene Proteins 0.000 description 2
- 102100034441 Neuroligin-4, X-linked Human genes 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 108700002045 Nod2 Signaling Adaptor Proteins 0.000 description 2
- 101150083031 Nod2 gene Proteins 0.000 description 2
- 102100022678 Nucleophosmin Human genes 0.000 description 2
- 102100023252 Nucleoside diphosphate kinase A Human genes 0.000 description 2
- 102100023258 Nucleoside diphosphate kinase B Human genes 0.000 description 2
- 102100040444 P2X purinoceptor 1 Human genes 0.000 description 2
- 102100037602 P2X purinoceptor 7 Human genes 0.000 description 2
- 102100037141 PAX-interacting protein 1 Human genes 0.000 description 2
- 101150035190 PSEN1 gene Proteins 0.000 description 2
- 102100037506 Paired box protein Pax-6 Human genes 0.000 description 2
- 102000003982 Parathyroid hormone Human genes 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 101000579647 Penaeus vannamei Penaeidin-2a Proteins 0.000 description 2
- 102100028467 Perforin-1 Human genes 0.000 description 2
- 102100022369 Peripheral-type benzodiazepine receptor-associated protein 1 Human genes 0.000 description 2
- 201000011252 Phenylketonuria Diseases 0.000 description 2
- 102100032615 Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha Human genes 0.000 description 2
- 101710169596 Phosphatidylinositol-binding clathrin assembly protein Proteins 0.000 description 2
- 101710202171 Phosphoenolpyruvate carboxykinase (ATP) 1 Proteins 0.000 description 2
- 102100024078 Plasma serine protease inhibitor Human genes 0.000 description 2
- 102100038124 Plasminogen Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 102100026554 Platelet-derived growth factor receptor-like protein Human genes 0.000 description 2
- 102100036142 Polycystin-2 Human genes 0.000 description 2
- 108010050254 Presenilins Proteins 0.000 description 2
- 102000015499 Presenilins Human genes 0.000 description 2
- 102100027178 Probable helicase senataxin Human genes 0.000 description 2
- 102100026286 Protein AF-10 Human genes 0.000 description 2
- 102100026375 Protein PML Human genes 0.000 description 2
- 206010051292 Protein S Deficiency Diseases 0.000 description 2
- 102100020866 Protein SCO1 homolog, mitochondrial Human genes 0.000 description 2
- 102100036567 Protein Wnt-11 Human genes 0.000 description 2
- 102100027331 Protein crumbs homolog 1 Human genes 0.000 description 2
- 102100038095 Protein-glutamine gamma-glutamyltransferase 2 Human genes 0.000 description 2
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 description 2
- 101710156592 Putative TATA-binding protein pB263R Proteins 0.000 description 2
- 102100022709 Putative alpha-1-antitrypsin-related protein Human genes 0.000 description 2
- 108700014121 Pyruvate Kinase Deficiency of Red Cells Proteins 0.000 description 2
- 102100034911 Pyruvate kinase PKM Human genes 0.000 description 2
- 101710188535 RNA ligase 2 Proteins 0.000 description 2
- 102000003890 RNA-binding protein FUS Human genes 0.000 description 2
- 108090000292 RNA-binding protein FUS Proteins 0.000 description 2
- 101710204104 RNA-editing ligase 2, mitochondrial Proteins 0.000 description 2
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 2
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 102100031176 Retinoid isomerohydrolase Human genes 0.000 description 2
- 102100026006 Ribonucleoside-diphosphate reductase subunit M2 Human genes 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- 102100033644 Ribosomal protein S6 kinase alpha-4 Human genes 0.000 description 2
- 108091006299 SLC2A2 Proteins 0.000 description 2
- 108091006300 SLC2A4 Proteins 0.000 description 2
- 102000005029 SLC6A3 Human genes 0.000 description 2
- 101700032040 SMAD1 Proteins 0.000 description 2
- 102100029807 SUMO-conjugating enzyme UBC9 Human genes 0.000 description 2
- 102100021463 Seipin Human genes 0.000 description 2
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 description 2
- 101150116689 Slc2a2 gene Proteins 0.000 description 2
- 102100028874 Sodium-dependent serotonin transporter Human genes 0.000 description 2
- 102100023537 Solute carrier family 2, facilitated glucose transporter member 2 Human genes 0.000 description 2
- 102100033939 Solute carrier family 2, facilitated glucose transporter member 4 Human genes 0.000 description 2
- 102100038803 Somatotropin Human genes 0.000 description 2
- 102100039024 Sphingosine kinase 1 Human genes 0.000 description 2
- 102100027662 Sphingosine kinase 2 Human genes 0.000 description 2
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 2
- 206010041660 Splenomegaly Diseases 0.000 description 2
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 2
- 102100038836 Superoxide dismutase [Cu-Zn] Human genes 0.000 description 2
- 208000012827 T-B+ severe combined immunodeficiency due to gamma chain deficiency Diseases 0.000 description 2
- 102100040365 T-cell acute lymphocytic leukemia protein 1 Human genes 0.000 description 2
- 102100035891 T-cell surface glycoprotein CD3 delta chain Human genes 0.000 description 2
- 102100040347 TAR DNA-binding protein 43 Human genes 0.000 description 2
- 101710145783 TATA-box-binding protein Proteins 0.000 description 2
- 108700012920 TNF Proteins 0.000 description 2
- 101150115335 TPH2 gene Proteins 0.000 description 2
- 102100036977 Talin-1 Human genes 0.000 description 2
- 102100028082 Tapasin Human genes 0.000 description 2
- 208000002903 Thalassemia Diseases 0.000 description 2
- 102100028709 Thyroxine-binding globulin Human genes 0.000 description 2
- 102100026637 Tight junction protein ZO-2 Human genes 0.000 description 2
- 101150079992 Timp3 gene Proteins 0.000 description 2
- 102000005406 Tissue Inhibitor of Metalloproteinase-3 Human genes 0.000 description 2
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 2
- 101150058700 Tph1 gene Proteins 0.000 description 2
- 102100025035 Transcription initiation factor TFIID subunit 4B Human genes 0.000 description 2
- 102100027059 Translation initiation factor eIF-2B subunit alpha Human genes 0.000 description 2
- 102100029290 Transthyretin Human genes 0.000 description 2
- 102100036474 Tryptophan 5-hydroxylase 2 Human genes 0.000 description 2
- 108010031944 Tryptophan Hydroxylase Proteins 0.000 description 2
- 102000005506 Tryptophan Hydroxylase Human genes 0.000 description 2
- 108010091356 Tumor Protein p73 Proteins 0.000 description 2
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 2
- 102100030018 Tumor protein p73 Human genes 0.000 description 2
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 2
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 102100031358 Urokinase-type plasminogen activator Human genes 0.000 description 2
- 102100039066 Very low-density lipoprotein receptor Human genes 0.000 description 2
- 102100032026 Vesicle-associated membrane protein-associated protein B/C Human genes 0.000 description 2
- 101150115477 Vldlr gene Proteins 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- 102000043366 Wnt-5a Human genes 0.000 description 2
- 102100040089 X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 Human genes 0.000 description 2
- 108010016200 Zinc Finger Protein GLI1 Proteins 0.000 description 2
- 108010088665 Zinc Finger Protein Gli2 Proteins 0.000 description 2
- 102100040314 Zinc finger and BTB domain-containing protein 16 Human genes 0.000 description 2
- 102100035535 Zinc finger protein GLI1 Human genes 0.000 description 2
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 208000025531 adult-onset foveomacular vitelliform dystrophy Diseases 0.000 description 2
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 description 2
- 108090000185 alpha-Synuclein Proteins 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 208000001978 aminoacylase 1 deficiency Diseases 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 101150089041 aph-1 gene Proteins 0.000 description 2
- 230000037007 arousal Effects 0.000 description 2
- 201000009562 autosomal recessive limb-girdle muscular dystrophy type 2C Diseases 0.000 description 2
- 201000009561 autosomal recessive limb-girdle muscular dystrophy type 2D Diseases 0.000 description 2
- 208000033651 b subunit deficiency of factor XIII Diseases 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 231100000359 cholestasis Toxicity 0.000 description 2
- 230000007870 cholestasis Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 208000001020 chondrodysplasia punctata Diseases 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 102100034175 eIF-2-alpha kinase GCN2 Human genes 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000001815 facial effect Effects 0.000 description 2
- 201000007386 factor VII deficiency Diseases 0.000 description 2
- 208000005376 factor X deficiency Diseases 0.000 description 2
- 201000007219 factor XI deficiency Diseases 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 201000004502 glycogen storage disease II Diseases 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 208000031169 hemorrhagic disease Diseases 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 208000009624 holoprosencephaly Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000015788 innate immune response Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000002414 leg Anatomy 0.000 description 2
- 208000007903 liver failure Diseases 0.000 description 2
- 231100000835 liver failure Toxicity 0.000 description 2
- 239000003580 lung surfactant Substances 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 208000022018 mucopolysaccharidosis type 2 Diseases 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 201000006938 muscular dystrophy Diseases 0.000 description 2
- 230000002151 myoclonic effect Effects 0.000 description 2
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 2
- 101150036168 ncstn gene Proteins 0.000 description 2
- 208000029140 neonatal diabetes Diseases 0.000 description 2
- 201000008026 nephroblastoma Diseases 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 102000046701 nicastrin Human genes 0.000 description 2
- 108700022821 nicastrin Proteins 0.000 description 2
- 239000000199 parathyroid hormone Substances 0.000 description 2
- 229960001319 parathyroid hormone Drugs 0.000 description 2
- 101150063226 parp-1 gene Proteins 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000009984 peri-natal effect Effects 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 208000007442 rickets Diseases 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 206010039722 scoliosis Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 208000007056 sickle cell anemia Diseases 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000001228 trophic effect Effects 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- QYAPHLRPFNSDNH-MRFRVZCGSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O QYAPHLRPFNSDNH-MRFRVZCGSA-N 0.000 description 1
- 102100028734 1,4-alpha-glucan-branching enzyme Human genes 0.000 description 1
- UVBYMVOUBXYSFV-XUTVFYLZSA-N 1-methylpseudouridine Chemical compound O=C1NC(=O)N(C)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UVBYMVOUBXYSFV-XUTVFYLZSA-N 0.000 description 1
- UVBYMVOUBXYSFV-UHFFFAOYSA-N 1-methylpseudouridine Natural products O=C1NC(=O)N(C)C=C1C1C(O)C(O)C(CO)O1 UVBYMVOUBXYSFV-UHFFFAOYSA-N 0.000 description 1
- 102100038028 1-phosphatidylinositol 3-phosphate 5-kinase Human genes 0.000 description 1
- YMZPQKXPKZZSFV-CPWYAANMSA-N 2-[3-[(1r)-1-[(2s)-1-[(2s)-2-[(1r)-cyclohex-2-en-1-yl]-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carbonyl]oxy-3-(3,4-dimethoxyphenyl)propyl]phenoxy]acetic acid Chemical compound C1=C(OC)C(OC)=CC=C1CC[C@H](C=1C=C(OCC(O)=O)C=CC=1)OC(=O)[C@H]1N(C(=O)[C@@H]([C@H]2C=CCCC2)C=2C=C(OC)C(OC)=C(OC)C=2)CCCC1 YMZPQKXPKZZSFV-CPWYAANMSA-N 0.000 description 1
- PYNVSZMFFVWFQA-NOMGDLSISA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(1-hydroxyethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound O[C@@H]1[C@H](O)[C@@H](C(O)C)O[C@H]1N1C(NC(N)=NC2=O)=C2N=C1 PYNVSZMFFVWFQA-NOMGDLSISA-N 0.000 description 1
- QNIZHKITBISILC-RPKMEZRRSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-methyloxolan-2-yl]-3h-purin-6-one Chemical compound C1=NC(C(NC(N)=N2)=O)=C2N1[C@]1(C)O[C@H](CO)[C@@H](O)[C@H]1O QNIZHKITBISILC-RPKMEZRRSA-N 0.000 description 1
- DIDGPCDGNMIUNX-UUOKFMHZSA-N 2-amino-9-[(2r,3r,4s,5r)-5-(dihydroxyphosphinothioyloxymethyl)-3,4-dihydroxyoxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=S)[C@@H](O)[C@H]1O DIDGPCDGNMIUNX-UUOKFMHZSA-N 0.000 description 1
- MZZYGYNZAOVRTG-UHFFFAOYSA-N 2-hydroxy-n-(1h-1,2,4-triazol-5-yl)benzamide Chemical compound OC1=CC=CC=C1C(=O)NC1=NC=NN1 MZZYGYNZAOVRTG-UHFFFAOYSA-N 0.000 description 1
- 108010037497 3'-nucleotidase Proteins 0.000 description 1
- 108010043797 4-alpha-glucanotransferase Proteins 0.000 description 1
- 102100035923 4-aminobutyrate aminotransferase, mitochondrial Human genes 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- YAWQLNSJZSCVAG-TURQNECASA-N 5-(3-aminopropyl)-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CCCN)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 YAWQLNSJZSCVAG-TURQNECASA-N 0.000 description 1
- AGFIRQJZCNVMCW-UAKXSSHOSA-N 5-bromouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 AGFIRQJZCNVMCW-UAKXSSHOSA-N 0.000 description 1
- KELXHQACBIUYSE-UHFFFAOYSA-N 5-methoxy-1h-pyrimidine-2,4-dione Chemical compound COC1=CNC(=O)NC1=O KELXHQACBIUYSE-UHFFFAOYSA-N 0.000 description 1
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 1
- OGHAROSJZRTIOK-KQYNXXCUSA-O 7-methylguanosine Chemical compound C1=2N=C(N)NC(=O)C=2[N+](C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OGHAROSJZRTIOK-KQYNXXCUSA-O 0.000 description 1
- ASUCSHXLTWZYBA-UMMCILCDSA-N 8-Bromoguanosine Chemical compound C1=2NC(N)=NC(=O)C=2N=C(Br)N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ASUCSHXLTWZYBA-UMMCILCDSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 208000033598 A subunit deficiency of factor XIII Diseases 0.000 description 1
- 108091007507 ADAM12 Proteins 0.000 description 1
- 208000028324 APO A-i deficiency Diseases 0.000 description 1
- 101150037123 APOE gene Proteins 0.000 description 1
- 101150111620 AQP1 gene Proteins 0.000 description 1
- 102100032922 ATP-dependent 6-phosphofructokinase, muscle type Human genes 0.000 description 1
- 101150030271 AXIN1 gene Proteins 0.000 description 1
- 208000035657 Abasia Diseases 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 102100036409 Activated CDC42 kinase 1 Human genes 0.000 description 1
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 102100036664 Adenosine deaminase Human genes 0.000 description 1
- 102100031786 Adiponectin Human genes 0.000 description 1
- 208000002485 Adiposis dolorosa Diseases 0.000 description 1
- 208000002004 Afibrinogenemia Diseases 0.000 description 1
- 230000007730 Akt signaling Effects 0.000 description 1
- 208000020506 Albright hereditary osteodystrophy Diseases 0.000 description 1
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 description 1
- 208000033337 Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3 Diseases 0.000 description 1
- 208000003808 Amyloid Neuropathies Diseases 0.000 description 1
- 101710185050 Angiotensin-converting enzyme Proteins 0.000 description 1
- 108050009514 Antigen peptide transporter 1 Proteins 0.000 description 1
- 206010002961 Aplasia Diseases 0.000 description 1
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 1
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 1
- 102100037320 Apolipoprotein A-IV Human genes 0.000 description 1
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 1
- 102100030970 Apolipoprotein C-III Human genes 0.000 description 1
- 101100224343 Arabidopsis thaliana DOF2.5 gene Proteins 0.000 description 1
- 101100288434 Arabidopsis thaliana LACS2 gene Proteins 0.000 description 1
- 101100345345 Arabidopsis thaliana MGD1 gene Proteins 0.000 description 1
- 101100243447 Arabidopsis thaliana PER53 gene Proteins 0.000 description 1
- 101000719121 Arabidopsis thaliana Protein MEI2-like 1 Proteins 0.000 description 1
- 241000180579 Arca Species 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 108090000448 Aryl Hydrocarbon Receptors Proteins 0.000 description 1
- 102100026792 Aryl hydrocarbon receptor Human genes 0.000 description 1
- 101710115247 Arylsulfatase B Proteins 0.000 description 1
- 102100023943 Arylsulfatase L Human genes 0.000 description 1
- 101150025446 Atn1 gene Proteins 0.000 description 1
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 description 1
- 208000002814 Autosomal Recessive Polycystic Kidney Diseases 0.000 description 1
- 208000035665 Autosomal dominant Charcot-Marie-Tooth disease type 2D Diseases 0.000 description 1
- 208000036075 Autosomal dominant tubulointerstitial kidney disease Diseases 0.000 description 1
- 208000017354 Autosomal recessive polycystic kidney disease Diseases 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 102100032305 Bcl-2 homologous antagonist/killer Human genes 0.000 description 1
- 108010040168 Bcl-2-Like Protein 11 Proteins 0.000 description 1
- 102000001765 Bcl-2-Like Protein 11 Human genes 0.000 description 1
- 102100021573 Bcl-2-binding component 3, isoforms 3/4 Human genes 0.000 description 1
- 206010004280 Benign lung neoplasm Diseases 0.000 description 1
- 102100022794 Bestrophin-1 Human genes 0.000 description 1
- 102100034732 Beta-1,3-glucuronyltransferase LARGE1 Human genes 0.000 description 1
- 102100029648 Beta-arrestin-2 Human genes 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102100030516 Beta-crystallin B1 Human genes 0.000 description 1
- 102100022549 Beta-hexosaminidase subunit beta Human genes 0.000 description 1
- 108010025544 Bleomycin hydrolase Proteins 0.000 description 1
- 102100027058 Bleomycin hydrolase Human genes 0.000 description 1
- 206010070918 Bone deformity Diseases 0.000 description 1
- 101000964894 Bos taurus 14-3-3 protein zeta/delta Proteins 0.000 description 1
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 1
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 1
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 102100031171 CCN family member 1 Human genes 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 201000006883 CLOVES syndrome Diseases 0.000 description 1
- 108091011896 CSF1 Proteins 0.000 description 1
- 101150062345 CX3CR1 gene Proteins 0.000 description 1
- 102100025805 Cadherin-1 Human genes 0.000 description 1
- 101100017502 Caenorhabditis elegans hlh-3 gene Proteins 0.000 description 1
- 101710192106 Calcineurin-binding protein cabin-1 Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100021534 Calcium/calmodulin-dependent protein kinase kinase 2 Human genes 0.000 description 1
- 102100029968 Calreticulin Human genes 0.000 description 1
- 101000809436 Candida albicans Sterol O-acyltransferase 2 Proteins 0.000 description 1
- 208000033910 Carbamoyl-phosphate synthetase 1 deficiency Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000000671 Carney triad Diseases 0.000 description 1
- 208000008462 Carney-Stratakis syndrome Diseases 0.000 description 1
- 102100037398 Casein kinase I isoform epsilon Human genes 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 102100028906 Catenin delta-1 Human genes 0.000 description 1
- 108091007854 Cdh1/Fizzy-related Proteins 0.000 description 1
- 201000008958 Charcot-Marie-Tooth disease type 2D Diseases 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 208000029448 Chylomicron retention disease Diseases 0.000 description 1
- 102100026127 Clathrin heavy chain 1 Human genes 0.000 description 1
- 102100040836 Claudin-1 Human genes 0.000 description 1
- 102100032887 Clusterin Human genes 0.000 description 1
- 108090000197 Clusterin Proteins 0.000 description 1
- 208000010200 Cockayne syndrome Diseases 0.000 description 1
- 102100024484 Codanin-1 Human genes 0.000 description 1
- 206010010099 Combined immunodeficiency Diseases 0.000 description 1
- 102000004381 Complement C2 Human genes 0.000 description 1
- 108090000955 Complement C2 Proteins 0.000 description 1
- 102000016916 Complement C8 Human genes 0.000 description 1
- 108010028777 Complement C8 Proteins 0.000 description 1
- 108010053085 Complement Factor H Proteins 0.000 description 1
- 102000016550 Complement Factor H Human genes 0.000 description 1
- 102100035436 Complement factor D Human genes 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 108700011014 Congenital Deficiency of Pulmonary Surfactant Protein B Proteins 0.000 description 1
- 206010053138 Congenital aplastic anaemia Diseases 0.000 description 1
- 208000029767 Congenital, Hereditary, and Neonatal Diseases and Abnormalities Diseases 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 108010002154 Cortisone Reductase Proteins 0.000 description 1
- 208000012609 Cowden disease Diseases 0.000 description 1
- 201000002847 Cowden syndrome Diseases 0.000 description 1
- 101150030419 Cx3cl1 gene Proteins 0.000 description 1
- 102100023583 Cyclic AMP-dependent transcription factor ATF-6 alpha Human genes 0.000 description 1
- 102000004480 Cyclin-Dependent Kinase Inhibitor p57 Human genes 0.000 description 1
- 108010017222 Cyclin-Dependent Kinase Inhibitor p57 Proteins 0.000 description 1
- 102100026865 Cyclin-dependent kinase 5 activator 1 Human genes 0.000 description 1
- 102100035429 Cystathionine gamma-lyase Human genes 0.000 description 1
- 108010045283 Cystathionine gamma-lyase Proteins 0.000 description 1
- 102100026278 Cysteine sulfinic acid decarboxylase Human genes 0.000 description 1
- 108010019961 Cysteine-Rich Protein 61 Proteins 0.000 description 1
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 description 1
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 102100025621 Cytochrome b-245 heavy chain Human genes 0.000 description 1
- 102100025620 Cytochrome b-245 light chain Human genes 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 208000017860 DEND syndrome Diseases 0.000 description 1
- 208000025939 DNA Repair-Deficiency disease Diseases 0.000 description 1
- 230000012746 DNA damage checkpoint Effects 0.000 description 1
- 102100029145 DNA damage-inducible transcript 3 protein Human genes 0.000 description 1
- 208000027816 DNA repair disease Diseases 0.000 description 1
- 102100034484 DNA repair protein RAD51 homolog 3 Human genes 0.000 description 1
- 101710158312 DNA-binding protein HU-beta Proteins 0.000 description 1
- 101710157974 DNA-binding protein SMUBP-2 Proteins 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 108010049207 Death Domain Receptors Proteins 0.000 description 1
- 102000009058 Death Domain Receptors Human genes 0.000 description 1
- 102100038713 Death domain-containing protein CRADD Human genes 0.000 description 1
- 102100033553 Delta-like protein 4 Human genes 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102100030074 Dickkopf-related protein 1 Human genes 0.000 description 1
- 102100023319 Dihydrolipoyl dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100031112 Disintegrin and metalloproteinase domain-containing protein 12 Human genes 0.000 description 1
- 102100024361 Disintegrin and metalloproteinase domain-containing protein 9 Human genes 0.000 description 1
- 102100037832 Docking protein 1 Human genes 0.000 description 1
- 102100033156 Dopamine beta-hydroxylase Human genes 0.000 description 1
- 101150097070 Drd3 gene Proteins 0.000 description 1
- 101150043870 Drd4 gene Proteins 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 108010036466 E2F2 Transcription Factor Proteins 0.000 description 1
- 102100037334 E3 ubiquitin-protein ligase CHIP Human genes 0.000 description 1
- 108700015856 ELAV-Like Protein 1 Proteins 0.000 description 1
- 102100034235 ELAV-like protein 1 Human genes 0.000 description 1
- 102100023226 Early growth response protein 1 Human genes 0.000 description 1
- 101150011861 Elavl1 gene Proteins 0.000 description 1
- 102100034239 Emerin Human genes 0.000 description 1
- 201000009344 Emery-Dreifuss muscular dystrophy Diseases 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 108091008815 Eph receptors Proteins 0.000 description 1
- 208000024658 Epilepsy syndrome Diseases 0.000 description 1
- 208000002877 Epileptic Syndromes Diseases 0.000 description 1
- 101710100588 Erythroid transcription factor Proteins 0.000 description 1
- 101000661485 Escherichia coli (strain K12) Cysteine desulfurase Proteins 0.000 description 1
- 101000956229 Escherichia coli (strain K12) Cysteine desulfurase CsdA Proteins 0.000 description 1
- 108010082945 Eukaryotic Initiation Factor-2B Proteins 0.000 description 1
- 208000005163 Extra-Adrenal Paraganglioma Diseases 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 101710105178 F-box/WD repeat-containing protein 7 Proteins 0.000 description 1
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 208000024720 Fabry Disease Diseases 0.000 description 1
- 208000037149 Facioscapulohumeral dystrophy Diseases 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 201000003542 Factor VIII deficiency Diseases 0.000 description 1
- 108010074864 Factor XI Proteins 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 201000007371 Factor XIII Deficiency Diseases 0.000 description 1
- 208000005050 Familial Hypophosphatemic Rickets Diseases 0.000 description 1
- 108010087740 Fanconi Anemia Complementation Group A protein Proteins 0.000 description 1
- 102000018825 Fanconi Anemia Complementation Group C protein Human genes 0.000 description 1
- 108010027673 Fanconi Anemia Complementation Group C protein Proteins 0.000 description 1
- 108010026653 Fanconi Anemia Complementation Group D2 protein Proteins 0.000 description 1
- 102000010634 Fanconi Anemia Complementation Group E protein Human genes 0.000 description 1
- 108010077898 Fanconi Anemia Complementation Group E protein Proteins 0.000 description 1
- 102000012216 Fanconi Anemia Complementation Group F protein Human genes 0.000 description 1
- 108010022012 Fanconi Anemia Complementation Group F protein Proteins 0.000 description 1
- 108700026162 Fanconi Anemia Complementation Group L protein Proteins 0.000 description 1
- 201000004939 Fanconi anemia Diseases 0.000 description 1
- 102100027286 Fanconi anemia group C protein Human genes 0.000 description 1
- 102100040306 Fanconi anemia group D2 protein Human genes 0.000 description 1
- 206010051998 Febrile infection Diseases 0.000 description 1
- 208000001362 Fetal Growth Retardation Diseases 0.000 description 1
- 101800000656 Fetal antigen 1 Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 102100031752 Fibrinogen alpha chain Human genes 0.000 description 1
- 108700018224 Flaujeac factor deficiency Proteins 0.000 description 1
- 208000010263 Fructose-1,6-Diphosphatase Deficiency Diseases 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 230000008051 G1/S transition checkpoint Effects 0.000 description 1
- 208000025499 G6PD deficiency Diseases 0.000 description 1
- 201000008892 GM1 Gangliosidosis Diseases 0.000 description 1
- 102100033452 GMP synthase [glutamine-hydrolyzing] Human genes 0.000 description 1
- 101710071060 GMPS Proteins 0.000 description 1
- 101150021949 GRIN1 gene Proteins 0.000 description 1
- 108010023555 GTP Cyclohydrolase Proteins 0.000 description 1
- 102100027346 GTP cyclohydrolase 1 Human genes 0.000 description 1
- 208000011370 GTP cyclohydrolase I deficiency Diseases 0.000 description 1
- 208000036893 GUCY2D-related dominant retinopathy Diseases 0.000 description 1
- 101710177291 Gag polyprotein Proteins 0.000 description 1
- 208000033136 Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5 Diseases 0.000 description 1
- 102100021337 Gap junction alpha-1 protein Human genes 0.000 description 1
- 208000015872 Gaucher disease Diseases 0.000 description 1
- 206010056696 Gaze palsy Diseases 0.000 description 1
- 102100028953 Gelsolin Human genes 0.000 description 1
- 208000010300 Genu Varum Diseases 0.000 description 1
- 201000006004 Gitelman syndrome Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 1
- 102100036264 Glucose-6-phosphatase catalytic subunit 1 Human genes 0.000 description 1
- 206010018444 Glucose-6-phosphate dehydrogenase deficiency Diseases 0.000 description 1
- 102100030651 Glutamate receptor 2 Human genes 0.000 description 1
- 102100024008 Glycerol-3-phosphate acyltransferase 1, mitochondrial Human genes 0.000 description 1
- 102100039264 Glycogen [starch] synthase, liver Human genes 0.000 description 1
- 102100029481 Glycogen phosphorylase, liver form Human genes 0.000 description 1
- 208000014324 Glycogen storage disease due to phosphorylase kinase deficiency Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 101150049131 Gria1 gene Proteins 0.000 description 1
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 1
- 102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 description 1
- 108010070742 Guanidinoacetate N-Methyltransferase Proteins 0.000 description 1
- 102000005756 Guanidinoacetate N-methyltransferase Human genes 0.000 description 1
- 101150050738 HTR1B gene Proteins 0.000 description 1
- 206010058423 Haemangioma-thrombocytopenia syndrome Diseases 0.000 description 1
- 102000003693 Hedgehog Proteins Human genes 0.000 description 1
- 108090000031 Hedgehog Proteins Proteins 0.000 description 1
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 1
- 102100039894 Hemoglobin subunit delta Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 208000036066 Hemophagocytic Lymphohistiocytosis Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 102000019267 Hepatic lipases Human genes 0.000 description 1
- 108050006747 Hepatic lipases Proteins 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 208000003923 Hereditary Corneal Dystrophies Diseases 0.000 description 1
- 208000032672 Histiocytosis haematophagic Diseases 0.000 description 1
- 102100025210 Histone-arginine methyltransferase CARM1 Human genes 0.000 description 1
- 102100028998 Histone-lysine N-methyltransferase SUV39H1 Human genes 0.000 description 1
- 102100032827 Homeodomain-interacting protein kinase 2 Human genes 0.000 description 1
- 101001058479 Homo sapiens 1,4-alpha-glucan-branching enzyme Proteins 0.000 description 1
- 101001025044 Homo sapiens 1-phosphatidylinositol 3-phosphate 5-kinase Proteins 0.000 description 1
- 101001000686 Homo sapiens 4-aminobutyrate aminotransferase, mitochondrial Proteins 0.000 description 1
- 101000985215 Homo sapiens 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 1
- 101001083755 Homo sapiens 5-aminolevulinate synthase, erythroid-specific, mitochondrial Proteins 0.000 description 1
- 101001029059 Homo sapiens ATP-binding cassette sub-family C member 10 Proteins 0.000 description 1
- 101000730838 Homo sapiens ATP-dependent 6-phosphofructokinase, muscle type Proteins 0.000 description 1
- 101000928956 Homo sapiens Activated CDC42 kinase 1 Proteins 0.000 description 1
- 101000929495 Homo sapiens Adenosine deaminase Proteins 0.000 description 1
- 101000775469 Homo sapiens Adiponectin Proteins 0.000 description 1
- 101000799972 Homo sapiens Alpha-2-macroglobulin Proteins 0.000 description 1
- 101000924727 Homo sapiens Alternative prion protein Proteins 0.000 description 1
- 101000893559 Homo sapiens Amylo-alpha-1,6-glucosidase Proteins 0.000 description 1
- 101000806793 Homo sapiens Apolipoprotein A-IV Proteins 0.000 description 1
- 101000889953 Homo sapiens Apolipoprotein B-100 Proteins 0.000 description 1
- 101000793223 Homo sapiens Apolipoprotein C-III Proteins 0.000 description 1
- 101000771674 Homo sapiens Apolipoprotein E Proteins 0.000 description 1
- 101000975827 Homo sapiens Arylsulfatase L Proteins 0.000 description 1
- 101000874566 Homo sapiens Axin-1 Proteins 0.000 description 1
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 description 1
- 101000798320 Homo sapiens Bcl-2 homologous antagonist/killer Proteins 0.000 description 1
- 101000971203 Homo sapiens Bcl-2-binding component 3, isoforms 1/2 Proteins 0.000 description 1
- 101000971209 Homo sapiens Bcl-2-binding component 3, isoforms 3/4 Proteins 0.000 description 1
- 101000903449 Homo sapiens Bestrophin-1 Proteins 0.000 description 1
- 101001090662 Homo sapiens Beta-1,3-glucuronyltransferase LARGE1 Proteins 0.000 description 1
- 101000919505 Homo sapiens Beta-crystallin B1 Proteins 0.000 description 1
- 101001045433 Homo sapiens Beta-hexosaminidase subunit beta Proteins 0.000 description 1
- 101000984541 Homo sapiens Bleomycin hydrolase Proteins 0.000 description 1
- 101000777599 Homo sapiens C-C chemokine receptor type 2 Proteins 0.000 description 1
- 101000946926 Homo sapiens C-C chemokine receptor type 5 Proteins 0.000 description 1
- 101000824531 Homo sapiens CAAX prenyl protease 1 homolog Proteins 0.000 description 1
- 101000971617 Homo sapiens Calcium/calmodulin-dependent protein kinase kinase 2 Proteins 0.000 description 1
- 101000793651 Homo sapiens Calreticulin Proteins 0.000 description 1
- 101001026376 Homo sapiens Casein kinase I isoform epsilon Proteins 0.000 description 1
- 101000916264 Homo sapiens Catenin delta-1 Proteins 0.000 description 1
- 101000912851 Homo sapiens Clathrin heavy chain 1 Proteins 0.000 description 1
- 101000749331 Homo sapiens Claudin-1 Proteins 0.000 description 1
- 101000980888 Homo sapiens Codanin-1 Proteins 0.000 description 1
- 101000737554 Homo sapiens Complement factor D Proteins 0.000 description 1
- 101000905751 Homo sapiens Cyclic AMP-dependent transcription factor ATF-6 alpha Proteins 0.000 description 1
- 101000855583 Homo sapiens Cysteine sulfinic acid decarboxylase Proteins 0.000 description 1
- 101000856723 Homo sapiens Cytochrome b-245 light chain Proteins 0.000 description 1
- 101001132271 Homo sapiens DNA repair protein RAD51 homolog 3 Proteins 0.000 description 1
- 101000736065 Homo sapiens DNA replication complex GINS protein PSF2 Proteins 0.000 description 1
- 101000599038 Homo sapiens DNA-binding protein Ikaros Proteins 0.000 description 1
- 101000957914 Homo sapiens Death domain-containing protein CRADD Proteins 0.000 description 1
- 101000872077 Homo sapiens Delta-like protein 4 Proteins 0.000 description 1
- 101000864646 Homo sapiens Dickkopf-related protein 1 Proteins 0.000 description 1
- 101000902365 Homo sapiens Dihydropteridine reductase Proteins 0.000 description 1
- 101000832769 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 9 Proteins 0.000 description 1
- 101000805172 Homo sapiens Docking protein 1 Proteins 0.000 description 1
- 101000927562 Homo sapiens Dopamine beta-hydroxylase Proteins 0.000 description 1
- 101000879619 Homo sapiens E3 ubiquitin-protein ligase CHIP Proteins 0.000 description 1
- 101000848191 Homo sapiens E3 ubiquitin-protein ligase FANCL Proteins 0.000 description 1
- 101001049697 Homo sapiens Early growth response protein 1 Proteins 0.000 description 1
- 101001024566 Homo sapiens Ecto-ADP-ribosyltransferase 4 Proteins 0.000 description 1
- 101100119754 Homo sapiens FANCL gene Proteins 0.000 description 1
- 101000914673 Homo sapiens Fanconi anemia group A protein Proteins 0.000 description 1
- 101000914680 Homo sapiens Fanconi anemia group C protein Proteins 0.000 description 1
- 101000846244 Homo sapiens Fibrinogen alpha chain Proteins 0.000 description 1
- 101000980756 Homo sapiens G1/S-specific cyclin-D1 Proteins 0.000 description 1
- 101000894966 Homo sapiens Gap junction alpha-1 protein Proteins 0.000 description 1
- 101001059150 Homo sapiens Gelsolin Proteins 0.000 description 1
- 101000886173 Homo sapiens Glucose-6-phosphate exchanger SLC37A4 Proteins 0.000 description 1
- 101001010449 Homo sapiens Glutamate receptor 2 Proteins 0.000 description 1
- 101001002170 Homo sapiens Glutamine amidotransferase-like class 1 domain-containing protein 3, mitochondrial Proteins 0.000 description 1
- 101000904268 Homo sapiens Glycerol-3-phosphate acyltransferase 1, mitochondrial Proteins 0.000 description 1
- 101001072736 Homo sapiens Glycine-tRNA ligase Proteins 0.000 description 1
- 101001036117 Homo sapiens Glycogen [starch] synthase, liver Proteins 0.000 description 1
- 101000700616 Homo sapiens Glycogen phosphorylase, liver form Proteins 0.000 description 1
- 101001035503 Homo sapiens Hemoglobin subunit delta Proteins 0.000 description 1
- 101000696705 Homo sapiens Histone-lysine N-methyltransferase SUV39H1 Proteins 0.000 description 1
- 101001066401 Homo sapiens Homeodomain-interacting protein kinase 2 Proteins 0.000 description 1
- 101001044940 Homo sapiens Insulin-like growth factor-binding protein 2 Proteins 0.000 description 1
- 101000840577 Homo sapiens Insulin-like growth factor-binding protein 7 Proteins 0.000 description 1
- 101000598002 Homo sapiens Interferon regulatory factor 1 Proteins 0.000 description 1
- 101001011382 Homo sapiens Interferon regulatory factor 3 Proteins 0.000 description 1
- 101001082060 Homo sapiens Interferon-induced protein with tetratricopeptide repeats 3 Proteins 0.000 description 1
- 101001034844 Homo sapiens Interferon-induced transmembrane protein 1 Proteins 0.000 description 1
- 101001043809 Homo sapiens Interleukin-7 receptor subunit alpha Proteins 0.000 description 1
- 101001046633 Homo sapiens Junctional adhesion molecule A Proteins 0.000 description 1
- 101100086477 Homo sapiens KRAS gene Proteins 0.000 description 1
- 101000998020 Homo sapiens Keratin, type I cytoskeletal 18 Proteins 0.000 description 1
- 101000975496 Homo sapiens Keratin, type II cytoskeletal 8 Proteins 0.000 description 1
- 101000945333 Homo sapiens Killer cell immunoglobulin-like receptor 2DL3 Proteins 0.000 description 1
- 101001137642 Homo sapiens Kinase suppressor of Ras 1 Proteins 0.000 description 1
- 101001091610 Homo sapiens Krev interaction trapped protein 1 Proteins 0.000 description 1
- 101001139134 Homo sapiens Krueppel-like factor 4 Proteins 0.000 description 1
- 101001004946 Homo sapiens Lactoylglutathione lyase Proteins 0.000 description 1
- 101001005166 Homo sapiens Lens fiber membrane intrinsic protein Proteins 0.000 description 1
- 101001003687 Homo sapiens Lipoma-preferred partner Proteins 0.000 description 1
- 101001051093 Homo sapiens Low-density lipoprotein receptor Proteins 0.000 description 1
- 101001039199 Homo sapiens Low-density lipoprotein receptor-related protein 6 Proteins 0.000 description 1
- 101000972291 Homo sapiens Lymphoid enhancer-binding factor 1 Proteins 0.000 description 1
- 101001018100 Homo sapiens Lysozyme C Proteins 0.000 description 1
- 101000634835 Homo sapiens M1-specific T cell receptor alpha chain Proteins 0.000 description 1
- 101000573901 Homo sapiens Major prion protein Proteins 0.000 description 1
- 101001008874 Homo sapiens Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- 101001011906 Homo sapiens Matrix metalloproteinase-14 Proteins 0.000 description 1
- 101000614988 Homo sapiens Mediator of RNA polymerase II transcription subunit 12 Proteins 0.000 description 1
- 101000588130 Homo sapiens Microsomal triglyceride transfer protein large subunit Proteins 0.000 description 1
- 101000891579 Homo sapiens Microtubule-associated protein tau Proteins 0.000 description 1
- 101000615261 Homo sapiens Multiple coagulation factor deficiency protein 2 Proteins 0.000 description 1
- 101000958866 Homo sapiens Myogenic factor 6 Proteins 0.000 description 1
- 101001128138 Homo sapiens NACHT, LRR and PYD domains-containing protein 2 Proteins 0.000 description 1
- 101001111187 Homo sapiens NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial Proteins 0.000 description 1
- 101000603172 Homo sapiens Neuroligin-3 Proteins 0.000 description 1
- 101000577540 Homo sapiens Neuropilin-1 Proteins 0.000 description 1
- 101000981336 Homo sapiens Nibrin Proteins 0.000 description 1
- 101000998855 Homo sapiens Nicotinamide phosphoribosyltransferase Proteins 0.000 description 1
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 1
- 101000598160 Homo sapiens Nuclear mitotic apparatus protein 1 Proteins 0.000 description 1
- 101000974015 Homo sapiens Nucleosome assembly protein 1-like 1 Proteins 0.000 description 1
- 101000613806 Homo sapiens Osteopetrosis-associated transmembrane protein 1 Proteins 0.000 description 1
- 101000614405 Homo sapiens P2X purinoceptor 1 Proteins 0.000 description 1
- 101001098175 Homo sapiens P2X purinoceptor 7 Proteins 0.000 description 1
- 101000601647 Homo sapiens Paired box protein Pax-6 Proteins 0.000 description 1
- 101000611202 Homo sapiens Peptidyl-prolyl cis-trans isomerase B Proteins 0.000 description 1
- 101000987578 Homo sapiens Peripherin Proteins 0.000 description 1
- 101000619805 Homo sapiens Peroxiredoxin-5, mitochondrial Proteins 0.000 description 1
- 101000619708 Homo sapiens Peroxiredoxin-6 Proteins 0.000 description 1
- 101000733743 Homo sapiens Phorbol-12-myristate-13-acetate-induced protein 1 Proteins 0.000 description 1
- 101000730665 Homo sapiens Phospholipase D1 Proteins 0.000 description 1
- 101000595674 Homo sapiens Pituitary homeobox 3 Proteins 0.000 description 1
- 101001074444 Homo sapiens Polycystin-1 Proteins 0.000 description 1
- 101000610107 Homo sapiens Pre-B-cell leukemia transcription factor 1 Proteins 0.000 description 1
- 101000808592 Homo sapiens Probable ubiquitin carboxyl-terminal hydrolase FAF-X Proteins 0.000 description 1
- 101001056707 Homo sapiens Proepiregulin Proteins 0.000 description 1
- 101000892338 Homo sapiens Protein AF1q Proteins 0.000 description 1
- 101001123963 Homo sapiens Protein O-mannosyl-transferase 1 Proteins 0.000 description 1
- 101000780643 Homo sapiens Protein argonaute-2 Proteins 0.000 description 1
- 101000928791 Homo sapiens Protein diaphanous homolog 1 Proteins 0.000 description 1
- 101000863978 Homo sapiens Protein downstream neighbor of Son Proteins 0.000 description 1
- 101000994437 Homo sapiens Protein jagged-1 Proteins 0.000 description 1
- 101000644045 Homo sapiens Protein unc-13 homolog D Proteins 0.000 description 1
- 101001086862 Homo sapiens Pulmonary surfactant-associated protein B Proteins 0.000 description 1
- 101000687448 Homo sapiens REST corepressor 1 Proteins 0.000 description 1
- 101000665452 Homo sapiens RNA binding protein fox-1 homolog 2 Proteins 0.000 description 1
- 101000641879 Homo sapiens Ras/Rap GTPase-activating protein SynGAP Proteins 0.000 description 1
- 101001075466 Homo sapiens Regulatory factor X-associated protein Proteins 0.000 description 1
- 101000742938 Homo sapiens Retinol dehydrogenase 12 Proteins 0.000 description 1
- 101000846336 Homo sapiens Ribitol-5-phosphate transferase FKTN Proteins 0.000 description 1
- 101000650588 Homo sapiens Roundabout homolog 3 Proteins 0.000 description 1
- 101100421141 Homo sapiens SELENON gene Proteins 0.000 description 1
- 101000864786 Homo sapiens Secreted frizzled-related protein 2 Proteins 0.000 description 1
- 101000873658 Homo sapiens Secretogranin-3 Proteins 0.000 description 1
- 101000867413 Homo sapiens Segment polarity protein dishevelled homolog DVL-1 Proteins 0.000 description 1
- 101000867469 Homo sapiens Segment polarity protein dishevelled homolog DVL-3 Proteins 0.000 description 1
- 101000644537 Homo sapiens Sequestosome-1 Proteins 0.000 description 1
- 101001026882 Homo sapiens Serine/threonine-protein kinase D2 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000755690 Homo sapiens Single-stranded DNA cytosine deaminase Proteins 0.000 description 1
- 101000881247 Homo sapiens Spectrin beta chain, erythrocytic Proteins 0.000 description 1
- 101000652369 Homo sapiens Spermatogenesis-associated protein 7 Proteins 0.000 description 1
- 101000829367 Homo sapiens Src substrate cortactin Proteins 0.000 description 1
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 description 1
- 101000617808 Homo sapiens Synphilin-1 Proteins 0.000 description 1
- 101000634836 Homo sapiens T cell receptor alpha chain MC.7.G5 Proteins 0.000 description 1
- 101000891113 Homo sapiens T-cell acute lymphocytic leukemia protein 1 Proteins 0.000 description 1
- 101000625330 Homo sapiens T-cell acute lymphocytic leukemia protein 2 Proteins 0.000 description 1
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 1
- 101000738413 Homo sapiens T-cell surface glycoprotein CD3 gamma chain Proteins 0.000 description 1
- 101100368708 Homo sapiens TACSTD2 gene Proteins 0.000 description 1
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 1
- 101000596277 Homo sapiens TSC22 domain family protein 3 Proteins 0.000 description 1
- 101000649068 Homo sapiens Tapasin Proteins 0.000 description 1
- 101000658622 Homo sapiens Testis-specific Y-encoded-like protein 2 Proteins 0.000 description 1
- 101000802084 Homo sapiens Thiosulfate sulfurtransferase Proteins 0.000 description 1
- 101000659879 Homo sapiens Thrombospondin-1 Proteins 0.000 description 1
- 101000715050 Homo sapiens Thromboxane A2 receptor Proteins 0.000 description 1
- 101000596771 Homo sapiens Transcription factor 7-like 2 Proteins 0.000 description 1
- 101000895882 Homo sapiens Transcription factor E2F4 Proteins 0.000 description 1
- 101000843556 Homo sapiens Transcription factor HES-1 Proteins 0.000 description 1
- 101000687905 Homo sapiens Transcription factor SOX-2 Proteins 0.000 description 1
- 101000642517 Homo sapiens Transcription factor SOX-6 Proteins 0.000 description 1
- 101000711846 Homo sapiens Transcription factor SOX-9 Proteins 0.000 description 1
- 101000894871 Homo sapiens Transcription regulator protein BACH1 Proteins 0.000 description 1
- 101001131930 Homo sapiens Transcriptional activator protein Pur-beta Proteins 0.000 description 1
- 101001057686 Homo sapiens Translation initiation factor eIF-2B subunit alpha Proteins 0.000 description 1
- 101001057681 Homo sapiens Translation initiation factor eIF-2B subunit beta Proteins 0.000 description 1
- 101000925982 Homo sapiens Translation initiation factor eIF-2B subunit delta Proteins 0.000 description 1
- 101000925985 Homo sapiens Translation initiation factor eIF-2B subunit epsilon Proteins 0.000 description 1
- 101001049688 Homo sapiens Translation initiation factor eIF-2B subunit gamma Proteins 0.000 description 1
- 101000631620 Homo sapiens Translocation protein SEC63 homolog Proteins 0.000 description 1
- 101000795167 Homo sapiens Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 1
- 101000611185 Homo sapiens Tumor necrosis factor receptor superfamily member 5 Proteins 0.000 description 1
- 101000836174 Homo sapiens Tumor protein p53-inducible nuclear protein 1 Proteins 0.000 description 1
- 101000613251 Homo sapiens Tumor susceptibility gene 101 protein Proteins 0.000 description 1
- 101000823271 Homo sapiens Tyrosine-protein kinase ABL2 Proteins 0.000 description 1
- 101001087422 Homo sapiens Tyrosine-protein phosphatase non-receptor type 13 Proteins 0.000 description 1
- 101000607909 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 1 Proteins 0.000 description 1
- 101000809243 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 10 Proteins 0.000 description 1
- 101000807524 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 22 Proteins 0.000 description 1
- 101000748141 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 32 Proteins 0.000 description 1
- 101000749634 Homo sapiens Uromodulin Proteins 0.000 description 1
- 101001061851 Homo sapiens V(D)J recombination-activating protein 2 Proteins 0.000 description 1
- 101000666295 Homo sapiens X-box-binding protein 1 Proteins 0.000 description 1
- 101001104102 Homo sapiens X-linked retinitis pigmentosa GTPase regulator Proteins 0.000 description 1
- 101100377226 Homo sapiens ZBTB16 gene Proteins 0.000 description 1
- 101000964425 Homo sapiens Zinc finger and BTB domain-containing protein 16 Proteins 0.000 description 1
- 101000633054 Homo sapiens Zinc finger protein SNAI2 Proteins 0.000 description 1
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
- 101001129796 Homo sapiens p53-induced death domain-containing protein 1 Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 102000016252 Huntingtin Human genes 0.000 description 1
- 108050004784 Huntingtin Proteins 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 208000013038 Hypocalcemia Diseases 0.000 description 1
- 206010050977 Hypocalciuria Diseases 0.000 description 1
- 206010021027 Hypomagnesaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 1
- 102000038455 IGF Type 1 Receptor Human genes 0.000 description 1
- 108010031792 IGF Type 2 Receptor Proteins 0.000 description 1
- 102000038460 IGF Type 2 Receptor Human genes 0.000 description 1
- 101150088952 IGF1 gene Proteins 0.000 description 1
- 101150016712 IKZF1 gene Proteins 0.000 description 1
- 201000003398 IMAGe syndrome Diseases 0.000 description 1
- 108010073816 IgE Receptors Proteins 0.000 description 1
- 102000009438 IgE Receptors Human genes 0.000 description 1
- 101150002416 Igf2 gene Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108050000123 Inactive phospholipase C-like protein 1 Proteins 0.000 description 1
- 101710128560 Initiator protein NS1 Proteins 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102100022710 Insulin-like growth factor-binding protein 2 Human genes 0.000 description 1
- 102100029228 Insulin-like growth factor-binding protein 7 Human genes 0.000 description 1
- 102100036981 Interferon regulatory factor 1 Human genes 0.000 description 1
- 102100029843 Interferon regulatory factor 3 Human genes 0.000 description 1
- 102100027302 Interferon-induced protein with tetratricopeptide repeats 3 Human genes 0.000 description 1
- 102100040021 Interferon-induced transmembrane protein 1 Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102100039068 Interleukin-10 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102100021593 Interleukin-7 receptor subunit alpha Human genes 0.000 description 1
- 208000034613 Isolated polycystic liver disease Diseases 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 108091082332 JAK family Proteins 0.000 description 1
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 102000019145 JUN kinase activity proteins Human genes 0.000 description 1
- 102100022304 Junctional adhesion molecule A Human genes 0.000 description 1
- 208000002838 Juvenile Xanthogranuloma Diseases 0.000 description 1
- 108700042464 KRIT1 Proteins 0.000 description 1
- 101150090242 KRIT1 gene Proteins 0.000 description 1
- 208000010299 Kasabach-Merritt syndrome Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 102100033421 Keratin, type I cytoskeletal 18 Human genes 0.000 description 1
- 102100023972 Keratin, type II cytoskeletal 8 Human genes 0.000 description 1
- 102100033634 Killer cell immunoglobulin-like receptor 2DL3 Human genes 0.000 description 1
- 102100021001 Kinase suppressor of Ras 1 Human genes 0.000 description 1
- 206010062061 Knee deformity Diseases 0.000 description 1
- 208000001182 Kniest dysplasia Diseases 0.000 description 1
- 201000003395 Koolen de Vries syndrome Diseases 0.000 description 1
- 101150105104 Kras gene Proteins 0.000 description 1
- 102100020677 Krueppel-like factor 4 Human genes 0.000 description 1
- 108010064700 L-arabinitol 4-dehydrogenase Proteins 0.000 description 1
- 102100026004 Lactoylglutathione lyase Human genes 0.000 description 1
- 201000002503 Leber congenital amaurosis 1 Diseases 0.000 description 1
- 208000005906 Leber congenital amaurosis 3 Diseases 0.000 description 1
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 description 1
- 101710115990 Lens fiber membrane intrinsic protein Proteins 0.000 description 1
- 102100026358 Lipoma-preferred partner Human genes 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- 102100040704 Low-density lipoprotein receptor-related protein 6 Human genes 0.000 description 1
- 101000964266 Loxosceles laeta Dermonecrotic toxin Proteins 0.000 description 1
- 206010025219 Lymphangioma Diseases 0.000 description 1
- 102100022699 Lymphoid enhancer-binding factor 1 Human genes 0.000 description 1
- 102100033448 Lysosomal alpha-glucosidase Human genes 0.000 description 1
- 208000033868 Lysosomal disease Diseases 0.000 description 1
- 108010009491 Lysosomal-Associated Membrane Protein 2 Proteins 0.000 description 1
- 102100038225 Lysosome-associated membrane glycoprotein 2 Human genes 0.000 description 1
- 102100033468 Lysozyme C Human genes 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 201000002961 MASA syndrome Diseases 0.000 description 1
- 208000024889 MECP2 duplication syndrome Diseases 0.000 description 1
- 108700012912 MYCN Proteins 0.000 description 1
- 101150022024 MYCN gene Proteins 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 208000035719 Maculopathy Diseases 0.000 description 1
- 208000035268 Mast Cell Activation disease Diseases 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 1
- 102100021070 Mediator of RNA polymerase II transcription subunit 12 Human genes 0.000 description 1
- 108700020845 Medullary Cystic Kidney Disease 2 Proteins 0.000 description 1
- 108010023338 Member 3 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 206010027423 Metabolic alkalosis Diseases 0.000 description 1
- 101000859568 Methanobrevibacter smithii (strain ATCC 35061 / DSM 861 / OCM 144 / PS) Carbamoyl-phosphate synthase Proteins 0.000 description 1
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 description 1
- 108010047660 Mitochondrial intermediate peptidase Proteins 0.000 description 1
- HDAJUGGARUFROU-JSUDGWJLSA-L MoO2-molybdopterin cofactor Chemical compound O([C@H]1NC=2N=C(NC(=O)C=2N[C@H]11)N)[C@H](COP(O)(O)=O)C2=C1S[Mo](=O)(=O)S2 HDAJUGGARUFROU-JSUDGWJLSA-L 0.000 description 1
- 102100030610 Mothers against decapentaplegic homolog 5 Human genes 0.000 description 1
- 101710143113 Mothers against decapentaplegic homolog 5 Proteins 0.000 description 1
- 208000008770 Multiple Hamartoma Syndrome Diseases 0.000 description 1
- 102100021387 Multiple coagulation factor deficiency protein 2 Human genes 0.000 description 1
- 101000920670 Mus musculus Erythropoietin Proteins 0.000 description 1
- 101000834850 Mus musculus KICSTOR complex protein SZT2 Proteins 0.000 description 1
- 101100127196 Mus musculus Kera gene Proteins 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 102100038379 Myogenic factor 6 Human genes 0.000 description 1
- VQAYFKKCNSOZKM-IOSLPCCCSA-N N(6)-methyladenosine Chemical class C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VQAYFKKCNSOZKM-IOSLPCCCSA-N 0.000 description 1
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 102100030124 N-myc proto-oncogene protein Human genes 0.000 description 1
- 102100031455 NAD-dependent protein deacetylase sirtuin-1 Human genes 0.000 description 1
- 102100023964 NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial Human genes 0.000 description 1
- 102000004019 NADPH Oxidase 1 Human genes 0.000 description 1
- 108090000424 NADPH Oxidase 1 Proteins 0.000 description 1
- 108010082739 NADPH Oxidase 2 Proteins 0.000 description 1
- GLNMNDFTODWBJZ-UHFFFAOYSA-N NC(=N)NCC(O)=O.NC(=N)NCC(O)=O Chemical compound NC(=N)NCC(O)=O.NC(=N)NCC(O)=O GLNMNDFTODWBJZ-UHFFFAOYSA-N 0.000 description 1
- 102000005591 NIMA-Interacting Peptidylprolyl Isomerase Human genes 0.000 description 1
- 108010059419 NIMA-Interacting Peptidylprolyl Isomerase Proteins 0.000 description 1
- 102100021867 Natural resistance-associated macrophage protein 2 Human genes 0.000 description 1
- 206010028933 Neonatal diabetes mellitus Diseases 0.000 description 1
- 208000031790 Neonatal hemochromatosis Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 102400000058 Neuregulin-1 Human genes 0.000 description 1
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 1
- 208000007382 Neurofibromatosis-Noonan syndrome Diseases 0.000 description 1
- 102100038940 Neuroligin-3 Human genes 0.000 description 1
- 108090000772 Neuropilin-1 Proteins 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 102100024403 Nibrin Human genes 0.000 description 1
- 102100033223 Nicotinamide phosphoribosyltransferase Human genes 0.000 description 1
- 101710144127 Non-structural protein 1 Proteins 0.000 description 1
- 102100036961 Nuclear mitotic apparatus protein 1 Human genes 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 208000005225 Opsoclonus-Myoclonus Syndrome Diseases 0.000 description 1
- 102100028200 Ornithine transcarbamylase, mitochondrial Human genes 0.000 description 1
- 206010031240 Osteodystrophy Diseases 0.000 description 1
- 102100040559 Osteopetrosis-associated transmembrane protein 1 Human genes 0.000 description 1
- 102100040557 Osteopontin Human genes 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 101710189973 P2X purinoceptor 1 Proteins 0.000 description 1
- 101710189965 P2X purinoceptor 7 Proteins 0.000 description 1
- 108010032788 PAX6 Transcription Factor Proteins 0.000 description 1
- 101150102323 PDYN gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 101150014691 PPARA gene Proteins 0.000 description 1
- 101150010978 PRKCE gene Proteins 0.000 description 1
- 102100036893 Parathyroid hormone Human genes 0.000 description 1
- 102000008880 Peptidase C12, ubiquitin carboxyl-terminal hydrolases Human genes 0.000 description 1
- 108010055817 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Proteins 0.000 description 1
- 102000000447 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- 102100040283 Peptidyl-prolyl cis-trans isomerase B Human genes 0.000 description 1
- 102100022078 Peroxiredoxin-5, mitochondrial Human genes 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- 108010069013 Phenylalanine Hydroxylase Proteins 0.000 description 1
- 102100038223 Phenylalanine-4-hydroxylase Human genes 0.000 description 1
- 102100033716 Phorbol-12-myristate-13-acetate-induced protein 1 Human genes 0.000 description 1
- 108010064209 Phosphoribosylglycinamide formyltransferase Proteins 0.000 description 1
- 101100352419 Pithecopus hypochondrialis psn1 gene Proteins 0.000 description 1
- 102100036088 Pituitary homeobox 3 Human genes 0.000 description 1
- 108090000113 Plasma Kallikrein Proteins 0.000 description 1
- 102000010752 Plasminogen Inactivators Human genes 0.000 description 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 108700026628 Plasmodium falciparum SEA-1 Proteins 0.000 description 1
- 108010054050 Plectin Proteins 0.000 description 1
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 1
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 1
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 1
- 102100040171 Pre-B-cell leukemia transcription factor 1 Human genes 0.000 description 1
- 108700018490 Prekallikrein Deficiency Proteins 0.000 description 1
- 206010063493 Premature ageing Diseases 0.000 description 1
- 208000032038 Premature aging Diseases 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 102100038603 Probable ubiquitin carboxyl-terminal hydrolase FAF-X Human genes 0.000 description 1
- 102100025498 Proepiregulin Human genes 0.000 description 1
- 108700003766 Promyelocytic Leukemia Zinc Finger Proteins 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical group CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 102100040665 Protein AF1q Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102100028120 Protein O-mannosyl-transferase 1 Human genes 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 108010066124 Protein S Proteins 0.000 description 1
- 102100036467 Protein delta homolog 1 Human genes 0.000 description 1
- 102100036490 Protein diaphanous homolog 1 Human genes 0.000 description 1
- 102100032702 Protein jagged-1 Human genes 0.000 description 1
- 102100023068 Protein kinase C-binding protein NELL1 Human genes 0.000 description 1
- 102100020988 Protein unc-13 homolog D Human genes 0.000 description 1
- 208000033876 Proximal Xq28 duplication syndrome Diseases 0.000 description 1
- 208000032225 Proximal spinal muscular atrophy type 1 Diseases 0.000 description 1
- 208000033522 Proximal spinal muscular atrophy type 2 Diseases 0.000 description 1
- 208000033526 Proximal spinal muscular atrophy type 3 Diseases 0.000 description 1
- 208000033550 Proximal spinal muscular atrophy type 4 Diseases 0.000 description 1
- 229930185560 Pseudouridine Natural products 0.000 description 1
- 102100032617 Pulmonary surfactant-associated protein B Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 102000013009 Pyruvate Kinase Human genes 0.000 description 1
- 108020005115 Pyruvate Kinase Proteins 0.000 description 1
- 102100034909 Pyruvate kinase PKLR Human genes 0.000 description 1
- 101710111658 Pyruvate kinase PKLR Proteins 0.000 description 1
- 102000001195 RAD51 Human genes 0.000 description 1
- 102000001183 RAG-1 Human genes 0.000 description 1
- 108060006897 RAG1 Proteins 0.000 description 1
- 102100024864 REST corepressor 1 Human genes 0.000 description 1
- 102100038187 RNA binding protein fox-1 homolog 2 Human genes 0.000 description 1
- 108010068097 Rad51 Recombinase Proteins 0.000 description 1
- 208000033866 Rare inborn errors of metabolism Diseases 0.000 description 1
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 1
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 1
- 102100039100 Ras-related protein Rab-5A Human genes 0.000 description 1
- 102100033428 Ras/Rap GTPase-activating protein SynGAP Human genes 0.000 description 1
- 101100148573 Rattus norvegicus S1pr5 gene Proteins 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 102100020981 Regulator of G-protein signaling 16 Human genes 0.000 description 1
- 101710148341 Regulator of G-protein signaling 16 Proteins 0.000 description 1
- 102100021043 Regulatory factor X-associated protein Human genes 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108010002342 Retinoblastoma-Like Protein p107 Proteins 0.000 description 1
- 102000000582 Retinoblastoma-Like Protein p107 Human genes 0.000 description 1
- 108010003494 Retinoblastoma-Like Protein p130 Proteins 0.000 description 1
- 102000004642 Retinoblastoma-Like Protein p130 Human genes 0.000 description 1
- 102100038054 Retinol dehydrogenase 12 Human genes 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- 102100039643 Rho-related GTP-binding protein Rho6 Human genes 0.000 description 1
- 101710199571 Rho-related GTP-binding protein Rho6 Proteins 0.000 description 1
- 102100039640 Rho-related GTP-binding protein RhoE Human genes 0.000 description 1
- 108050007494 Rho-related GTP-binding protein RhoE Proteins 0.000 description 1
- 102100031754 Ribitol-5-phosphate transferase FKTN Human genes 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 208000032822 Ring chromosome 11 syndrome Diseases 0.000 description 1
- MBZJHWDGHMQCDF-FDDDBJFASA-N SCCC=1C(NC(N([C@H]2[C@H](O)[C@H](O)[C@@H](CO)O2)C1)=O)=O Chemical compound SCCC=1C(NC(N([C@H]2[C@H](O)[C@H](O)[C@@H](CO)O2)C1)=O)=O MBZJHWDGHMQCDF-FDDDBJFASA-N 0.000 description 1
- 101150019520 SGCA gene Proteins 0.000 description 1
- 108091006618 SLC11A2 Proteins 0.000 description 1
- 108091006647 SLC9A1 Proteins 0.000 description 1
- 108060009345 SORL1 Proteins 0.000 description 1
- 101000825534 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 40S ribosomal protein S2 Proteins 0.000 description 1
- 101100294206 Schizosaccharomyces pombe (strain 972 / ATCC 24843) fta4 gene Proteins 0.000 description 1
- 201000010848 Schnitzler Syndrome Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 102100030054 Secreted frizzled-related protein 2 Human genes 0.000 description 1
- 102100032758 Segment polarity protein dishevelled homolog DVL-1 Human genes 0.000 description 1
- 102100032754 Segment polarity protein dishevelled homolog DVL-3 Human genes 0.000 description 1
- 241000252141 Semionotiformes Species 0.000 description 1
- 102100020814 Sequestosome-1 Human genes 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 108010041191 Sirtuin 1 Proteins 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 101150028423 Slc6a4 gene Proteins 0.000 description 1
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 description 1
- 101710142969 Somatoliberin Proteins 0.000 description 1
- 102100025639 Sortilin-related receptor Human genes 0.000 description 1
- 102100037613 Spectrin beta chain, erythrocytic Human genes 0.000 description 1
- 102100030257 Spermatogenesis-associated protein 7 Human genes 0.000 description 1
- 206010041509 Spherocytic anaemia Diseases 0.000 description 1
- 108010061312 Sphingomyelin Phosphodiesterase Proteins 0.000 description 1
- 101710168942 Sphingosine-1-phosphate phosphatase 1 Proteins 0.000 description 1
- 208000033145 Spinal muscular atrophy with respiratory distress type 1 Diseases 0.000 description 1
- 102100023719 Src substrate cortactin Human genes 0.000 description 1
- 108010087999 Steryl-Sulfatase Proteins 0.000 description 1
- 102100038021 Steryl-sulfatase Human genes 0.000 description 1
- 102100032723 Structural maintenance of chromosomes protein 3 Human genes 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 102100035721 Syndecan-1 Human genes 0.000 description 1
- 102100021997 Synphilin-1 Human genes 0.000 description 1
- 208000018359 Systemic autoimmune disease Diseases 0.000 description 1
- 102100029452 T cell receptor alpha chain constant Human genes 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 102100025039 T-cell acute lymphocytic leukemia protein 2 Human genes 0.000 description 1
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 1
- 102100037911 T-cell surface glycoprotein CD3 gamma chain Human genes 0.000 description 1
- 108700012457 TACSTD2 Proteins 0.000 description 1
- 101150080074 TP53 gene Proteins 0.000 description 1
- 102100035260 TSC22 domain family protein 3 Human genes 0.000 description 1
- 101800000849 Tachykinin-associated peptide 2 Proteins 0.000 description 1
- 101150117918 Tacstd2 gene Proteins 0.000 description 1
- 102100034917 Testis-specific Y-encoded-like protein 2 Human genes 0.000 description 1
- 206010069116 Tetrahydrobiopterin deficiency Diseases 0.000 description 1
- 102100036034 Thrombospondin-1 Human genes 0.000 description 1
- 102100036704 Thromboxane A2 receptor Human genes 0.000 description 1
- 208000026062 Tissue disease Diseases 0.000 description 1
- 241000723792 Tobacco etch virus Species 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 108010057666 Transcription Factor CHOP Proteins 0.000 description 1
- 102100035101 Transcription factor 7-like 2 Human genes 0.000 description 1
- 102100024024 Transcription factor E2F2 Human genes 0.000 description 1
- 102100021783 Transcription factor E2F4 Human genes 0.000 description 1
- 102100030798 Transcription factor HES-1 Human genes 0.000 description 1
- 102100024270 Transcription factor SOX-2 Human genes 0.000 description 1
- 102100036694 Transcription factor SOX-6 Human genes 0.000 description 1
- 102100034204 Transcription factor SOX-9 Human genes 0.000 description 1
- 102100034549 Transcriptional activator protein Pur-beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 102100027065 Translation initiation factor eIF-2B subunit beta Human genes 0.000 description 1
- 102100034266 Translation initiation factor eIF-2B subunit delta Human genes 0.000 description 1
- 102100034267 Translation initiation factor eIF-2B subunit epsilon Human genes 0.000 description 1
- 102100023225 Translation initiation factor eIF-2B subunit gamma Human genes 0.000 description 1
- 102100029006 Translocation protein SEC63 homolog Human genes 0.000 description 1
- 108010047933 Tumor Necrosis Factor alpha-Induced Protein 3 Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 102100024596 Tumor necrosis factor alpha-induced protein 3 Human genes 0.000 description 1
- 102100029675 Tumor necrosis factor receptor superfamily member 13B Human genes 0.000 description 1
- 102100027224 Tumor protein p53-inducible nuclear protein 1 Human genes 0.000 description 1
- 102100040879 Tumor susceptibility gene 101 protein Human genes 0.000 description 1
- 208000006391 Type 1 Hyper-IgM Immunodeficiency Syndrome Diseases 0.000 description 1
- 102100022651 Tyrosine-protein kinase ABL2 Human genes 0.000 description 1
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 1
- 102100033014 Tyrosine-protein phosphatase non-receptor type 13 Human genes 0.000 description 1
- 101150044377 UBA1 gene Proteins 0.000 description 1
- 101150035006 UBA3 gene Proteins 0.000 description 1
- 208000033130 UMOD-related autosomal dominant tubulointerstitial kidney disease Diseases 0.000 description 1
- 101150020913 USP7 gene Proteins 0.000 description 1
- 102100039865 Ubiquitin carboxyl-terminal hydrolase 1 Human genes 0.000 description 1
- 102100038426 Ubiquitin carboxyl-terminal hydrolase 10 Human genes 0.000 description 1
- 102100037184 Ubiquitin carboxyl-terminal hydrolase 22 Human genes 0.000 description 1
- 102100021013 Ubiquitin carboxyl-terminal hydrolase 7 Human genes 0.000 description 1
- 108700011958 Ubiquitin-Specific Peptidase 7 Proteins 0.000 description 1
- 229940126752 Ubiquitin-specific protease 7 inhibitor Drugs 0.000 description 1
- 101000868086 Unknown prokaryotic organism Cysteine/Cysteine sulfinic acid decarboxylase Proteins 0.000 description 1
- 101710160987 Uracil-DNA glycosylase Proteins 0.000 description 1
- 108700043443 Urocanase deficiency Proteins 0.000 description 1
- 102100040613 Uromodulin Human genes 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 102100029591 V(D)J recombination-activating protein 2 Human genes 0.000 description 1
- 208000009443 Vascular Malformations Diseases 0.000 description 1
- 206010047050 Vascular anomaly Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 102100028885 Vitamin K-dependent protein S Human genes 0.000 description 1
- 101710088929 Voltage-dependent L-type calcium channel subunit alpha-1S Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027276 Von Willebrand disease Diseases 0.000 description 1
- 101150112441 Vsx1 gene Proteins 0.000 description 1
- 208000026481 Werdnig-Hoffmann disease Diseases 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- 108050003627 Wnt Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 102100038151 X-box-binding protein 1 Human genes 0.000 description 1
- 201000006035 X-linked dominant hypophosphatemic rickets Diseases 0.000 description 1
- 201000001696 X-linked hyper IgM syndrome Diseases 0.000 description 1
- 208000031878 X-linked hypophosphatemia Diseases 0.000 description 1
- 208000001001 X-linked ichthyosis Diseases 0.000 description 1
- 241000269370 Xenopus <genus> Species 0.000 description 1
- 101100445056 Xenopus laevis elavl1-a gene Proteins 0.000 description 1
- 101100445057 Xenopus laevis elavl1-b gene Proteins 0.000 description 1
- 102100029570 Zinc finger protein SNAI2 Human genes 0.000 description 1
- FHHZHGZBHYYWTG-INFSMZHSSA-N [(2r,3s,4r,5r)-5-(2-amino-7-methyl-6-oxo-3h-purin-9-ium-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl [[[(2r,3s,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] phosphate Chemical compound N1C(N)=NC(=O)C2=C1[N+]([C@H]1[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=C(C(N=C(N)N4)=O)N=C3)O)O1)O)=CN2C FHHZHGZBHYYWTG-INFSMZHSSA-N 0.000 description 1
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 201000006960 adult spinal muscular atrophy Diseases 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 1
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 208000028435 angiomyxoma Diseases 0.000 description 1
- 210000000040 apocrine gland Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 108010018755 aquaporin 0 Proteins 0.000 description 1
- 210000000617 arm Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000008045 autosomal dominant osteopetrosis 2 Diseases 0.000 description 1
- 208000021033 autosomal dominant polycystic liver disease Diseases 0.000 description 1
- 201000001038 autosomal recessive chronic granulomatous disease cytochrome b-positive type II Diseases 0.000 description 1
- 201000000527 autosomal recessive distal spinal muscular atrophy 1 Diseases 0.000 description 1
- 201000003291 autosomal recessive osteopetrosis 1 Diseases 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 108010032967 beta-Arrestin 2 Proteins 0.000 description 1
- WGDUUQDYDIIBKT-UHFFFAOYSA-N beta-Pseudouridine Natural products OC1OC(CN2C=CC(=O)NC2=O)C(O)C1O WGDUUQDYDIIBKT-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007698 birth defect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 230000011496 cAMP-mediated signaling Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000028956 calcium-mediated signaling Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 201000009847 cataract 14 multiple types Diseases 0.000 description 1
- 201000009853 cataract 16 multiple types Diseases 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 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
- 108010030886 coactivator-associated arginine methyltransferase 1 Proteins 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 201000003056 complement component 2 deficiency Diseases 0.000 description 1
- 201000006754 cone-rod dystrophy Diseases 0.000 description 1
- 201000000464 cone-rod dystrophy 2 Diseases 0.000 description 1
- 201000000440 cone-rod dystrophy 6 Diseases 0.000 description 1
- 201000000398 cone-rod dystrophy 9 Diseases 0.000 description 1
- 108700017143 congenital Anti-plasmin deficiency Proteins 0.000 description 1
- 201000007182 congenital afibrinogenemia Diseases 0.000 description 1
- 208000006111 contracture Diseases 0.000 description 1
- 201000003046 cornea plana Diseases 0.000 description 1
- 206010011005 corneal dystrophy Diseases 0.000 description 1
- 201000004046 cortisone reductase deficiency 1 Diseases 0.000 description 1
- 201000004051 cystathioninuria Diseases 0.000 description 1
- 108091000099 cysteine desulfurase Proteins 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 201000011290 dilated cardiomyopathy 1G Diseases 0.000 description 1
- 108010083141 dipeptidyl carboxypeptidase Proteins 0.000 description 1
- 208000021347 distal spinal muscular atrophy 1 Diseases 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 208000027110 duplication/inversion 15q11 Diseases 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 208000008570 facioscapulohumeral muscular dystrophy Diseases 0.000 description 1
- 229940012413 factor vii Drugs 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 201000007249 familial juvenile hyperuricemic nephropathy Diseases 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 208000030941 fetal growth restriction Diseases 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 208000008605 glucosephosphate dehydrogenase deficiency Diseases 0.000 description 1
- 201000003702 glycerol kinase deficiency Diseases 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 208000007345 glycogen storage disease Diseases 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940094892 gonadotropins Drugs 0.000 description 1
- 101150002245 grin2a gene Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000009459 hedgehog signaling Effects 0.000 description 1
- 101150055960 hemB gene Proteins 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000014752 hemophagocytic syndrome Diseases 0.000 description 1
- 208000009429 hemophilia B Diseases 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 208000009601 hereditary spherocytosis Diseases 0.000 description 1
- 208000002557 hidradenitis Diseases 0.000 description 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000026095 hyper-IgM syndrome type 1 Diseases 0.000 description 1
- 208000018949 hyper-IgM syndrome type 2 Diseases 0.000 description 1
- 208000025762 hyper-IgM syndrome type 4 Diseases 0.000 description 1
- 201000005991 hyperphosphatemia Diseases 0.000 description 1
- 230000000705 hypocalcaemia Effects 0.000 description 1
- 230000000396 hypokalemic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008102 immune modulation Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 201000001373 immunodeficiency with hyper-IgM type 2 Diseases 0.000 description 1
- 201000001399 immunodeficiency with hyper-IgM type 4 Diseases 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000016245 inborn errors of metabolism Diseases 0.000 description 1
- 208000026203 inborn glycerol kinase deficiency Diseases 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229960003786 inosine Drugs 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
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 201000006913 intermediate spinal muscular atrophy Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940029329 intrinsic factor Drugs 0.000 description 1
- 208000013049 isolated hemihyperplasia Diseases 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 208000028507 juvenile open angle glaucoma Diseases 0.000 description 1
- 201000004815 juvenile spinal muscular atrophy Diseases 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000020796 long term synaptic depression Effects 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 108700021021 mRNA Vaccine Proteins 0.000 description 1
- 229940126582 mRNA vaccine Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 201000010828 metaphyseal dysplasia Diseases 0.000 description 1
- 208000005135 methemoglobinemia Diseases 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 108010046778 molybdenum cofactor Proteins 0.000 description 1
- 208000001488 molybdenum cofactor deficiency Diseases 0.000 description 1
- 201000002273 mucopolysaccharidosis II Diseases 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 201000006946 muscular dystrophy-dystroglycanopathy type B6 Diseases 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000001123 neurodevelopmental effect Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 108010064131 neuronal Cdk5 activator (p25-p35) Proteins 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000005064 nitric oxide mediated signal transduction Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 208000002865 osteopetrosis Diseases 0.000 description 1
- 201000001937 osteoporosis-pseudoglioma syndrome Diseases 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 102100031691 p53-induced death domain-containing protein 1 Human genes 0.000 description 1
- 208000007312 paraganglioma Diseases 0.000 description 1
- 102000045222 parkin Human genes 0.000 description 1
- 208000034425 periodic bone pain Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108010034343 phosphoribosylamine-glycine ligase Proteins 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 108010083529 poly A specific exoribonuclease Proteins 0.000 description 1
- 208000030761 polycystic kidney disease Diseases 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 208000001000 prekallikrein deficiency Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 208000018065 pseudohypoparathyroidism type 1A Diseases 0.000 description 1
- 230000004144 purine metabolism Effects 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 230000004147 pyrimidine metabolism Effects 0.000 description 1
- 108010032037 rab5 GTP-Binding Proteins Proteins 0.000 description 1
- 208000026079 recessive X-linked ichthyosis Diseases 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 125000000548 ribosyl group Chemical class C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 201000006956 rigid spine muscular dystrophy 1 Diseases 0.000 description 1
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 description 1
- 229960004617 sapropterin Drugs 0.000 description 1
- 208000010532 sarcoglycanopathy Diseases 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 208000024105 semilobar holoprosencephaly Diseases 0.000 description 1
- 230000035946 sexual desire Effects 0.000 description 1
- 231100001055 skeletal defect Toxicity 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000009211 stress pathway Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000031906 susceptibility to X-linked 2 autism Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 108010059434 tapasin Proteins 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- WWJZWCUNLNYYAU-UHFFFAOYSA-N temephos Chemical compound C1=CC(OP(=S)(OC)OC)=CC=C1SC1=CC=C(OP(=S)(OC)OC)C=C1 WWJZWCUNLNYYAU-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 102000014898 transaminase activity proteins Human genes 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- OHOTVSOGTVKXEL-UHFFFAOYSA-K trisodium;2-[bis(carboxylatomethyl)amino]propanoate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C(C)N(CC([O-])=O)CC([O-])=O OHOTVSOGTVKXEL-UHFFFAOYSA-K 0.000 description 1
- HDZZVAMISRMYHH-KCGFPETGSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HDZZVAMISRMYHH-KCGFPETGSA-N 0.000 description 1
- 208000032471 type 1 spinal muscular atrophy Diseases 0.000 description 1
- 208000032521 type II spinal muscular atrophy Diseases 0.000 description 1
- 208000032527 type III spinal muscular atrophy Diseases 0.000 description 1
- 208000005606 type IV spinal muscular atrophy Diseases 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 206010055031 vascular neoplasm Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000022814 xenobiotic metabolic process Effects 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Images
Classifications
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1003—Transferases (2.) transferring one-carbon groups (2.1)
- C12N9/1018—Carboxy- and carbamoyl transferases (2.1.3)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- 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
- C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
- C07K14/445—Plasmodium
-
- 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/463—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from amphibians
-
- 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4712—Cystic fibrosis
-
- 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4717—Plasma globulins, lactoglobulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/505—Erythropoietin [EPO]
-
- 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
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/524—Thrombopoietin, i.e. C-MPL ligand
-
- 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
- C07K14/575—Hormones
-
- 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
- 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
- C07K14/745—Blood coagulation or fibrinolysis factors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/795—Porphyrin- or corrin-ring-containing peptides
- C07K14/805—Haemoglobins; Myoglobins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8121—Serpins
- C07K14/8125—Alpha-1-antitrypsin
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1048—Glycosyltransferases (2.4)
- C12N9/1051—Hexosyltransferases (2.4.1)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
- C12N9/2405—Glucanases
- C12N9/2451—Glucanases acting on alpha-1,6-glucosidic bonds
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/644—Coagulation factor IXa (3.4.21.22)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/88—Lyases (4.)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y114/00—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14)
- C12Y114/16—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14) with reduced pteridine as one donor, and incorporation of one atom of oxygen (1.14.16)
- C12Y114/16001—Phenylalanine 4-monooxygenase (1.14.16.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y201/00—Transferases transferring one-carbon groups (2.1)
- C12Y201/03—Carboxy- and carbamoyltransferases (2.1.3)
- C12Y201/03003—Ornithine carbamoyltransferase (2.1.3.3)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y204/00—Glycosyltransferases (2.4)
- C12Y204/01—Hexosyltransferases (2.4.1)
- C12Y204/01025—4-Alpha-glucanotransferase (2.4.1.25)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
- C12Y207/01—Phosphotransferases with an alcohol group as acceptor (2.7.1)
- C12Y207/0104—Pyruvate kinase (2.7.1.40)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01033—Amylo-alpha-1,6-glucosidase (3.2.1.33)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21022—Coagulation factor IXa (3.4.21.22)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y403/00—Carbon-nitrogen lyases (4.3)
- C12Y403/02—Amidine-lyases (4.3.2)
- C12Y403/02001—Argininosuccinate lyase (4.3.2.1)
-
- 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
-
- 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
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
- C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- 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
- C12N2840/00—Vectors comprising a special translation-regulating system
- C12N2840/10—Vectors comprising a special translation-regulating system regulates levels of translation
- C12N2840/105—Vectors comprising a special translation-regulating system regulates levels of translation enhancing translation
-
- 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
- C12N2840/00—Vectors comprising a special translation-regulating system
- C12N2840/60—Vectors comprising a special translation-regulating system from viruses
Definitions
- Synthetic mRNA can be designed with inherent translational activity for making an active protein, which could be used in various therapeutic strategies.
- the expression of protein involves a number of steps that are localized and/or regulated.
- plentiful RNase enzymes can degrade mRNA.
- use of a synthetic mRNA requires clinical formulation and delivery to cells. These steps of mRNA delivery, partitioning and dynamics increase the need for stability and longevity of the synthetic mRNA.
- mRNA transcripts incorporate a 5′ 7-methylguanosine cap and a 3′ polyA tail.
- PolyA binding proteins PABPs
- a 3′ polyA tail of at least about 20 nucleotides is needed to activate the mRNA for translation. Translational activity can decrease to low levels in the absence of either the 5′ cap or the 3′ polyA tail.
- mRNA degradation pathways actively clear out transcripts from the mRNA pool.
- the principle pathways for mRNA degradation involve deadenylation or trimming of the 3′ polyA tail by 3′-exoribonucleases and cleavage of the 5′-5′ triphosphate linkage that attaches the methylguanosine cap by a decapping complex.
- One way to increase mRNA longevity might be to increase 3′-nuclease resistance by incorporating nucleotide analogues or chemical modifications in either the phosphodiester backbone or the nucleotides, which are localized to the 3′ end to be compatible with enzymatic synthesis and efficient translation.
- a drawback of this approach is that it may not be possible to selectively incorporate such chemical modifications at 3′ termini, or to retain activity.
- translatable molecules that have increased specific activity and/or lifetime over native mRNA, to be used in methods and compositions for producing and delivering active peptides and proteins in medicines.
- This invention relates to the fields of molecular biology and genetics, as well as to biopharmaceuticals and therapeutics generated from translatable molecules. More particularly, this invention relates to methods, structures and compositions for molecules having translational activity for making active peptides or proteins in vivo.
- This invention provides methods and compositions for novel molecules having translational activity, which can be used to provide active peptides and proteins.
- the molecules of this invention can have functional cytoplasmic half-life for producing peptides and proteins.
- the peptides and proteins can be active for therapeutic modalities, as well as in vaccines and immunotherapies.
- the molecules of this invention can be translatable messenger molecules, which can have long half-life, particularly in the cytoplasm of a cell.
- the longer duration of the translatable messenger molecules of this invention can be significant for providing a translation product that is active for ameliorating, preventing or treating various diseases.
- the diseases can be associated with undesirable modulation of protein concentration, or undesirable activity of a protein.
- translatable molecules of this invention can be used in medicines, and for methods and compositions for producing and delivering active peptides and proteins.
- Embodiments of this disclosure provide a wide range of novel, translatable messenger molecules.
- the translatable messenger molecules can contain monomers that are unlocked nucleomonomers (UNA monomers).
- UNA monomers monomers that are unlocked nucleomonomers
- the long duration of translatable messenger UNA molecules (mUNA molecules) of this invention can be useful for providing an active peptide or protein translation product.
- the mUNA molecules of this invention can be used in medicines for ameliorating, preventing or treating disease.
- translatable mUNA molecules of this invention can be used to provide peptides or proteins in vitro, ex vivo, or in vivo.
- translatable mUNA molecules of this invention can provide high-efficiency expression of virtually any protein.
- the mUNA molecules of this invention have increased cytoplasmic half-life over a native, mature mRNA that provides the same peptide or protein.
- the mUNA structures and compositions of this invention can provide increased functional half-life with respect to native, mature mRNAs.
- a mUNA molecule of this invention can provide increased activity as a drug providing a peptide or protein product, as compared to a native, mature mRNA. In some embodiments, a mUNA molecule can reduce the expected dose level that would be required for efficacious therapy.
- Additional embodiments of this invention can provide vaccine compositions for immunization and immunotherapies using mUNA molecules.
- a mUNA molecule containing one or more UNA monomers, and containing nucleic acid monomers, wherein the mUNA molecule is translatable to express a polypeptide or protein.
- the molecule may have from 200 to 12,000 monomers, or from 200 to 4,000 monomers. In some embodiments, the molecule can have from 1 to 8,000 UNA monomers, or from 1 to 100 UNA monomers, or from 1 to 20 UNA monomers.
- a mUNA molecule can have one or more modified nucleic acid nucleotides, and/or one or more chemically-modified nucleic acid nucleotides.
- a mUNA molecule can contain a 5′ cap, a 5′ untranslated region of monomers, a coding region of monomers, a 3′ untranslated region of monomers, and a tail region of monomers.
- the molecule can contain a translation enhancer in a 5′ or 3′ untranslated region.
- the mUNA molecules of this invention can be translatable in vivo, or in vitro, or in a mammalian cell, or in a human in vivo.
- a translation product of a mUNA molecule can be an active peptide or protein.
- a translation product of a mUNA molecule is human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
- a mUNA molecule in another aspect, can exhibit at least 2-fold, 3-fold, 5-fold, or 10-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
- a mUNA molecule can have a cytoplasmic half-life in a cell at least 2-fold greater than a native mRNA of the cell that encodes the same translation product.
- Embodiments of this invention further contemplate therapeutic mUNA agents for a rare disease, a liver disease, or a cancer.
- a mUNA molecule can be an immunization agent or vaccine component for a rare disease, a liver disease, or a cancer.
- compositions containing a mUNA molecule and a pharmaceutically acceptable carrier and vaccine or immunization compositions containing a mUNA molecule.
- the carrier can be a nanoparticle or liposome.
- this invention provides methods for ameliorating, preventing or treating a disease or condition in a subject comprising administering to the subject a composition containing a mUNA molecule.
- the disease or condition can be a rare disease, liver disease, or cancer.
- this invention provides methods for producing a polypeptide or protein in vivo, by administering to a mammal a composition containing a mUNA molecule.
- the polypeptide or protein may be deficient in a disease or condition of a subject or mammal.
- the protein can be human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
- This invention further provides methods for producing a polypeptide or protein in vitro, by transfecting a cell with a mUNA molecule.
- the polypeptide or protein can be deficient in a disease or condition of a subject or mammal.
- the protein can be human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
- FIG. 1 shows the results of expressing human Factor IX (F9) in vivo using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of Factor IX.
- FIG. 1 shows that the translation efficiency of this mUNA molecule was doubled as compared to the native mRNA of F9.
- the mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human F9.
- FIG. 2 shows the results of expressing human Factor IX (F9) in vitro using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of Factor IX.
- FIG. 2 shows that the translation efficiency of this mUNA molecule was increased by 5-fold after 48 hours, as compared to the native mRNA of F9.
- the mUNA molecule of this embodiment was traslated in mouse hepatocyte cell line Hepa1-6 to produce human F9.
- FIG. 3 shows the results of expressing human Erythropoietin (EPO) in vitro using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of human EPO.
- FIG. 3 shows that the translation efficiency of this mUNA molecule was increased nearly 3-fold after 48 hours, as compared to the native mRNA of EPO.
- the mUNA molecule of this embodiment was translated in mouse hepatocyte cell line Hepa1-6 to produce human EPO.
- FIG. 4 shows the results of expressing mouse Erythropoietin (EPO) in vitro using several translatable mUNA molecules of this invention, as compared to expression of a native mRNA of mouse EPO.
- FIG. 4 shows that the translation efficiencies of the mUNA molecules (#2, 3, 4, 5, 6, 7, 8, 9, 10 and 11) were increased by up to 10-fold after 72 hours, as compared to the native mRNA of EPO.
- the mUNA molecules of this embodiment were translated in mouse hepatocyte cell line Hepa1-6 to produce mouse EPO.
- FIG. 5 shows the results of expressing human alpha-1-antitrypsin in vivo using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of human alpha-1-antitrypsin.
- FIG. 5 shows that the translation efficiency of this mUNA molecule at 72 hrs was increased more than 3-fold as compared to the native mRNA of human alpha-1-antitrypsin.
- the mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human alpha-1-antitrypsin.
- FIG. 6 shows the results of expressing human erythropoietin (EPO) in vivo using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of human EPO.
- FIG. 6 shows that the translation efficiency of this mUNA molecule at 72 hrs was increased more than 10-fold as compared to the native mRNA of human EPO.
- the mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human EPO.
- FIG. 7 shows the primary structure of a functional mRNA transcript in the cytoplasm.
- the mRNA includes a 5′ methylguanosine cap, a protein coding sequence flanked by untranslated regions (UTRs), and a polyadenosine (polyA) tail bound by polyA binding proteins (PABPs).
- UTRs untranslated regions
- PABPs polyadenosine binding proteins
- FIG. 8 shows the 5′ cap and PABPs cooperatively interacting with proteins involved in translation to facilitate the recruitment and recycling of ribosome complexes.
- FIG. 9 shows the splint-mediated ligation scheme, in which an acceptor RNA with a 30-monomer stub polyA tail (A(30)) was ligated to a 30-monomer donor oligomer A(30).
- the splint-mediated ligation used a DNA oligomer splint which was complementary to the 3′ UTR sequence upstream of the stub polyA tail, and included a 60-monomer oligo(dT) 5′ heel (T(60)) to splint the ligation.
- the anchoring region of the splint was complementary to the UTR sequence to ensure that a 5′ dT 30 overhang was presented upon hybridization to the acceptor. This brings the donor oligomer into juxtaposition with the 3′ terminus of the stub tail, dramatically improving the kinetics of ligation.
- FIG. 10 shows experimental results of splint-mediated ligation of a donor oligomer to an acceptor.
- FIG. 10 shows the results of ligation using 2 ug of a 120-monomer acceptor with an A 30 stub tail that was ligated to a 5′-phosphorylated A 30 RNA donor oligomer using T4 RNA Ligase 2. The reaction was incubated overnight at 37° C. The ligation and a mock reaction done without enzyme were purified, treated with DNAse I for 1 hour to degrade and detach the splint oligomers, and re-purified in a volume of 30 uL. The ligation efficiency was nearly 100%. The absence of a size shift in the mock-reaction prep shows that the acceptor and donor were truly ligated and not simply held together by undigested splint oligomers.
- FIG. 11 shows the results of splint-mediated ligation using an acceptor RNA with a 30-monomer stub polyA tail (A(30)).
- the ligation reactions were performed with three different donor oligomer species: A(30), A(60), and A(120). Based on the gel shifts, the ligations have attained nearly 100% efficiency.
- FIG. 12 shows the results of one-hour splint-mediated ligations that were performed on nGFP-A 30 transcripts.
- the resulting ligation products were compared to untreated transcripts and native nGFP-A 60 IVT products.
- the native nGFP-A 60 and the ligated products were up-shifted on the gel relative to the untreated nGFP-A 30 transcripts and mock-ligated material, showing that the ligation yield was nearly 100%.
- FIG. 13 shows increased lifetime and translational activity for an nGFP-A 60 ligation product.
- nuclearized transcripts were transfected into fibroblasts, and a comparison of fluoresence signals was made for nGFP-A 30 , mock-ligated nGFP-A 30 , and an nGFP-A 60 ligation product ( FIG. 13 , left to right).
- the significantly higher fluorescence signal observed for the nGFP-A 60 ligation product shows that it has markedly increased translational activity.
- FIG. 14 shows the results of a ligation performed with a 100-monomer acceptor RNA that was treated for 3 hours at room temperature with T4 RNA Ligase 2 (truncated KQ mutant) using a 10 uM concentration of a polyA tail 30-monomer donor oligomer. 15% PEG 8000 was included in the reaction as a volume excluder to promote efficient ligation. The ligation reaction showed that a high molecular weight product was formed, having a size in between the 100-monomer acceptor RNA and a 180-monomer RNA transcript included as a size standard. These results show that the ligation reaction produced a predominant product having high molecular weight with nearly 100% ligation of the donor to the acceptor. Additional experiments with concentrations of the polyA tail at 10 uM, 20 uM, and 40 uM showed that from about 50% to about 100% of the acceptor RNA was ligated.
- This invention provides a range of novel agents and compositions to be used for therapeutic applications.
- the molecules and compositions of this invention can be used for ameliorating, preventing or treating various diseases associated with genomic functionalities.
- the molecules of this invention can be translatable messenger UNA molecules, which can have long half-life, particularly in the cytoplasm.
- the long duration mUNA molecules can be used for ameliorating, preventing or treating various diseases associated with undesirable modulation of protein concentration, or activity of a protein.
- the properties of the mUNA compounds of this invention arise according to their molecular structure, and the structure of the molecule in its entirety, as a whole, can provide significant benefits based on those properties.
- Embodiments of this invention can provide mUNA molecules having one or more properties that advantageously provide enhanced effectiveness in regulating protein expression or concentration, or modulating protein activity.
- the molecules and compositions of this invention can provide formulations for therapeutic agents for various diseases and conditions, which can provide clinical agents.
- This invention provides a range of mUNA molecules that are surprisingly translatable to provide active peptide or protein, in vitro and in vivo.
- the mUNA structures and compositions can have increased translational activity and cytoplasmic half-life.
- the mUNA structures and compositions can provide increased functional half-life in the cytoplasm of mammalian cells over native mRNA molecules.
- the inventive mUNA molecules can have increased half-life of activity with respect to a corresponding native mRNA.
- linker groups can be attached in a chain in the mUNA molecule.
- Each linker group can also be attached to a nucleobase.
- a linker group can be a monomer. Monomers can be attached to form a chain molecule. In a chain molecule of this invention, a linker group monomer can be attached at any point in the chain.
- linker group monomers can be attached in a chain molecule of this invention so that the linker group monomers reside near the ends of the chain, or at any position in the chain.
- a chain molecule can also be referred to as an oligomer.
- the linker groups of a chain molecule can each be attached to a nucleobase.
- the presence of nucleobases in the chain molecule can provide a sequence of nucleobases in the chain molecule.
- this invention provides oligomer mUNA molecules having chain structures that incorporate novel combinations of the linker group monomers, along with certain natural nucleotides, or non-natural nucleotides, or modified nucleotides, or chemically-modified nucleotides.
- the oligomer mUNA molecules of this invention can display a sequence of nucleobases, and can be designed to express a polypeptide or protein, in vitro, ex vivo, or in vivo.
- the expressed polypeptide or protein can have activity in various forms, including activity corresponding to protein expressed from natural mRNA, or activity corresponding to a negative or dominant negative protein.
- this invention can provide active mUNA oligomer molecules having a base sequence that corresponds to at least a fragment of a native nucleic acid molecule of a cell.
- the cell can be a eukaryotic cell, a mammalian cell, or a human cell.
- This invention provides structures, methods and compositions for oligomeric mUNA agents that incorporate the linker group monomers.
- the oligomeric molecules of this invention can be used as active agents in formulations for therapeutics.
- This invention provides a range of mUNA molecules that are useful for providing therapeutic effects because of their longevity of activity in providing an expressed peptide or protein.
- an active mUNA molecule can be structured as an oligomer composed of monomers.
- the oligomeric structures of this invention may contain one or more linker group monomers, along with certain nucleotides.
- An expressed peptide or protein can be modified or mutated as compared to a native variant, or can be a homolog or ortholog for enhanced expression in a eukaryotic cell.
- An active mUNA molecule can be human codon optimized. Methodologies for optimizing codons are known in the art.
- a mUNA molecule may contain a sequence of nucleobases, and can be designed to express a peptide or protein of any isoform, in part by having sufficient homology with a native polynucleotide sequence.
- a mUNA molecule can be from about 200 to about 12,000 monomers in length, or more. In certain embodiments, a mUNA molecule can be from 200 to 12,000 monomers in length, or 200 to 10,000 monomers, or 200 to 8,000 monomers, or 200 to 6000 monomers, or 200 to 5000 monomers, or 200 to 4000 monomers, or 200 to 3600 monomers, or 200 to 3200 monomers, or 200 to 3000 monomers, or 200 to 2800 monomers, or 200 to 2600 monomers, or 200 to 2400 monomers, or 200 to 2200 monomers, or 600 to 3200 monomers, or 600 to 3000 monomers, or 600 to 2600 monomers.
- a mUNA molecule can contain from 1 to about 8,000 UNA monomers. In certain embodiments, a mUNA molecule can contain from 1 to 8,000 UNA monomers, or 1 to 6,000 UNA monomers, or 1 to 4,000 UNA monomers, or 1 to 3,000 UNA monomers, or 1 to 2,000 UNA monomers, or 1 to 1,000 UNA monomers, or 1 to 500 UNA monomers, or 1 to 300 UNA monomers, or 1 to 200 UNA monomers, or 1 to 100 UNA monomers, or 1 to 50 UNA monomers, or 1 to 40 UNA monomers, or 1 to 30 UNA monomers, or 1 to 20 UNA monomers, or 1 to 10 UNA monomers, or 1 to 6 UNA monomers.
- a mUNA molecule can be from about 200 to about 12,000 bases in length, or more. In certain embodiments, a mUNA molecule can be from 200 to 12,000 bases in length, or 200 to 10,000 bases, or 200 to 8,000 bases, or 200 to 6000 bases, or 200 to 5000 bases, or 200 to 4000 bases, or 200 to 3600 bases, or 200 to 3200 bases, or 200 to 3000 bases, or 200 to 2800 bases, or 200 to 2600 bases, or 200 to 2400 bases, or 200 to 2200 bases, or 600 to 3200 bases, or 600 to 3000 bases, or 600 to 2600 bases.
- a mUNA molecule of this invention may comprise a 5′ cap, a 5′ untranslated region of monomers, a coding region of monomers, a 3′ untranslated region of monomers, and a tail region of monomers. Any of these regions of monomers may comprise one or more UNA monomers.
- a mUNA molecule of this invention may comprise a 5′ untranslated region of monomers containing one or more UNA monomers.
- a mUNA molecule of this invention may comprise a coding region of monomers containing one or more UNA monomers.
- a mUNA molecule of this invention may comprise a 3′ untranslated region of monomers containing one or more UNA monomers.
- a mUNA molecule of this invention may comprise a tail region of monomers containing one or more UNA monomers.
- a mUNA molecule of this invention may comprise a 5′ cap containing one or more UNA monomers.
- a mUNA molecule of this invention can be translatable, and may comprise regions of sequences or structures that are operable for translation in a cell, or which have the functionality of regions of an mRNA including, for example, a 5′ cap, a 5′ untranslated region, a coding region, a 3′ untranslated region, and a polyA tail.
- This invention further contemplates methods for delivering one or more vectors, or one or more mUNA molecules to a cell.
- one or more mUNA molecules can be delivered to a cell, in vitro, ex vivo, or in vivo. Viral and non-viral transfer methods as are known in the art can be used to introduce mUNA molecules in mammalian cells. mUNA molecules can be delivered with a pharmaceutically acceptable vehicle, or for example, encapsulated in a liposome.
- a peptide or protein expressed by a mUNA molecule can be any peptide or protein, endogenous or exogenous in nature with respect to a eukaryotic cell, and may be a synthetic or non-natural peptide or protein with activity or effect in the cell.
- mUNA structures and compositions of this invention can reduce the number and frequency of transfections required for cell-fate manipulation in culture as compared to utilizing native compositions.
- this invention provides increased activity for mUNA-based drugs as compared to utilizing native compositions, and can reduce the dose levels required for efficacious therapy.
- this invention provides increased activity for mUNA-based molecules, as compared to utilizing a native mRNA as active agent.
- this invention can provide mUNA molecules that may reduce the cellular innate immune response, as compared to that induced by a natural nucleic acid, peptide or protein.
- embodiments of this invention can provide increased efficacy for single-dose therapeutic modalities, including mUNA immunization and immunotherapies.
- This invention can provide synthetic mUNA molecules that are refractory to deadenylation as compared to native molecules.
- this invention can provide synthetic mUNA molecules with increased specific activity and longer functional half-life as compared to native molecules.
- the synthetic mUNA molecules of this invention can provide increased levels of ectopic protein expression.
- cellular-delivery can be at increased levels, and cytotoxic innate immune responses can be restrained so that higher levels of ectopic protein expression can be achieved.
- the mUNA molecules of this invention can have increased specific activity and longer functional half-life than mRNAs.
- a mUNA molecule may have a number of mutations from a native mRNA, or from a disease associated mRNA.
- this invention can provide mUNA molecules having cleavable delivery and targeting moieties attached at the 3′ end.
- the specific activity for a synthetic translatable molecule delivered by transfection can be viewed as the number of molecules of protein expressed per delivered transcript per unit time.
- translation efficiency refers to a measure of the production of a protein or polypeptide by translation of a messenger molecule in vitro or in vivo.
- This invention provides a range of mUNA molecules, which can contain one or more UNA monomers, and a number of nucleic acid monomers, wherein the mUNA molecule can be translated to express a polypeptide or protein.
- this invention includes a range of mUNA molecules, which contain one or more UNA monomers in one or more untranslated regions, and a number of nucleic acid monomers, wherein the mUNA molecule can be translated to express a polypeptide or protein.
- this invention includes a range of mUNA molecules, which contain one or more UNA monomers in a tail region or monomers, and a number of nucleic acid monomers, wherein the mUNA molecule can be translated to express a polypeptide or protein.
- a mUNA molecule can contain a modified 5′ cap.
- a mUNA molecule can contain one ore more UNA monomers in a 5′ cap.
- a mUNA molecule can contain a translation enhancing 5′ untranslated region of monomers.
- a mUNA molecule can contain one or more UNA monomers in a 5′ untranslated region.
- a mUNA molecule can contain a translation enhancing 3′ untranslated region of monomers.
- a mUNA molecule can contain one or more UNA monomers in a 3′ untranslated region of monomers.
- a mUNA molecule can contain one or more UNA monomers in a tail region of monomers.
- a mUNA molecule can contain one or more UNA monomers in a polyA tail.
- a mUNA molecule in another aspect, can exhibit at least 2-fold, 3-fold, 5-fold, or 10-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
- a mUNA molecule can produce at least 2-fold, 3-fold, 5-fold, or 10-fold increased polypeptide or protein in vivo as compared to a native mRNA that encodes the same polypeptide or protein.
- this invention provides methods for treating a rare disease or condition in a subject by administering to the subject a composition containing a mUNA molecule.
- this invention provides methods for treating a liver disease or condition in a subject by administering to the subject a composition containing a mUNA molecule.
- a mUNA molecule of this invention may be used for ameliorating, preventing or treating a disease through enzyme modulation or replacement.
- a mUNA molecule of this invention can be administered to regulate, modulate, increase, or decrease the concentration or effectiveness of a natural enzyme in a subject.
- the enzyme can be an unmodified, natural enzyme for which the patient has an abnormal quantity.
- a mUNA molecule can be delivered to cells or subjects, and translated to supply increased levels of the natural enzyme.
- a mUNA molecule of this invention may be used for ameliorating, preventing or treating a disease through modulation or introduction of a peptide or protein.
- a mUNA molecule of this invention can be administered to regulate, modulate, increase, or decrease the concentration or effectiveness of a peptide or protein in a subject, where the peptide or protein is non-natural or mutated, as compared to a native peptide or protein.
- the peptide or protein can be a modified, non-natural, exogenous, or synthetic peptide or protein, which has a pharmacological effect in a subject.
- a mUNA molecule can be delivered to cells or subjects, and translated to supply a concentration of the peptide or protein.
- diseases for enzyme modulation include lysosomal diseases, for example, Gaucher disease, Fabry disease, Mucopolysaccharidoses (MPS) and related diseases including MPS I, MPS II (Hunter syndrome), and MPS VI, as well as Glycogen storage disease type II.
- lysosomal diseases for example, Gaucher disease, Fabry disease, Mucopolysaccharidoses (MPS) and related diseases including MPS I, MPS II (Hunter syndrome), and MPS VI, as well as Glycogen storage disease type II.
- diseases for enzyme modulation include hematologic diseases, for example, sickle-cell disease, thalassemia, methemoglobinemia, anemia due to deficiency of hemoglobin or B 12 intrinsic factor, spherocytosis, glucose-6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency.
- hematologic diseases for example, sickle-cell disease, thalassemia, methemoglobinemia, anemia due to deficiency of hemoglobin or B 12 intrinsic factor, spherocytosis, glucose-6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency.
- diseases for enzyme modulation include hemophilia, Von Willebrand disease, Protein S deficiency, age-related macular degeneration, trinucleotide repeat disorders, muscular dystrophy, insertion mutation diseases, DNA repair-deficiency disorders, and deletion mutation diseases.
- Examples of diseases and/or conditions for which the mUNA molecules of this invention can be translatable to provide an active agent include those in Table 1.
- DEND Syndrome Generally severe form of neonatal diabetes mellitus characterized by a t
- Glycerol Kinase Deficiency X-linked recessive enzyme defect that is heterozygous in nature, responsible gene in a region containing genes in which deletions can cause DMD and adrenal hypoplasia congenita Glycogen Storage Disease type 9 Caused by the inability to break down glycogen.
- the different forms of the condition can affect glycogen breakdown in liver cells, muscle cells or both gm1 gangliosidosis Autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes Hereditary spherocytosis Affects red blood cells, shortage of red blood cells, yellowing of the eyes and skin, and an enlarged spleen Hidradenitis Suppurativa Stage III Disorder of the terminal follicular epithelium in the apocrine gland-bearing skin, frequently causing keloids, contractures, and immobility.
- Stage III is defined as multiple lesions, with more extensive sinus tracts and scarring Horizonatal Gaze Palsy with Disorder that affects vision and also causes an abnormal Progressive Scoliosis curvature of the spine IMAGe syndrome
- the combination of intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (only about 20 cases reported in the medical literature) Isodicentric 15 Chromosome abnormality in which a child is born with extra genetic material from chromosome 15 isolated hemihyperplasia
- One side of the body grows more than other, causing asymmetry
- Juvenile Xanthogranuloma Usually benign and self-limiting.
- liver cells are less able to secrete a digestive fluid called bile.
- the buildup of bile in liver cells causes liver disease in affected individuals Pseudohypoparathyroidism type 1a Characterized by renal resistance to parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia, and elevated PTH; resistance to other hormones including thydroid stimulating hormone, gonadotropins and growth- hormone-releasing hormone PTEN Hamartoma Tumor
- the gene was identified as a tumor suppressor that is Syndrome mutated in a large number of cancers at high frequency Schnitzler syndrome Characterised by chronic hives and periodic fever, bone pain and joint pain (sometimes with joint inflammation), weight loss, malaise, fatigue, swollen lymph glands and enlarged spleen and liver Scleroderma Chronic hardening and tightening of the skin and connective tissues
- Semi Lobar Holoprosencephany Holoprosencephany: birth defect of the brain, which often can also affect facial features, including closely spaced eyes, small head size, and sometimes clefts of the lip and roof of the mouth.
- Semilobar holoprosencephaly is a subtype of holoprosencephaly characterised by an incomplete forebrain division Sjogren's Syndrome Immune system disorder characterized by dry eyes and dry mouth Specific Antibody Deficiency Immune Disease SYNGAP 1 A ras GTPase-activating protein that is critical for the development of cognition and proper synapse function Trigeminal Trophic Syndrome This is the wing of tissue at the end of the nose above the nostril.
- Trigeminal trophic syndrome is due to damage to the trigeminal nerve Undiffentiated Connective Tissue Systemic autoimmune disease Disease X-linked hypophosphatemia X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that ingestion of vitamin D is relatively ineffective. It can cause bone deformity including short stature and genu varum
- the mUNA molecules of this invention can be translatable to provide an active protein.
- a translatable mUNA molecule can provide an active mRNA immunization agent, or an mRNA vaccine component.
- a mUNA vaccine of this disclosure can advantageously provide a safe and efficacious genetic vaccine by inducing an immune response having both cellular and humoral components.
- protein can be expressed using a mUNA vaccine of this invention.
- a mUNA vaccine can advantageously provide protein synthesis in the cytoplasm.
- a mUNA vaccine of this invention can provide internalization, release and transport of an exogenous mRNA in the cytoplasm.
- a mUNA vaccine of this invention can encode for a protein antigen that can be translated by host cells.
- some mUNA vaccines of this disclosure can encode for tumor antigens, viral antigens, or allergens.
- Modalities for administering a mUNA vaccine of this invention can include intravenous, intranodal, intradermal, subcutaneous and intrasplenic.
- Embodiments of this invention further provide mUNA vaccines having increased half-life of translation, which can be used to reduce the necessary dose and exposure to antigen, and reduce the risk of inducing tolerance.
- a mUNA vaccine of this invention can provide an immunological effect without the risk of integration of a component into the genome, and may reduce the risk of mutagenesis as compared to other genetic vaccines.
- Additional embodiments of this disclosure include mUNA molecules having translational activity, where the translational activity can be described by a cytoplasmic half-life in a mammalian cell.
- the half-life can be determined by the time required for 50% of the mUNA molecule to be degraded in the cell.
- a translatable mUNA molecule of this invention can be a precursor of an active molecule, which can be used in the treatment of a condition or disease in a subject.
- a translatable mUNA molecule of this invention can be a pharmacologically active molecule having increased half-life in the cytoplasm of mammalian cells.
- mUNA molecules of this invention include a mUNA molecule that provides an mRNA encoding HIV-1 gag antigen, a mUNA molecule that provides an mRNA encoding antigens overexpressed in lung cancers, a mUNA molecule that provides an mRNA encoding malarial P. falciparum reticulocyte-binding protein homologue 5 (PfRHS), and a mUNA molecule that provides an mRNA encoding malarial Plasmodium falciparum PfSEA-1, a 244 KD malaria antigen expressed in schizont-infected RBCs.
- PfRHS malarial P. falciparum reticulocyte-binding protein homologue 5
- linker group monomers can be unlocked nucleomonomers (UNA monomers), which are small organic molecules based on a propane-1,2,3-tri-yl-trisoxy structure as shown below:
- UNA monomers unlocked nucleomonomers
- R 1 and R 2 are H, and R 1 and R 2 can be phosphodiester linkages
- Base can be a nucleobase
- R 3 is a functional group described below.
- the UNA monomer main atoms can be drawn in IUPAC notation as follows:
- nucleobase examples include uracil, thymine, cytosine, 5-methylcytosine, adenine, guanine, inosine, and natural and non-natural nucleobase analogues.
- nucleobase examples include pseudouracil, 1-methylpseudouracil, and 5-methoxyuracil.
- a UNA monomer which is not a nucleotide, can be an internal linker monomer in an oligomer.
- An internal UNA monomer in an oligomer is flanked by other monomers on both sides.
- a UNA monomer can participate in base pairing when the oligomer forms a complex or duplex, for example, and there are other monomers with nucleobases in the complex or duplex.
- a UNA monomer can be a terminal monomer of an oligomer, where the UNA monomer is attached to only one monomer at either the propane-1-yl position or the propane-3-yl position. Because the UNA monomers are flexible organic structures, unlike nucleotides, the terminal UNA monomer can be a flexible terminator for the oligomer.
- a UNA monomer can be a flexible molecule
- a UNA monomer as a terminal monomer can assume widely differing conformations.
- An example of an energy minimized UNA monomer conformation as a terminal monomer attached at the propane-3-yl position is shown below.
- the structure of the UNA monomer allows it to be attached to naturally-occurring nucleotides.
- a UNA oligomer can be a chain composed of UNA monomers, as well as various nucleotides that may be based on naturally-occurring nucleosides.
- the functional group R 3 of a UNA monomer can be —OR 4 , —SR 4 , —NR 4 2 , —NH(C ⁇ O)R 4 , morpholino, morpholin-1-yl, piperazin-1-yl, or 4-alkanoyl-piperazin-1-yl, where R 4 is the same or different for each occurrence, and can be H, alkyl, a cholesterol, a lipid molecule, a polyamine, an amino acid, or a polypeptide.
- the UNA monomers are organic molecules. UNA monomers are not nucleic acid monomers or nucleotides, nor are they naturally-occurring nucleosides or modified naturally-occurring nucleosides.
- a UNA oligomer of this invention is a synthetic chain molecule.
- a UNA monomer can be UNA-A (designated ⁇ ), UNA-U (designated ⁇ ), UNA-C (designated ⁇ hacek over (C) ⁇ ) and UNA-G (designated ⁇ hacek over (G) ⁇ ).
- Designations that may be used herein include mA, mG, mC, and mU, which refer to the 2′-O-Methyl modified ribonucleotides.
- Designations that may be used herein include dT, which refers to a 2′-deoxy T nucleotide.
- the symbol X represents a UNA monomer.
- the UNA monomers of the mUNA oligomer can have any base attached that would be complementary to the monomer with which it is paired in the nucleic acid molecule.
- N can represent any natural nucleotide monomer, or any modified nucleotide monomer.
- an N monomer of the mUNA oligomer can have any base attached that would be complementary to the monomer with which it is paired in the nucleic acid molecule.
- the symbol Q represents a non-natural, modified, or chemically-modified nucleotide monomer.
- a Q monomer of the mUNA oligomer can have any base attached that would be complementary to the monomer with which it is paired in the nucleic acid molecule.
- nucleic acid monomers include non-natural, modified, and chemically-modified nucleotides, including any such nucleotides known in the art.
- non-natural, modified, and chemically-modified nucleotide monomers include any such nucleotides known in the art, for example, 2′-O-methyl ribonucleotides, 2′-O-methyl purine nucleotides, 2′-deoxy-2′-fluoro ribonucleotides, 2′-deoxy-2′-fluoro pyrimidine nucleotides, 2′-deoxy ribonucleotides, 2′-deoxy purine nucleotides, universal base nucleotides, 5-C-methyl-nucleotides, and inverted deoxyabasic monomer residues.
- non-natural, modified, and chemically-modified nucleotide monomers include 3′-end stabilized nucleotides, 3′-glyceryl nucleotides, 3′-inverted abasic nucleotides, and 3′-inverted thymidine.
- Non-natural, modified, and chemically-modified nucleotide monomers include locked nucleic acid nucleotides (LNA), 2′-O,4′-C-methylene-(D-ribofuranosyl) nucleotides, 2′-methoxyethoxy (MOE) nucleotides, 2′-methyl-thio-ethyl, 2′-deoxy-2′-fluoro nucleotides, and 2′-O-methyl nucleotides.
- LNA locked nucleic acid nucleotides
- MOE 2′-methoxyethoxy
- non-natural, modified, and chemically-modified nucleotide monomers examples include 2′, 4′-Constrained 2′-O-Methoxyethyl (cMOE) and 2′-O-Ethyl (cEt) Modified DNAs.
- cMOE 2′, 4′-Constrained 2′-O-Methoxyethyl
- cEt 2′-O-Ethyl
- non-natural, modified, and chemically-modified nucleotide monomers examples include 2′-amino nucleotides, 2′-O-amino nucleotides, 2′-C-allyl nucleotides, and 2′-O-allyl nucleotides.
- non-natural, modified, and chemically-modified nucleotide monomers include N 6 -methyladenosine nucleotides.
- nucleotide monomers examples include nucleotide monomers with modified bases 5-(3-amino)propyluridine, 5-(2-mercapto)ethyluridine, 5-bromouridine; 8-bromoguanosine, or 7-deazaadenosine.
- non-natural, modified, and chemically-modified nucleotide monomers include 2′-O-aminopropyl substituted nucleotides.
- non-natural, modified, and chemically-modified nucleotide monomers include replacing the 2′-OH group of a nucleotide with a 2′-R, a 2′-OR, a 2′-halogen, a 2′-SR, or a 2′-amino, where R can be H, alkyl, alkenyl, or alkynyl.
- nucleotide monomers examples include pseudouridine (psi-Uridine) and 1-methylpseudouridine.
- modified nucleotides are given in Saenger, Principles of Nucleic Acid Structure, Springer-Verlag, 1984.
- aspects of this invention provide structures and compositions for mUNA molecules that are oligomeric compounds.
- the mUNA compounds can be active agents for pharmaceutical compositions.
- An oligomeric mUNA agent of this invention may contain one or more UNA monomers. Oligomeric molecules of this invention can be used as active agents in formulations for supplying peptide and protein therapeutics.
- this invention provides oligomeric mUNA compounds having a structure that incorporates novel combinations of UNA monomers with certain natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides.
- Oligomeric mUNA compounds of this invention can have a length of from about 200 to about 12,000 bases in length. Oligomeric mUNA compounds of this invention can have a length of about 1800, or about 1900, or about 2000, or about 2100, or about 2200, or about 2300, or about 2400, or about 2500 bases.
- the oligomeric mUNA compounds of this invention can be pharmacologically active molecules.
- a mUNA molecule can be used as an active pharmaceutical ingredient for generating a peptide or protein active agent in vitro, in vivo, or ex vivo.
- a mUNA molecule of this invention can have the structure of Formula I
- L 1 is a linkage, n is from 200 to 12,000, and for each occurrence L 2 is a UNA linker group having the formula —C 1 —C 2 —C 3 —, where R is attached to C 2 and has the formula —OCH(CH 2 R 3 )R 5 , where R 3 is —OR 4 , —SR 4 , —NR 4 2 , —NH(C ⁇ O)R 4 , morpholino, morpholin-1-yl, piperazin-1-yl, or 4-alkanoyl-piperazin-1-yl, where R 4 is the same or different for each occurrence and is H, alkyl, a cholesterol, a lipid molecule, a polyamine, an amino acid, or a polypeptide, and where R 5 is a nucleobase, or L 2 (R) is a sugar such as a ribose and R is a nucleobase, or L 2 is a modified sugar such as a modified ribos
- the base sequence of a mUNA molecule can be any sequence of nucleobases.
- a mUNA molecule of this invention can have any number of phosphorothioate intermonomer linkages in any intermonomer location.
- any one or more of the intermonomer linkages of a mUNA molecule can be a phosphodiester, a phosphorothioate including dithioates, a chiral phosphorothioate, and other chemically modified forms.
- the terminal position When a mUNA molecule terminates in a UNA monomer, the terminal position has a 1-end, or the terminal position has a 3-end, according to the positional numbering shown above.
- a mUNA molecule of this invention can incorporate a region that enhances the translational efficiency of the mUNA molecule.
- translational enhancer regions as known in the art can be incorporated into the structure of a mUNA molecule to increase peptide or protein yields.
- a mUNA molecule containing a translation enhancer region can provide increased production of peptide or protein.
- a translation enhancer region can comprise, or be located in a 5′ or 3′ untranslated region of a mUNA molecule.
- translation enhancer regions include naturally-occurring enhancer regions from TEV 5′UTR and Xenopus beta-globin 3′UTR.
- a mUNA molecule can be designed to express a target peptide or protein.
- the target peptide or protein can be associated with a condition or disease in a subject.
- the base sequence of a mUNA molecule can include a portion that is identical to at least an effective portion or domain of a base sequence of an mRNA, where an effective portion is sufficient to impart a therapeutic activity to a translation product of the mUNA molecule.
- this invention provides active mUNA oligomer molecules having a base sequence identical to at least a fragment of a native nucleic acid molecule of a cell.
- the base sequence of a mUNA molecule can include a portion that is identical to a base sequence of an mRNA, except for one or more base mutations.
- the number of mutations for the mUNA molecule should not exceed an amount that would produce a translation product of the mUNA molecule having substantially less activity than the mRNA.
- the oligomer mUNA molecules of this invention can display a sequence of nucleobases, and can be designed to express a peptide or protein, in vitro, ex vivo, or in vivo.
- the expressed peptide or protein can have activity in various forms, including activity corresponding to protein expressed from a native or natural mRNA.
- a mUNA molecule of this invention may have a chain length of about 400 to 15,000 monomers, where any monomer that is not a UNA monomer can be a Q monomer.
- a mUNA molecule of this invention may have a 5′-end capped with various groups and their analogues as are known in the art.
- the 5′ cap may be a m7GpppGm cap.
- the 5′ cap may be an ARCA cap (3′-OMe-m7G(5′)pppG).
- the 5′ cap may be an mCAP (m7G(5′)ppp(5′)G, N 7 -Methyl-Guanosine-5′-Triphosphate-5′-Guanosine).
- the 5′ cap may be resistant to hydrolysis.
- the mUNA molecules of this invention can be structured to provide peptides or proteins that are nominally expressed by any portion of a genome. Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein are set forth below.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neoplasia, PTEN; ATM; ATR; EGFR; ERBB2; ERBB3; ERBB4; Notch1; Notch2; Notch3; Notch4; AKT; AKT2; AKT3; HIF; HIF1a; HIF3a; Met; HRG; Bc12; PPAR alpha; PPAR gamma; WT1 (Wilms Tumor); FGF Receptor Family members (5 members: 1, 2, 3, 4, 5); CDKN2a; APC; RB (retinoblastoma); MEN1; VHL; BRCA1; BRCA2; AR (Androgen Receptor); TSG101; IGF; IGF Receptor; Igf1 (4 variants); Igf2 (3 variants); Igf 1 Receptor; Igf 2 Receptor; Bax; Bc12; caspases family (9 members: 1,
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Age-related Macular Degeneration, Schizophrenia, Aber; Cc12; Cc2; cp (ceruloplasmin); Timp3; cathepsinD; Vldlr; Ccr2 Neuregulin1 (Nrg 1); Erb4 (receptor for Neuregulin); Complexin1 (Cplx1); Tph1 Tryptophan hydroxylase; Tph2 Tryptophan hydroxylase 2; Neurexin 1; GSK3; GSK3a; GSK3b.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: 5-HTT (Slc6a4); COMT; DRD (Drd1a); SLC6A3; DAOA; DTNBP1; Dao (Dao1).
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Trinucleotide Repeat Disorders, HTT (Huntington's Dx); SBMA/SMAX1/AR (Kennedy's Dx); FXN/X25 (Friedrich's Ataxia); ATX3 (Machado-Joseph's Dx); ATXN1 and ATXN2 (spinocerebellar ataxias); DMPK (myotonic dystrophy); Atrophin-1 and Atn 1 (DRPLA Dx); CBP (Creb-BP-global instability); VLDLR (Alzheimer's); Atxn7; Atxn10.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fragile X Syndrome, FMR2; FXR1; FXR2; mGLUR5.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Secretase Related Disorders, APH-1 (alpha and beta); Presenilin (Psen1); nicastrin (Ncstn); PEN-2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nos1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Parp1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nat1; Nat2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Prion-related disorders, Prp.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: ALS disease, SOD1; ALS2; STEX; FUS; TARDBP; VEGF (VEGF-a; VEGF-b; VEGF-c).
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Drug addiction, Prkce (alcohol); Drd2; Drd4; ABAT (alcohol); GRIA2; Grm5; Grin1; Htr1b; Grin2a; Drd3; Pdyn; Gria1 (alcohol).
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Autism, Mecp2; BZRAP1; MDGA2; Sema5A; Neurexin 1; Fragile X (FMR2 (AFF2); FXR1; FXR2; Mglur5).
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Alzheimer's Disease, E1; CHIP; UCH; UBB; Tau; LRP; PICALM; Clusterin; PS1; SORL1; CR1; Vld1r; Uba1; Uba3; CHIP28 (Aqp1, Aquaporin 1); Uch11; Uch13; APP.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inflammation, 1L-10; IL-1 (1L-1a; IL-1b); 1L-13; IL-17 (IL-17a (CTLA8); IL-17b; IL-17c; IL-17d; IL-17f); II-23; Cx3er1; ptpn22; TNFa; NOD2/CARD15 for IBD; IL-6; 1L-12 (1L-12a; 1L-12b); CTLA4; Cx3cl1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Parkinson's Disease, x-Synuclein; DJ-1; LRRK2; Parkin; PINK1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Blood and coagulation diseases and disorders, Anemia (CDAN1, CDA1, RPS19, DBA, PKLR, PK1, NT5C3, UMPH1, PSN1, RHAG, RH50A, NRAMP2, SPTB, ALAS2, ANH1, ASB, ABCB7, ABC7, ASAT); Bare lymphocyte syndrome (TAPBP, TPSN, TAP2, ABCB3, PSF2, RING11, MHC2TA, C2TA, RFX5, RFXAP, RFX5), Bleeding disorders (TBXA2R, P2RX1, P2X1); Factor H and factor H-like 1 (HF1, CFH, HUS); Factor V and factor VIII (MCFD2); Factor VII deficiency (F7); Factor X deficiency (F10); Factor XI deficiency (F11); Factor XII deficiency
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cell dysregulation and oncology diseases and disorders, B-cell non-Hodgkin lymphoma (BCL7A, BCL7); Leukemia (TAL1 TCL5, SCL, TAL2, FLT3, NBS1, NBS, ZNFN1A1, IK1, LYF1, HOXD4, HOX4B, BCR, CML, PHL, ALL, ARNT, KRAS2, RASK2, GMPS, AF10, ARHGEF12, LARG, KIAA0382, CALM, CLTH, CEBPA, CEBP, CHIC2, BTL, FLT3, KIT, PBT, LPP, NPM1, NUP214, D9S46E, CAN, CAIN, RUNX1, CBFA2, AML1, WHSC1L1, NSD3, FLT3, AF1Q, NPM1, NUMA1, ZNF145, PLZF, PML, MYL,
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inflammation and immune related diseases and disorders, AIDS (KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1, IFNG, CXCL12, SDF1); Autoimmune lymphoproliferative syndrome (TNFRSF6, APT1, FAS, CD95, ALPS1A); Combined immuno-deficiency, (IL2RG, SCIDX1, SCIDX, IMD4); HIV-1 (CCL5, SCYA5, D17S136E, TCP228), HIV susceptibility or infection (IL10, CSIF, CMKBR2, CCR2, CMKBR5, CCCKR5 (CCR5)); Immuno-deficiencies (CD3E, CD3G, AICDA, AID, HIGM2, TNFRSF5, CD40, UNG, DGU, HIGM4, TNFSF5, CD40LG, HIGM1, IGM, FOXP3, IPEX
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Metabolic, liver, kidney and protein diseases and disorders, Amyloid neuropathy (TTR, PALB); Amyloidosis (APOA1, APP, AAA, CVAP, AD1, GSN, FGA, LYZ, TTR, PALB); Cirrhosis (KRT18, KRT8, CIRH1A, NAIC, TEX292, KIAA1988); Cystic fibrosis (CFTR, BG213071, ABCC7, CF, MRP7); Glycogen storage diseases (SLC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM); Hepatic adenoma, 142330 (TCF1, HNF1A, MODY3), Hepatic failure, early onset, and neurologic disorder (SCOD1, SCO1), Hepatic
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Lipoprotein lipase, APOA1, APOC3 and APOA4.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Muscular/skeletal diseases and disorders, Becker muscular dystrophy (DMD, BMD, MYF6), Duchenne Muscular Dystrophy (DMD, BMD); Emery-Dreifuss muscular dystrophy (LMNA, LMN1, EMD2, FPLD, CMD1A, HGPS, LGMD1B, LMNA, LMN1, EMD2, FPLD, CMD1A); Facio-scapulohumeral muscular dystrophy (FSHMD1A, FSHD1A); Muscular dystrophy (FKRP, MDC1C, LGMD2I, LAMA2, LAMM, LARGE, KIAA0609, MDC1D, FCMD, TTID, MYOT, CAPN3, CANP3, DYSF, LGMD2B, SGCG, LGMD2C, DMDA1, SCG3, SGCA, ADL, DAG2, LGMD2
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neurological and neuronal diseases and disorders, ALS (SOD1, ALS2, STEX, FUS, TARDBP, VEGF (VEGF-a, VEGF-b, VEGF-c); Alzheimer's Disease (APP, AAA, CVAP, AD1, APOE, AD2, PSEN2, AD4, STM2, APBB2, FE65L1, NOS3, PLAU, URK, ACE, DCP1, ACE1, MPO, PACIP1, PAXIP1L, PTIP, A2M, BLMH, BMH, PSEN1, AD3); Autism (Mecp2, BZRAP1, MDGA2, Sema5A, Neurexin 1, GLO1, MECP2, RTT, PPMX, MRX16, MRX79, NLGN3, NLGN4, KIAA1260, AUTSX2); Fragile X Syndrome (FMR2, FXR1, FXR1,
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Occular diseases and disorders, Age-related macular degeneration (Aber, Cc12, Cc2, cp (ceruloplasmin), Timp3, cathepsinD, Vldlr, Ccr2); Cataract (CRYAA, CRYA1, CRYBB2, CRYB2, PITX3, BFSP2, CP49, CP47, CRYAA, CRYA1, PAX6, AN2, MGDA, CRYBA1, CRYB1, CRYGC, CRYG3, CCL, LIM2, MP19, CRYGD, CRYG4, BFSP2, CP49, CP47, HSF4, CTM, HSF4, CTM, MIP, AQP0, CRYAB, CRYA2, CTPP2, CRYBB1, CRYGD, CRYG4, CRYBB2, CRYB2, CRYGC, CRYG3, CCL, CRYAA, CRYA1, GJA
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Epilepsy, myoclonic, EPM2A, MELF, EPM2 Lafora type, 254780 Epilepsy, myoclonic, NHLRC1, EPM2A, EPM2B Lafora type, 254780.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Duchenne muscular DMD, BMD dystrophy, 310200 (3) AIDS, delayed/rapid KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1 progression to (3).
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: AIDS, delayed/rapid KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1 progression to (3) AIDS, rapid IFNG progression to, 609423 (3) AIDS, resistance to CXCL12, SDF1 (3).
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Alpha-1-Antitrypsin Deficiency, SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1]; SERPINA2 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 2]; SERPINA3 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3]; SERPINA5 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 5]; SERPINA6 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 6]; SERPINA7 [serpin peptidase inhibitor, clade A (
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PI3K/AKT Signaling, PRKCE; ITGAM; ITGA5; IRAK1; PRKAA2; EIF2AK2; PTEN; EIF4E; PRKCZ; GRK6; MAPK1; TSC1; PLK1; AKT2; IKBKB; PIK3CA; CDK8; CDKN1B; NFKB2; BCL2; PIK3CB; PPP2R1A; MAPK8; BCL2L1; MAPK3; TSC2; ITGA1; KRAS; EIF4EBP1; RELA; PRKCD; NOS3; PRKAA1; MAPK9; CDK2; PPP2CA; PIM1; ITGB7; YWHAZ; ILK; TP53; RAF1.; IKBKG; RELB; DYRK1A; CDKN1A; ITGB1; MAP2
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: ERK/MAPK Signaling, PRKCE; ITGAM; ITGA5; HSPB1; IRAK1; PRKAA2; EIF2AK2; RAC1; RAP1A; TLN1; EIF4E; ELK1; GRK6; MAPK1; RAC2; PLK1; AKT2; PIK3CA; CDK8; CREB1; PRKCI; PTK2; FOS; RPS6KA4; PIK3CB; PPP2R1A; PIK3C3; MAPK8; MAPK3; ITGA1; ETS1; KRAS; MYCN; EIF4EBP1; PPARG; PRKCD; PRKAA1; MAPK9; SRC; CDK2; PPP2CA; PIM1; PIK3C2A; ITGB7; YWHAZ; PPP1CC; KSR
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Serine/Threonine-Protein Kinase, CDK16; PCTK1; CDK5R1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glucocorticoid Receptor Signaling, RAC1; TAF4B; EP300; SMAD2; TRAF6; PCAF; ELK1; MAPK1; SMAD3; AKT2; IKBKB; NCOR2; UBE2I; PIK3CA; CREB1; FOS; HSPA5; NFKB2; BCL2; MAP3K14; STAT5B; PIK3CB; PIK3C3; MAPK8; BCL2L1; MAPK3; TSC22D3; MAPK10; NRIP1; KRAS; MAPK13; RELA; STAT5A; MAPK9; NOS2A; PBX1; NR3C1; PIK3C2A; CDKN1C; TRAF2; SERPINE1; NCOA3; MAPK14; TNF; RAF1; IKBKG;
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Axonal Guidance Signaling, PRKCE; ITGAM; ROCK1; ITGA5; CXCR4; ADAM12; IGF1; RAC1; RAP1A; E1F4E; PRKCZ; NRP1; NTRK2; ARHGEF7; SMO; ROCK2; MAPK1; PGF; RAC2; PTPN11; GNAS; AKT2; PIK3CA; ERBB2; PRKC1; PTK2; CFL1; GNAQ; PIK3CB; CXCL12; PIK3C3; WNT11; PRKD1; GNB2L1; ABL1; MAPK3; ITGA1; KRAS; RHOA; PRKCD; PIK3C2A; ITGB7; GLI2; PXN; VASP; RAF1; FYN; ITGB1; MAP2K2; PA
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Ephrin Receptor Signaling, PRKCE; ITGAM; ROCK1; ITGA5; CXCR4; IRAK1; PRKAA2; EIF2AK2; RAC1; RAP1A; GRK6; ROCK2; MAPK1; PGF; RAC2; PTPN11; GNAS; PLK1; AKT2; DOK1; CDK8; CREB1; PTK2; CFL1; GNAQ; MAP3K14; CXCL12; MAPK8; GNB2L1; ABL1; MAPK3; ITGA1; KRAS; RHOA; PRKCD; PRKAA1; MAPK9; SRC; CDK2; PIM1; ITGB7; PXN; RAF1; FYN; DYRK1A; ITGB1; MAP2K2; PAK4, AKT1; JAK2; STAT
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Actin Cytoskeleton Signaling, ACTN4; PRKCE; ITGAM; ROCK1; ITGA5; IRAK1; PRKAA2; EIF2AK2; RAC1; INS; ARHGEF7; GRK6; ROCK2; MAPK1; RAC2; PLK1; AKT2; PIK3CA; CDK8; PTK2; CFL1; PIK3CB; MYH9; DIAPH1; PIK3C3; MAPK8; F2R; MAPK3; SLC9A1; ITGA1; KRAS; RHOA; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; PIK3C2A; ITGB7; PPP1CC; PXN; VIL2; RAF1; GSN; DYRK1A; ITGB1; MAP2K2; PAK
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Huntington's Disease Signaling, PRKCE; IGF1; EP300; RCOR1.; PRKCZ; HDAC4; TGM2; MAPK1; CAPNS1; AKT2; EGFR; NCOR2; SP1; CAPN2; PIK3CA; HDAC5; CREB1; PRKC1; HSPA5; REST; GNAQ; PIK3CB; PIK3C3; MAPK8; IGF1R; PRKD1; GNB2L1; BCL2L1; CAPN1; MAPK3; CASP8; HDAC2; HDAC7A; PRKCD; HDAC11; MAPK9; HDAC9; PIK3C2A; HDAC3; TP53; CASP9; CREBBP; AKT1; PIK3R1; PDPK1; CASP1; APAF1; FRAP1; C
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Apoptosis Signaling, PRKCE; ROCK1; BID; IRAK1; PRKAA2; EIF2AK2; BAK1; BIRC4; GRK6; MAPK1; CAPNS1; PLK1; AKT2; IKBKB; CAPN2; CDK8; FAS; NFKB2; BCL2; MAP3K14; MAPK8; BCL2L1; CAPN1; MAPK3; CASP8; KRAS; RELA; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; TP53; TNF; RAF1; IKBKG; RELB; CASP9; DYRK1A; MAP2K2; CHUK; APAF1; MAP2K1; NFKB1; PAK3; LMNA; CASP2; BIRC2; TTK; CSNK1A1;
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: B Cell Receptor Signaling, RAC1; PTEN; LYN; ELK1; MAPK1; RAC2; PTPN11; AKT2; IKBKB; PIK3CA; CREB1; SYK; NFKB2; CAMK2A; MAP3K14; PIK3CB; PIK3C3; MAPK8; BCL2L1; ABL1; MAPK3; ETS1; KRAS; MAPK13; RELA; PTPN6; MAPK9; EGR1; PIK3C2A; BTK; MAPK14; RAF1; IKBKG; RELB; MAP3K7; MAP2K2; AKT1; PIK3R1; CHUK; MAP2K1; NFKB1; CDC42; GSK3A; FRAP1; BCL6; BCL10; JUN; GSK3A
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Leukocyte Extravasation Signaling, ACTN4; CD44; PRKCE; ITGAM; ROCK1; CXCR4; CYBA; RAC1; RAP1A; PRKCZ; ROCK2; RAC2; PTPN11; MMP14; PIK3CA; PRKCI; PTK2; PIK3CB; CXCL12; PIK3C3; MAPK8; PRKD1; ABL1; MAPK10; CYBB; MAPK13; RHOA; PRKCD; MAPK9; SRC; PIK3C2A; BTK; MAPK14; NOX1; PXN; VIL2; VASP; ITGB1; MAP2K2; CTNND1; PIK3R1; CTNNB1; CLDN1; CDC42; F11R; ITK; CRKL; VAV3; CTTN; PRK
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Integrin Signaling, ACTN4; ITGAM; ROCK1; ITGA5; RAC1; PTEN; RAP1A; TLN1; ARHGEF7; MAPK1; RAC2; CAPNS1; AKT2; CAPN2; P1K3CA; PTK2; PIK3CB; PIK3C3; MAPK8; CAV1; CAPN1; ABL1; MAPK3; ITGA1; KRAS; RHOA; SRC; PIK3C2A; ITGB7; PPP1CC; ILK; PXN; VASP; RAF1; FYN; ITGB1; MAP2K2; PAK4; AKT1; PIK3R1; TNK2; MAP2K1; PAK3; ITGB3; CDC42; RND3; ITGA2; CRKL; BRAF; GSK3B; A
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Acute Phase Response Signaling, IRAK1; SOD2; MYD88; TRAF6; ELK1; MAPK1; PTPN11; AKT2; IKBKB; PIK3CA; FOS; NFKB2; MAP3K14; PIK3CB; MAPK8; RIPK1; MAPK3; IL6ST; KRAS; MAPK13; IL6R; RELA; SOCS1; MAPK9; FTL; NR3C1; TRAF2; SERPINE1; MAPK14; TNF; RAF1; PDK1; IKBKG; RELB; MAP3K7; MAP2K2; AKT1; JAK2; PIK3R1; CHUK; STAT3; MAP2K1; NFKB1; FRAP1; CEBPB; JUN; AKT3; IL1R1; IL6.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PTEN Signaling, ITGAM; ITGA5; RAC1; PTEN; PRKCZ; BCL2L11; MAPK1; RAC2; AKT2; EGFR; IKBKB; CBL; PIK3CA; CDKN1B; PTK2; NFKB2; BCL2; PIK3CB; BCL2L1; MAPK3; ITGA1; KRAS; ITGB7; ILK; PDGFRB; INSR; RAF1; IKBKG; CASP9; CDKN1A; ITGB1; MAP2K2; AKT1; PIK3R1; CHUK; PDGFRA; PDPK1; MAP2K1; NFKB1; ITGB3; CDC42; CCND1; GSK3A; ITGA2; GSK3B; AKT3; FOXO1; CASP3; RPS6KB1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: p53 Signaling, PTEN; EP300; BBC3; PCAF; FASN; BRCA1; GADD45A; BIRC5; AKT2; PIK3CA; CHEK1; TP53INP1; BCL2; PIK3CB; PIK3C3; MAPK8; THBS1; ATR; BCL2L1; E2F1; PMAIP1; CHEK2; TNFRSF10B; TP73; RBI; HDAC9; CDK2; PIK3C2A; MAPK14; TP53; LRDD; CDKN1A; HIPK2; AKT1; RIK3R1; RRM2B; APAF1; CTNNB1; SIRT1; CCND1; PRKDC; ATM; SFN; CDKN2A; JUN; SNAI2; GSK3B; BAX; A
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Aryl Hydrocarbon Receptor Signaling, HSPB1; EP300; FASN; TGM2; RXRA; MAPK1; NQO1; NCOR2; SP1; ARNT; CDKN1B; FOS; CHEK1; SMARCA4; NFKB2; MAPK8; ALDH1A1; ATR; E2F1; MAPK3; NRIP1; CHEK2; RELA; TP73; GSTP1; RB1; SRC; CDK2; AHR; NFE2L2; NCOA3; TP53; TNF; CDKN1A; NCOA2; APAF1; NFKB1; CCND1; ATM; ESR1; CDKN2A; MYC; JUN; ESR2; BAX; IL6; CYP1B1; HSP90AA1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Xenobiotic Metabolism Signaling, PRKCE; EP300; PRKCZ; RXRA; MAPK1; NQO1; NCOR2; PIK3CA; ARNT; PRKCI; NFKB2; CAMK2A; PIK3CB; PPP2R1A; PIK3C3; MAPK8; PRKD1; ALDH1A1; MAPK3; NRIP1; KRAS; MAPK13; PRKCD; GSTP1; MAPK9; NOS2A; ABCB1; AHR; PPP2CA; FTL; NFE2L2; PIK3C2A; PPARGC1A; MAPK14; TNF; RAF1; CREBBP; MAP2K2; PIK3R1; PPP2R5C; MAP2K1; NFKB1; KEAP1; PRKCA; EIF2
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: SAPK/JNK Signaling, PRKCE; IRAK1; PRKAA2; EIF2AK2; RAC1; ELK1; GRK6; MAPK1; GADD45A; RAC2; PLK1; AKT2; PIK3CA; FADD; CDK8; PIK3CB; PIK3C3; MAPK8; RIPK1; GNB2L1; IRS1; MAPK3; MAPK10; DAXX; KRAS; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; PIK3C2A; TRAF2; TP53; LCK; MAP3K7; DYRK1A; MAP2K2; PIK3R1; MAP2K1; PAK3; CDC42; JUN; TTK; CSNK1A1; CRKL; BRAF; SG
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PPAr/RXR Signaling, PRKAA2; EP300; INS; SMAD2; TRAF6; PPARA; FASN; RXRA; MAPK1; SMAD3; GNAS; IKBKB; NCOR2; ABCA1; GNAQ; NFKB2; MAP3K14; STAT5B; MAPK8; IRS1; MAPK3; KRAS; RELA; PRKAA1; PPARGC1A; NCOA3; MAPK14; INSR; RAF1; IKBKG; RELB; MAP3K7; CREBBP; MAP2K2; JAK2; CHUK; MAP2K1; NFKB1; TGFBR1; SMAD4; JUN; IL1R1; PRKCA; IL6; HSP90AA1; ADIPOQ.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: NF-KB Signaling, IRAK1; EIF2AK2; EP300; INS; MYD8; PRKCZ: TRAF6; TBK1; AKT2; EGFR; IKBKB; PIK3CA; BTRC; NFKB2; MAP3K14; PIK3CB; PIK3C3; MAPK8; RIPK1; HDAC2; KRAS; RELA; PIK3C2A; TRAF2; TLR4: PDGFRB; TNF; INSR; LCK; IKBKG; RELB; MAP3K7; CREBBP; AKT1; PIK3R1; CHUK; PDGFRA; NFKB1; TLR2; BCL10; GSK3B; AKT3; TNFAIP3; IL1R1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neuregulin Signaling, ERBB4; PRKCE; ITGAM; ITGA5: PTEN; PRKCZ; ELK1; MAPK1; PTPN11; AKT2; EGFR; ERBB2; PRKCI; CDKN1B; STAT5B; PRKD1; MAPK3; ITGA1; KRAS; PRKCD; STAT5A; SRC; ITGB7; RAF1; ITGB1; MAP2K2; ADAM17; AKT1; PIK3R1; PDPK1; MAP2K1; ITGB3; EREG; FRAP1; PSEN1; ITGA2; MYC; NRG1; CRKL; AKT3; PRKCA; HSP90AA1; RPS6KB1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Wnt & Beta catenin Signaling, CD44; EP300; LRP6; DVL3; CSNK1E; GJA1; SMO; AKT2; PIN1; CDH1; BTRC; GNAQ; MARK2; PPP2R1A; WNT11; SRC; DKK1; PPP2CA; SOX6; SFRP2: ILK; LEF1; SOX9; TP53; MAP3K7; CREBBP; TCF7L2; AKT1; PPP2R5C; WNT5A; LRP5; CTNNB1; TGFBR1; CCND1; GSK3A; DVL1; APC; CDKN2A; MYC; CSNK1A1; GSK3B; AKT3; SOX2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Insulin Receptor Signaling, PTEN; INS; EIF4E; PTPN1; PRKCZ; MAPK1; TSC1; PTPN11; AKT2; CBL; PIK3CA; PRKCI; PIK3CB; PIK3C3; MAPK8; IRS1; MAPK3; TSC2; KRAS; EIF4EBP1; SLC2A4; PIK3C2A; PPP1CC; INSR; RAF1; FYN; MAP2K2; JAK1; AKT1; JAK2; PIK3R1; PDPK1; MAP2K1; GSK3A; FRAP1; CRKL; GSK3B; AKT3; FOXO1; SGK; RPS6KB1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-6 Signaling, HSPB1; TRAF6; MAPKAPK2; ELK1; MAPK1; PTPN11; IKBKB; FOS; NFKB2: MAP3K14; MAPK8; MAPK3; MAPK10; IL6ST; KRAS; MAPK13; IL6R; RELA; SOCS1; MAPK9; ABCB1; TRAF2; MAPK14; TNF; RAF1; IKBKG; RELB; MAP3K7; MAP2K2; IL8; JAK2; CHUK; STAT3; MAP2K1; NFKB1; CEBPB; JUN; IL1R1; SRF; IL6.
- IL-6 Signaling HSPB1; TRAF6; MAPKAPK2; ELK1; MAPK1; PTPN11; IKBKB; FOS; NFKB2: MAP3K
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Hepatic Cholestasis, PRKCE; IRAK1; INS; MYD8; PRKCZ; TRAF6; PPARA; RXRA; IKBKB; PRKCI; NFKB2; MAP3K14; MAPK8; PRKD1; MAPK10; RELA; PRKCD; MAPK9; ABCB1; TRAF2; TLR4; TNF; INSR; IKBKG; RELB; MAP3K7; IL8; CHUK; NR1H2; TJP2; NFKB1; ESR1; SREBF1; FGFR4; JUN; IL1R1; PRKCA; IL6.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IGF-1 Signaling, IGF1; PRKCZ; ELK1; MAPK1; PTPN11; NEDD4; AKT2; PIK3CA; PRKC1; PTK2; FOS; PIK3CB; PIK3C3; MAPK8; 1GF1R; IRS1; MAPK3; IGFBP7; KRAS; PIK3C2A; YWHAZ; PXN; RAF1; CASP9; MAP2K2; AKT1; PIK3R1; PDPK1; MAP2K1; IGFBP2; SFN; JUN; CYR61; AKT3; FOXO1; SRF; CTGF; RPS6KB1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: NRF2-mediated Oxidative Stress Response, PRKCE; EP300; SOD2; PRKCZ; MAPK1; SQSTM1; NQO1; PIK3CA; PRKC1; FOS; PIK3CB; P1K3C3; MAPK8; PRKD1; MAPK3; KRAS; PRKCD; GSTP1; MAPK9; FTL; NFE2L2; PIK3C2A; MAPK14; RAF1; MAP3K7; CREBBP; MAP2K2; AKT1; PIK3R1; MAP2K1; PPIB; JUN; KEAP1; GSK3B; ATF4; PRKCA; EIF2AK3; HSP90AA1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Hepatic, Fibrosis/Hepatic Stellate Cell Activation, EDN1; IGF1; KDR; FLT1; SMAD2; FGFR1; MET; PGF; SMAD3; EGFR; FAS; CSF1; NFKB2; BCL2; MYH9; IGF1R; IL6R; RELA; TLR4; PDGFRB; TNF; RELB; IL8; PDGFRA; NFKB1; TGFBR1; SMAD4; VEGFA; BAX; IL1R1; CCL2; HGF; MMP1; STAT1; IL6; CTGF; MMP9.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PPAR Signaling, EP300; INS; TRAF6; PPARA; RXRA; MAPK1; IKBKB; NCOR2; FOS; NFKB2; MAP3K14; STAT5B; MAPK3; NRIP1; KRAS; PPARG; RELA; STAT5A; TRAF2; PPARGC1A; PDGFRB; TNF; INSR; RAF1; IKBKG; RELB; MAP3K7; CREBBP; MAP2K2; CHUK; PDGFRA; MAP2K1; NFKB1; JUN; IL1R1; HSP90AA1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fc Epsilon RI Signaling, PRKCE; RAC1; PRKCZ; LYN; MAPK1; RAC2; PTPN11; AKT2; PIK3CA; SYK; PRKCI; PIK3CB; PIK3C3; MAPK8; PRKD1; MAPK3; MAPK10; KRAS; MAPK13; PRKCD; MAPK9; PIK3C2A; BTK; MAPK14; TNF; RAF1; FYN; MAP2K2; AKT1; PIK3R1; PDPK1; MAP2K1; AKT3; VAV3; PRKCA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: G-Protein Coupled Receptor Signaling, PRKCE; RAP1A; RGS16; MAPK1; GNAS; AKT2; IKBKB; PIK3CA; CREB1; GNAQ; NFKB2; CAMK2A; PIK3CB; PIK3C3; MAPK3; KRAS; RELA; SRC; PIK3C2A; RAF1; IKBKG; RELB; FYN; MAP2K2; AKT1; PIK3R1; CHUK; PDPK1; STAT3; MAP2K1; NFKB1; BRAF; ATF4; AKT3; PRKCA.
- PRKCE G-Protein Coupled Receptor Signaling
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inositol Phosphate Metabolism, PRKCE; IRAK1; PRKAA2; EIF2AK2; PTEN; GRK6; MAPK1; PLK1; AKT2; PIK3CA; CDK8; PIK3CB; PIK3C3; MAPK8; MAPK3; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; PIK3C2A; DYRK1A; MAP2K2; PIP5K1A; PIK3R1; MAP2K1; PAK3; ATM; TTK; CSNK1A1; BRAF; SGK.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PDGF Signaling, EIF2AK2; ELK1; ABL2; MAPK1; PIK3CA; FOS; PIK3CB;PIK3C3; MAPK8; CAV1; ABL1; MAPK3; KRAS; SRC; PIK3C2A; PDGFRB; RAF1; MAP2K2; JAK1; JAK2; PIK3R1; PDGFRA; STAT3; SPHK1; MAP2K1; MYC; JUN; CRKL; PRKCA; SRF; STAT1; SPHK2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: VEGF Signaling, ACTN4; ROCK1; KDR; FLT1; ROCK2; MAPK1; PGF; AKT2; PIK3CA; ARNT; PTK2; BCL2; PIK3CB; PIK3C3; BCL2L1; MAPK3; KRAS; HIF1A; NOS3; PIK3C2A; PXN; RAF1; MAP2K2; ELAVL1; AKT1; PIK3R1; MAP2K1; SFN; VEGFA; AKT3; FOXO1; PRKCA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Natural Killer Cell Signaling, PRKCE; RAC1; PRKCZ; MAPK1; RAC2; PTPN11; KIR2DL3; AKT2; PIK3CA; SYK; PRKCI; PIK3CB; PIK3C3; PRKD1; MAPK3; KRAS; PRKCD; PTPN6; PIK3C2A; LCK; RAF1; FYN; MAP2K2; PAK4; AKT1; PIK3R1; MAP2K1; PAK3; AKT3; VAV3; PRKCA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cell Cycle: G1/S Checkpoint Regulation, HDAC4; SMAD3; SUV39H1; HDAC5; CDKN1B; BTRC; ATR; ABL1; E2F1; HDAC2; HDAC7A; RB1; HDAC11; HDAC9; CDK2; E2F2; HDAC3; TP53; CDKN1A; CCND1; E2F4; ATM; RBL2; SMAD4; CDKN2A; MYC; NRG1; GSK3B; RBL1; HDAC 6 .
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: T Cell Receptor Signaling, RAC1; ELK1; MAPK1; IKBKB; CBL; PIK3CA; FOS; NFKB2; PIK3CB; PIK3C3; MAPK8; MAPK3; KRAS; RELA, PIK3C2A; BTK; LCK; RAF1; IKBKG; RELB, FYN; MAP2K2; PIK3R1; CHUK; MAP2K1; NFKB1; ITK; BCL10; JUN; VAV3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Death Receptor Signaling, CRADD; HSPB1; BID; BIRC4; TBK1; IKBKB; FADD; FAS; NFKB2; BCL2; MAP3K14; MAPK8; RIPK1; CASP8; DAXX; TNFRSF10B; RELA; TRAF2; TNF; IKBKG; RELB; CASP9; CHUK; APAF1; NFKB1; CASP2; BIRC2; CASP3; BIRC3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: FGF Signaling RAC1; FGFR1; MET; MAPKAPK2; MAPK1; PTPN11; AKT2; PIK3CA; CREB1; PIK3CB; PIK3C3; MAPK8; MAPK3; MAPK13; PTPN6; PIK3C2A; MAPK14; RAF1; AKT1; PIK3R1; STAT3; MAP2K1; FGFR4; CRKL; ATF4; AKT3; PRKCA; HGF.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: GM-CSF Signaling, LYN; ELK1; MAPK1; PTPN11; AKT2; PIK3CA; CAMK2A; STAT5B; PIK3CB; PIK3C3; GNB2L1; BCL2L1; MAPK3; ETS1; KRAS; RUNX1; PIM1; PIK3C2A; RAF1; MAP2K2; AKT1; JAK2; PIK3R1; STAT3; MAP2K1; CCND1; AKT3; STAT1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Amyotrophic Lateral Sclerosis Signaling, BID; IGF1; RAC1; BIRC4; PGF; CAPNS1; CAPN2; PIK3CA; BCL2; PIK3CB; PIK3C3; BCL2L1; CAPN1; PIK3C2A; TP53; CASP9; PIK3R1; RAB5A; CASP1; APAF1; VEGFA; BIRC2; BAX; AKT3; CASP3; BIRC3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: JAK/Stat Signaling, PTPN1; MAPK1; PTPN11; AKT2; PIK3CA; STAT5B; PIK3CB; PIK3C3; MAPK3; KRAS; SOCS1; STAT5A; PTPN6; PIK3C2A; RAF1; CDKN1A; MAP2K2; JAK1; AKT1; JAK2; PIK3R1; STAT3; MAP2K1; FRAP1; AKT3; STAT1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nicotinate and Nicotinamide Metabolism, PRKCE; IRAK1; PRKAA2; EIF2AK2; GRK6; MAPK1; PLK1; AKT2; CDK8; MAPK8; MAPK3; PRKCD; PRKAA1; PBEF1; MAPK9; CDK2; PIM1; DYRK1A; MAP2K2; MAP2K1; PAK3; NT5E; TTK; CSNK1A1; BRAF; SGK.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Chemokine Signaling, CXCR4; ROCK2; MAPK1; PTK2; FOS; CFL1; GNAQ; CAMK2A; CXCL 1 2; MAPK8; MAPK3; KRAS; MAPK13; RHOA; CCR3; SRC; PPP1CC; MAPK14; NOXI; RAF1; MAP2K2; MAP2K1; JUN; CCL2; PRKCA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-2 Signaling, ELK1; MAPK1; PTPN11; AKT2; PIK3CA; SYK; FOS; STAT5B; PIK3CB; PIK3C3; MAPK8; MAPK3; KRAS; SOCS1; STAT5A; PIK3C2A: LCK; RAF1; MAP2K2; JAK1; AKT1; PIK3R1; MAP2K1; JUN; AKT3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Synaptic Long Term Depression, PRKCE; IGF1; PRKCZ; PRDX6; LYN; MAPK1; GNAS; PRKC1; GNAQ; PPP2R1A; IGF1R; PRKID1; MAPK3; KRAS; GRN; PRKCD; NOS3; NOS2A; PPP2CA; YWHAZ; RAF1; MAP2K2; PPP2R5C; MAP2K1; PRKCA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Estrogen Receptor Signaling, TAF4B; EP300; CARM1; PCAF; MAPK1; NCOR2; SMARCA4; MAPK3; NRIP1; KRAS; SRC; NR3C1; HDAC3; PPARGC1A; RBM9; NCOA3; RAF1; CREBBP; MAP2K2; NCOA2; MAP2K1; PRKDC; ESR1; ESR2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Protein Ubiquitination Pathway, TRAF6; SMURF1; BIRC4; BRCA1; UCHL1; NEDD4; CBL; UBE2I; BTRC; HSPA5; USP7; USP10; FBXW7; USP9X; STUB1; USP 2 2; B2M; BIRC2; PARK2; USPS; USP1; VHL; HSP90AA1; BIRC3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-10 Signaling, TRAF6; CCR1; ELK1; IKBKB; SP1; FOS; NFKB2; MAP3K14; MAPK8; MAPK13; RELA; MAPK14; TNF; IKBKG; RELB; MAP3K7; JAK1; CHUK; STAT3; NFKB1; JUN; IL1R1; IL6.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: VDR/RXR Activation, PRKCE; EP300; PRKCZ; RXRA; GADD 4 5A; HEST; NCOR2; SP1; PRKC1; CDKN1B; PRKD1; PRKCD; RUNX2; KLF4; YY1; NCOA3; CDKN1A; NCOA2; SPP1; LRP5; CEBPB; FOXO1; PRKCA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: TGF-beta Signaling, EP300; SMAD2; SMURF1; MAPK1; SMAD3; SMAD1; FOS; MAPK8; MAPK3; KRAS; MAPK9; RUNX2; SERPINE1; RAF1; MAP3K7; CREBBP; MAP2K2; MAP2K1; TGFBR1; SMAD4; JUN; SMAD5.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Toll-like Receptor Signaling, IRAK1; EIF2AK2; MYD8; TRAF6; PPARA; ELK1; IKBKB; FOS; NFKB2; MAP3K14; MAPK8; MAPK13; RELA; TLR4; MAPK14; IKBKG; RELB; MAP3K7; CHUK; NFKB1; TLR2; JUN.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: p38 MAPK Signaling, HSPB1; IRAK1; TRAF6; MAPKAPK2; ELK1; FADD; FAS; CREB1; DDIT3; RPS6KA4; DAXX; MAPK13; TRAF2; MAPK14; TNF; MAP3K7; TGFBR1; MYC; ATF4; IL1R1; SRF; STAT 1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neurotrophin/TRK Signaling, NTRK2; MAPK1; PTPN11; PIK3CA; CREB1; FOS; PIK3CB; PIK3C3; MAPK8; MAPK3; KRAS; PIK3C2A; RAF1; MAP2K2; AKT1; PIK3R1; PDPK1; MAP2K1; CDC42; JUN; ATF4.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: FXR/RXR Activation, INS; PPARA; FASN; RXRA; AKT2; SDC1; MAPK8; APOB; MAPK10; PPARG; MTTP; MAPK9; PPARGC1A; TNF; CREBBP; AKT1; SREBF1; FGFR4; AKT3; FOXO1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Synaptic Long Term Potentiation, PRKCE; RAP1A; EP300; PRKCZ; MAPK1; CREB1; PRKC1; GNAQ; CAMK2A; PRKD1; MAPK3; KRAS; PRKCD; PPP1CC; RAF1; CREBBP; MAP2K2; MAP2K1; ATF4; PRKCA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Calcium Signaling, RAP1A; EP300; HDAC4; MAPK1; HDAC5; CREB1; CAMK2A; MYH9; MAPK3; HDAC2; HDAC7A; HDAC11; HDAC9; HDAC3; CREBBP; CALR; CAMKK2; ATF4; HDAC6.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: EGF Signaling, ELK1; MAPK1; EGFR; PIK3CA; FOS; PIK3CB; PIK3C3; MAPK8; MAPK3; PIK3C2A; RAF1; JAK1; PIK3R1; STAT3; MAP2K1; JUN; PRKCA; SRF; STAT1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Hypoxia Signaling in the Cardiovascular System, EDN1; PTEN; EP300; NQO1; UBE 2 1; CREB1; ARNT; HIF1A; SLC2A4; NOS3; TP53; LDHA; AKT1; ATM; VEGFA; JUN; ATF4; VHL; HSP90AA1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: LPS/IL-1 Mediated Inhibition of RXR Function, IRAK1; MYD88; TRAF6; PPARA; RXRA; ABCA1, MAPK8; ALDH1A1; GSTP1; MAPK9; ABCB1; TRAF2; TLR4; TNF; MAP3K7; NR1H2; SREBF1; JUN; IL1R1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: LXR/RXR Activation, FASN; RXRA; NCOR2; ABCA1; NFKB2; IRF3; RELA; NOS2A; TLR4; TNF; RELB; LDLR; NR1H2; NFKB1; SREBF1; IL1R1; CCL2; IL6; MMP9.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Amyloid Processing, PRKCE; CSNK11E; MAPK1; CAPNS1; AKT2; CAPN2; CAPN1; MAPK3; MAPK13; MAPT; MAPK14; AKT1; PSEN1; CSNK1A1; GSK3B; AKT3; APP.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-4 Signaling, AKT2; PIK3CA; PIK3CB; PIK3C3; IRS1; KRAS; SOCS1; PTPN6; NR3C1; PIK3C2A; JAK1; AKT1; JAK2; PIK3R1; FRAP1; AKT3; RPS6KB1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cell Cycle: G2/M DNA Damage Checkpoint Regulation, EP300; PCAF; BRCA1; GADD45A; PLK1; BTRC; CHEK1; ATR; CHEK2; YWHAZ; TP53; CDKN1A; PRKDC; ATM; SFN; CDKN2A.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nitric Oxide Signaling in the Cardiovascular System, KDR; FLT1; PGF; AKT2; PIK3CA; PIK3CB; PIK3C3; CAV1; PRKCD; NOS3; PIK3C2A; AKT1; PIK3R1; VEGFA; AKT3; HSP90AA1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Purine Metabolism NME2; SMARCA4; MYH9; RRM2; ADAR; EIF2AK4; PKM2; ENTPD1; RAD51; RRM2B; TJP2; RAD51C; NT5E; POLD1; NME1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: cAMP-mediated Signaling, RAP1A; MAPK1; GNAS; CREB1; CAMK2A; MAPK3; SRC; RAF1; MAP2K2; STAT3; MAP2K1; BRAF; ATF4.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Mitochondrial Dysfunction Notch Signaling, SOD2; MAPK8; CASP8; MAPK10; MAPK9; CASP9; PARK7; PSEN1; PARK2; APP; CASP3 HES1; JAG1; NUMB; NOTCH4; ADAM17; NOTCH2; PSEN1; NOTCH3; NOTCH1; DLL4.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Endoplasmic Reticulum Stress Pathway, HSPA5; MAPK8; XBP1; TRAF2; ATF6; CASP9; ATF4; EIF2AK3; CASP3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pyrimidine Metabolism, NME2; AICDA; RRM2; EIF2AK4; ENTPD1; RRM2B; NT5E; POLD1; NME1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Parkinson's Signaling, UCHL1; MAPK8; MAPK13; MAPK14; CASP9; PARK7; PARK2; CASP3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cardiac & Beta Adrenergic Signaling, GNAS; GNAQ; PPP2R1A; GNB2L1; PPP2CA; PPP1CC; PPP2R5C.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycolysis/Gluco-neogenesis, HK2; GCK; GPI; ALDH1A1; PKM2; LDHA; HK1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Interferon Signaling, IRF1; SOCS1; JAK1; JAK2; IFITM1; STAT1; IFIT3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Sonic Hedgehog Signaling, ARRB2; SMO; GLI2; DYRK1A; GLI1; GSK3B; DYRKIB.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycerophospholipid Metabolism, PLD1; GRN; GPAM; YWHAZ; SPHK1; SPHK2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Phospholipid Degradation, PRDX6; PLD1; GRN; YWHAZ; SPHK1; SPHK2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Tryptophan Metabolism, SIAH2; PRMT5; NEDD4; ALDH1A1; CYP1B1; SIAH1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Lysine Degradation, SUV39H1; EHMT2; NSD1; SETD7; PPP2R5C.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nucleotide Excision, ERCC5; ERCC4; XPA; XPC; ERCC1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Repair Pathway Starch and Sucrose Metabolism, UCHL1; HK2; GCK; GPI; HK1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Aminosugars Metabolism, NQO1; HK2; GCK; HK1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Arachidonic Acid Metabolism, PRDX6; GRN; YWHAZ; CYP1B1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Circadian Rhythm Signaling, CSNK1E; CREB1; ATF4; NR1D1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Coagulation System, BDKRB1; F2R; SERPINE1; F3.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Dopamine Receptor Signaling, PPP2R1A; PPP2CA; PPP1CC; PPP2R5C.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glutathione Metabolism, IDH2; GSTP1; ANPEP; IDH1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycerolipid Metabolism, ALDH1A1; GPAM; SPHK1; SPHK2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Linoleic Acid Metabolism, PRDX6; GRN; YWHAZ; CYP1B1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Methionine Metabolism, DNMT1; DNMT3B; AHCY; DNMT3A.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pyruvate Metabolism, GLO1; ALDH1A1; PKM2; LDHA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Arginine and Proline Metabolism, ALDH1A1; NOS3; NOS2A.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Eicosanoid Signaling, PRDX6; GRN; YWHAZ.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fructose and Mannose Metabolism, HK2; GCK; HK1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Galactose Metabolism, HK2; GCK; HK1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Stilbene, Coumarine and Lignin Biosynthesis, PRDX6; PRDX1; TYR.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Antigen Presentation Pathway, CALR; B2M.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Biosynthesis of Steroids, NQO1; DHCR7.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Butanoate Metabolism, ALDH1A1; NLGN1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Citrate Cycle, IDH2; IDH1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fatty Acid Metabolism, ALDH1A1; CYP1B1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycerophospholipid Metabolism, PRDX6; CHKA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Histidine Metabolism, PRMT5; ALDH1A1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inositol Metabolism, ERO1L; APEX1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Metabolism of Xenobiotics by Cytochrome p450, GSTP1; CYP1B1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Methane Metabolism, PRDX6; PRDX1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Phenylalanine Metabolism, PRDX6; PRDX1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Propanoate Metabolism, ALDH1A1; LDHA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Selenoamino Acid Metabolism, PRMT5; AHCY.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Sphingolipid Metabolism, SPHK1; SPHK2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Aminophosphonate Metabolism, PRMT5.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Androgen and Estrogen Metabolism, PRMT5.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Ascorbate and Aldarate Metabolism, ALDH1A1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Bile Acid Biosynthesis, ALDH1A1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cysteine Metabolism, LDHA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fatty Acid Biosynthesis, FASN.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glutamate Receptor Signaling, GNB2L1.
- genes and/or polynucleotides that can be edited with the guide molecules of this invention include: NRF2-mediated Oxidative Stress Response, PRDX1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pentose Phosphate Pathway, GPI.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pentose and Glucuronate Interconversions, UCHL1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Retinol Metabolism, ALDH1A1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Riboflavin Metabolism, TYR.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Tyrosine Metabolism, PRMT5, TYR.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Ubiquinone Biosynthesis, PRMT5.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Valine, Leucine and Isoleucine Degradation, ALDH1A1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycine, Serine and Threonine Metabolism, CHKA.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Lysine Degradation, ALDH1A1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pain/Taste, TRPM5; TRPA1.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pain, TRPM7; TRPC5; TRPC6; TRPC1; Cnr1; cnr2; Grk2; Trpa1; Pomc; Cgrp; Crf; Pka; Era; Nr2b; TRPM5; Prkaca; Prkacb; Prkar1a; Prkar2a.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Mitochondrial Function, AIF; CytC; SMAC (Diablo); Aifm-1; Aifm-2.
- genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Developmental Neurology, BMP-4; Chordin (Chrd); Noggin (Nog); WNT (Wnt2; Wnt2b; Wnt3a; Wnt4; Wnt5a; Wnt6; Wnt7b; Wnt8b; Wnt9a; Wnt9b; Wnt10a; Wnt10b; Wnt16); beta-catenin; Dick-1; Frizzled related proteins; Otx-2; Gbx2; FGF-8; Reelin; Dab1; unc-86 (Pou4f1 or Brn3a); Numb; Reln.
- this invention provides methods for synthesis of mUNA messenger UNA oligomer molecules.
- mUNA oligomer molecules of this invention can be synthesized and isolated using methods disclosed herein, as well as any pertinent techniques known in the art.
- nucleic acids Some methods for preparing nucleic acids are given in, for example, Merino, Chemical Synthesis of Nucleoside Analogues, (2013); Gait, Oligonucleotide synthesis: a practical approach (1984); Herdewijn, Oligonucleotide Synthesis, Methods in Molecular Biology, Vol. 288 (2005).
- a ligase can be used to link a synthetic oligomer to the 3′ end of an RNA molecule or an RNA transcript to form a mUNA molecule.
- the synthetic oligomer that is ligated to the 3′ end can provide the functionality of a polyA tail, and advantageously provide resistance to its removal by 3′-exoribonucleases.
- the ligated product mUNA molecule can have increased specific activity and provide increased levels of ectopic protein expression.
- ligated product mUNA molecules of this invention can be made with an RNA transcript that has native specificity.
- the ligated product can be a synthetic molecule that retains the structure of the RNA transcript at the 5′ end to ensure compatibility with the native specificity.
- ligated product mUNA molecules of this invention can be made with an exogenous RNA transcript or non-natural RNA.
- the ligated product can be a synthetic molecule that retains the structure of the RNA.
- the canonical mRNA degradation pathway in cells includes the steps: (i) the polyA tail is gradually cut back to a stub by 3′ exonucleases, shutting down the looping interaction required for efficient translation and leaving the cap open to attack; (ii) decapping complexes remove the 5′ cap; (iii) the unprotected and translationally incompetent residuum of the transcript is degraded by 5′ and 3′ exonuclease activity.
- Embodiments of this invention involve new mUNA structures which can have increased translational activity over a native transcript.
- the mUNA molecules can prevent exonucleases from trimming back the polyA tail in the process of de-adenylation.
- Embodiments of this invention provide structures, compositions and methods for translatable mUNA molecules.
- Embodiments of this invention can provide translatable mUNA molecules containing one or more UNA monomers and having increased functional half-life.
- ligation of a synthetic oligomer to the 3′ end of an mRNA transcript can surprisingly be accomplished with high conversion of the mRNA transcript to the ligation product.
- the ligase can catalyze the joining of the 3′-hydroxyl terminus of the RNA transcript to a synthetic oligomer bearing a 5′ monophosphate group.
- the 3′ end of the synthetic oligomer can be blocked to prevent circularization and concatemerization, while the presence of a triphosphate or cap moiety at the 5′ terminus of the mRNA transcript can prevent its entry into undesired side reactions.
- the yield of conversion of the mRNA transcript to the ligation product mUNA molecule can be from 70% to 100%. In some embodiments, the yield of conversion of the mRNA transcript to the ligation product can be 70%, 80%, 90%, 95%, 99%, or 100%.
- polyA tail and polyA oligomer refer to an oligomer of monomers, wherein the monomers can include nucleotides based on adenine, UNA monomers, naturally-occurring nucelotides, modified nucleotides, or nucleotide analogues.
- a modified nucleotide can be base-modified, sugar-modified, or linkage modified.
- Embodiments of this invention can employ splint ligation to synthesize mUNA molecules.
- ligation of a tail oligomer to the 3′ end of an RNA molecule can surprisingly be accomplished with high conversion of the RNA molecule to the ligation product by using a DNA splint oligomer.
- Splint ligation of specific RNA molecules can be done with a DNA ligase and a bridging DNA splint oligomer that is complementary to the RNAs.
- a molecule to which a tail oligomer is added can be referred to as an acceptor oligomer, and a tail oligomer to be ligated to an acceptor oligomer can be referred to as a donor oligomer.
- a donor oligomer of this invention may contain one or more UNA monomers.
- a donor oligomer may be composed of UNA monomers and adenylate nucleotides.
- a donor oligomer of this invention may include any number of UNA monomers within its total length.
- An acceptor oligomer of this invention can be a RNA of any length, an mRNA, or a mammalian gene transcript.
- ligation of a donor oligomer of any length to the 3′ end of an acceptor RNA molecule can surprisingly be accomplished with high conversion to the ligation product mUNA molecule by using a DNA splint oligomer.
- a DNA splint oligomer can hybridize to the end of an mRNA having a short polyA tail, anchored in a specific position based on a region complementary to the end of the mRNA's 3′ UTR.
- the polyA tail can be about 30 monomers or less in length.
- the DNA splint oligomer can incorporate a poly(dT) tail that overhangs beyond the native polyA tail of the mRNA transcript. The poly(dT) tail can bring a polyA oligomer into position for efficient ligation to the synthetic mRNA.
- Embodiments of this invention can employ splint ligation to introduce UNA monomers, modified nucleotides, or nucleotide analogues into RNA molecules.
- the DNA ligase in splint ligation can be used to join RNA molecules in an RNA:DNA hybrid.
- the donor can be from 2 to 120 monomers in length, or from 3 to 120 monomers, or from 4 to 120 monomers, or from 5 to 120 monomers, or from 6 to 120 monomers, or longer.
- the splint oligomer can be removed from the ligation product using a DNAse treatment, which can be required post-IVT to remove the DNA template for transcription.
- a wild-type T4 RNA ligase can be used to join the 3′ hydroxyl terminus of an RNA transcript to a tail oligomer bearing a 5′ monophosphate group.
- a KQ mutant variant of T4 RNA Ligase 2 which requires a pre-adenylated donor, was used to join the 3′ hydroxyl terminus of an RNA transcript to a pre-adenylated tail oligomer.
- a preponderance of the tail can advantageously be incorporated co-transcriptionally in the IVT synthetic RNA transcript, and the donor oligomer can be correspondingly shortened.
- a 3′-exonuclease treatment can be used to remove the unligated fraction of the product of the ligation reaction.
- a 3′-exonuclease include Exonuclease T, Ribonuclease R, and analogs thereof.
- Ribonuclease R can be used with high processivity, and the ligation can be insensitive to sequence content and variations, as well as secondary structure.
- the 100% bulk ligation of a tail oligomer to the 3′ end of an RNA has been achieved.
- Donor oligomers of this invention for ligation to the 3′ end of an mRNA may be from 2 to 120 monomers in length, or from 3 to 120 monomers in length, or from 4 to 120 monomers in length, or from 5 to 120 monomers in length, or longer.
- a donor oligomer may have a 3′-terminal modification to block circularization or oligimerization of the synthetic oligomer in ligation reactions.
- a 3′-terminal modification include a 3′-terminal C3 spacer.
- a donor oligomer of this invention may contain one or more UNA monomers.
- a donor oligomer can include one or more nucleic acid monomers that are naturally-occurring nucleotides, modified naturally-occurring nucleotides, or non-naturally-occurring nucleotides.
- a donor oligomer can include a nucleic acid monomer that is base-modified, sugar-modified, or linkage modified.
- this invention provides pharmaceutical compositions containing a mUNA oligomeric compound and a pharmaceutically acceptable carrier.
- a pharmaceutical composition can be capable of local or systemic administration.
- a pharmaceutical composition can be capable of any modality of administration.
- the administration can be intravenous, subcutaneous, pulmonary, intramuscular, intraperitoneal, dermal, oral, or nasal administration.
- Embodiments of this invention include pharmaceutical compositions containing an oligomeric compound in a lipid formulation.
- a pharmaceutical composition may comprise one or more lipids selected from cationic lipids, anionic lipids, sterols, pegylated lipids, and any combination of the foregoing.
- a pharmaceutical composition can be substantially free of liposomes.
- a pharmaceutical composition can include liposomes or nanoparticles.
- lipids and lipid compositions for delivery of an active molecule of this invention are given in WO/2015/074085, which is hereby incorporated by reference in its entirety.
- a pharmaceutical composition can contain an oligomeric compound within a viral or bacterial vector.
- a pharmaceutical composition of this disclosure may include carriers, diluents or excipients as are known in the art. Examples of pharmaceutical compositions and methods are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro ed. 1985), and Remington, The Science and Practice of Pharmacy, 21st Edition (2005).
- excipients for a pharmaceutical composition include antioxidants, suspending agents, dispersing agents, preservatives, buffering agents, tonicity agents, and surfactants.
- An effective dose of an agent or pharmaceutical formulation of this invention can be an amount that is sufficient to cause translation of a mUNA molecule in a cell.
- a therapeutically effective dose can be an amount of an agent or formulation that is sufficient to cause a therapeutic effect.
- a therapeutically effective dose can be administered in one or more separate administrations, and by different routes.
- a therapeutically effective dose, upon administration, can result in serum levels of an active agent of 1-1000 pg/ml, or 1-1000 ng/ml, or 1-1000 ⁇ g/ml, or more.
- a therapeutically effective dose of an active agent in vivo can be a dose of 0.001-0.01 mg/kg body weight, or 0.01-0.1 mg/kg, or 0.1-1 mg/kg, or 1-10 mg/kg, or 10-100 mg/kg.
- a therapeutically effective dose of an active agent in vivo can be a dose of 0.001 mg/kg body weight, or 0.01 mg/kg, or 0.1 mg/kg, or 1 mg/kg, or 2 mg/kg, or 3 mg/kg, or 4 mg/kg, or 5 mg/kg, or more.
- a subject can be an animal, or a human subject or patient.
- the comparative mUNA and mRNA molecules in the examples below were synthesized with the 5′ cap being a m7GpppGm cap. Unless otherwise specified, the mUNA molecules in the examples below contained a 5′-UTR of TEV, and a 3′ UTR of xenopus beta-globin.
- a translatable mUNA molecule was made and used for expressing human Factor IX (FT9) in vivo with advantageously increased efficiency of translation, as compared to the mRNA of Factor IX.
- the translatable mUNA molecule expressing human Factor IX in vivo exhibited activity suitable for use in methods for ameliorating or treating hemophilia B.
- the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a F9 CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- the translation efficiency of this mUNA molecule is shown in FIG. 1 , as compared to the mRNA of F9.
- the mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human F9.
- FIG. 1 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of F9. In particular, after 55 hours, the translation efficiency of this mUNA molecule was increased by more than 2-fold (827/388) as compared to the mRNA of F9.
- the translatable mUNA molecule of Example 1 (SEQ ID NO: 1) was made and used for expressing human Factor IX (F9) in vitro with advantageously increased efficiency of translation, as compared to the mRNA of Factor IX.
- the translatable mUNA molecule expressing human Factor IX exhibited activity suitable for use in methods for ameliorating or treating hemophilia B.
- the mUNA molecule of this embodiment was traslated in mouse hepatocyte cell line Hepa1-6 to produce human F9.
- FIG. 2 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of F9. In particular, after 48 hours, the translation efficiency of this mUNA molecule was increased by 5-fold (91/16) as compared to the mRNA of F9.
- a translatable mUNA molecule was made and used for expressing human Erythropoietin (EPO) in vitro with advantageously increased efficiency of translation, as compared to the mRNA of EPO.
- the translatable mUNA molecule expressing human EPO exhibited activity suitable for use in methods for ameliorating or treating certain anemias, inflammatory bowel disease, and/or certain myelodysplasias.
- the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a human EPO CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- the translation efficiency of this mUNA molecule is shown in FIG. 3 , as compared to the mRNA of EPO.
- the mUNA molecule of this embodiment was translated in mouse hepatocyte cell line Hepa1-6 to produce human EPO.
- FIG. 3 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of F9. In particular, after 48 hours, the translation efficiency of this mUNA molecule was more than doubled (4500/1784) as compared to the mRNA of EPO.
- translatable mUNA molecules were made and used for expressing mouse Erythropoietin (EPO) in vitro with advantageously increased efficiency of translation, as compared to the mRNA of EPO.
- the translatable mUNA molecules each comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a mouse EPO CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- the mUNA molecules of this embodiment were translated in mouse hepatocyte cell line Hepa1-6 to produce mouse EPO.
- FIG. 4 shows that the translation efficiency of the mUNA molecules (#2, 3, 4, 5, 6, 7, 8, 9, 10 and 11) was advantageously and surprisingly increased as compared to the mRNA of EPO (#1).
- the translation efficiency of the mUNA molecules was increased by up to 8-fold (0.203/0.025) as compared to the mRNA of EPO, and the translation efficiency of every mUNA molecule (#2, 3, 4, 5, 6, 7, 8, 9, 10 and 11) was increased as compared to the mRNA of EPO (#1).
- a translatable mUNA molecule was made and used for expressing human alpha-1-Antitrypsin in vivo with advantageously increased efficiency of translation, as compared to the mRNA of human alpha-1-Antitrypsin.
- the translatable mUNA molecule expressing human alpha-1-Antitrypsin exhibited activity suitable for use in methods for ameliorating or treating alpha-1-Antitrypsin deficiency.
- the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a human alpha-1-Antitrypsin CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- the translation efficiency of this mUNA molecule is shown in FIG. 5 , as compared to the mRNA of human alpha-1-Antitrypsin.
- the mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human alpha-1-Antitrypsin.
- FIG. 5 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of human alpha-1-Antitrypsin. In particular, after 72 hours, the translation efficiency of this mUNA molecule was increased by more than 3-fold (87.8/25.4) as compared to the mRNA of human alpha-1-Antitrypsin.
- a translatable mUNA molecule was made and used for expressing human Erythropoietin (EPO) in vivo with advantageously increased efficiency of translation, as compared to the mRNA of EPO.
- the translatable mUNA molecule expressing human EPO exhibited activity suitable for use in methods for ameliorating or treating certain anemias, inflammatory bowel disease, and/or certain myelodysplasias.
- the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a human EPO CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- the translation efficiency of this mUNA molecule is shown in FIG. 6 , as compared to the mRNA of EPO.
- the mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human EPO.
- FIG. 6 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of EPO. In particular, after 72 hours, the translation efficiency of this mUNA molecule was increased by more than 10-fold (1517/143) as compared to the mRNA of EPO.
- a translatable mUNA molecule is made for use in expressing human CFTR in vivo.
- the translatable mUNA molecule expressing human CFTR in vivo is suitable for use in methods for ameliorating or treating cystic fibrosis.
- the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a CFTR CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human CFTR is accession NM_000492.3.
- a translatable mUNA molecule is made for use in expressing human argininosuccinate lyase (ASL) in vivo.
- the translatable mUNA molecule expressing human ASL in vivo is suitable for use in methods for ameliorating or treating ASL deficiency.
- the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a ASL CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human ASL is accession NM_001024943.1.
- a translatable mUNA molecule is made for use in expressing human Phenylalanine-4-hydroxylase (PAH) in vivo.
- the translatable mUNA molecule expressing human PAH in vivo is suitable for use in methods for ameliorating or treating Phenylketonuria (PKU).
- the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a PAH CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human PAH is accession NM_000277.1.
- a translatable mUNA molecule is made for use in expressing human Sodium/iodide cotransporter (NIS) in vivo.
- the translatable mUNA molecule expressing human NIS in vivo is suitable for use in methods for ameliorating or treating thyroid disease.
- the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a NIS CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human NIS is accession BC105047.
- a translatable mUNA molecule is made for use in expressing human Sodium/iodide cotransporter (NIS) in vivo.
- the translatable mUNA molecule expressing human NIS in vivo is suitable for use in methods for ameliorating or treating thyroid disease.
- the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a NIS CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human NIS is accession BC105047.
- a translatable mUNA molecule is made for use in expressing human Hepcidin in vivo.
- the translatable mUNA molecule expressing human Hepcidin in vivo is suitable for use in methods for ameliorating or treating iron deficiency disease.
- the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a Hepcidin CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human Hepcidin is accession NM_021175.3.
- Factor IX (F9) is associated with hemophilia B.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Factor IX.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Factor IX.
- Human Factor IX is accession NM_000133.3.
- SEQ ID NO: 15 AU ⁇ circumflex over ( G ) ⁇ CAGCGCGUGAACAUGAUCAUGGCAGAAUC ⁇ tilde over ( A ) ⁇ CCAGGCCUCAUCACCA UCUGCCUUUUAGG ⁇ tilde over ( A ) ⁇ UAUCUACUCAGUGCUGAAUGUACAGUUUU ⁇ tilde over ( U ) ⁇ CUUGA UCAUGAAAACGCCAACAAAAUUCU ⁇ circumflex over ( G ) ⁇ AAUCGGCCAAAGAGGUAUAAUUCA GGUAA ⁇ tilde over ( A ) ⁇ UUGGAAGAGUUUGUUCAAGGGAACCUUGA ⁇ circumflex over ( G ) ⁇ AGAGAAUGUAUGG AAGAAAAGUGUAGUUU ⁇ tilde over ( U ) ⁇ GAAGAAGCACGAGAAGUUUUGAAAACAC ⁇ tilde over ( U ) ⁇ GA AAGAACAACUGAAUUU
- Alpha-1-Antitrypsin is associated with alpha-1-Antitrypsin deficiency disease, cystic fibrosis, interstitial lung disease, and pulmonary arterial hypertension.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of alpha-1-Antitrypsin.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of alpha-1-Antitrypsin.
- Alpha-1-Antitrypsin is associated with alpha-1-Antitrypsin deficiency disease, cystic fibrosis, interstitial lung disease, and pulmonary arterial hypertension.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 5′-UTR of the native mRNA of alpha-1-Antitrypsin.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm) upstream of the sequence below, and coding region (CDS) for human alpha-1-Antitrypsin, a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of alpha-1-Antitrypsin.
- Erythropoietin is available as a commercial drug and is indicated for anemia resulting from chronic kidney disease, inflammatory bowel disease including Crohn's disease and ulcer colitis, and myelodysplasia from the treatment of cancer with chemotherapy or radiation.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Erythropoietin.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Erythropoietin.
- Ornithine transcarbamylase is associated with Ornithine transcarbamylase deficiency.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Ornithine transcarbamylase.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Ornithine transcarbamylase.
- Beta-globin may be associated with sickle-cell disease, beta thalassemia, and genetic resistance to malaria.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 3′-UTR of the native mRNA of human beta-globin.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), 5′-UTR, and coding region (CDS) for human beta-globin upstream of the sequence below, and a polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human beta-globin.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 3′-UTR of Xenopus beta-globin.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), 5′-UTR, and coding region (CDS) upstream of the sequence below, and a polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of a native human mRNA.
- CDS coding region
- Xenopus beta-globin is accession NM_001096347.1.
- SEQ ID NO: 142 C ⁇ tilde over ( U ) ⁇ AGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACC CGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUU GUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUU CUUCAC ⁇ tilde over ( A ) ⁇ U
- SEQ ID NO: 143 C ⁇ tilde over ( U ) ⁇ tilde over ( A ) ⁇ circumflex over ( G ) ⁇ UGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACC CGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUU GUCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUU CUUC ⁇ tilde over ( A
- Thrombopoietin is associated with liver and kidney disease.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Thrombopoietin.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Thrombopoietin.
- mUNA molecules for use in expressing human amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) are shown.
- AGL is associated with glycogen storage disease.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human AGL.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human AGL.
- Human protein S (alpha) is associated with Protein S deficiency, thrombosis, and arterial occlusive disease.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human protein S (alpha).
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human protein S (alpha).
- Human protein S is accession NM_001314077.1.
- SEQ ID NO: 152 A ⁇ tilde over ( U ) ⁇ circumflex over ( G ) ⁇ tilde over ( A ) ⁇ GGGUCCUGGGUGGGCGCUGCGGGGCGCUGCUGGCGUGUCUCCUC CUAGUGCUUCCCGUCUCAGAGGCAAACUUUUGUUUAUAUUUUAGAAAUG AUUUUAUAUACAACCGUGCAUGCAUUUCUGUAUUGGUCGGCUUAUCUGG AUGCAAUCUUUUUCUAUUCUAUAUGCUUUUUGAAAGCAACAGGCUUCA CAAGUCCUGGUUAGGAAGCGUCGUGCAAAUUCUUUACUUGAAGAAACCA AACAGGGUAAUCUUGAAAGAGAAUGCAUCGAAGAACUGUGCAAUAAAGA AGAAGCCAGGGAGGUCUUUGAAAAUGACCCGGAAACGGAUUAUUUUUAU CCAAAAUACUUAGUUUGUGUUGU
- PKLR Human Pyruvate Kinase, Liver and RBC
- PKLR liver and RBC
- PKLR Human pyruvate kinase, liver and RBC
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human pyruvate kinase, liver and RBC (PKLR).
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human pyruvate kinase, liver and RBC (PKLR).
- Human phenylalanine hydroxylase is associated with phenylketonuria.
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human phenylalanine hydroxylase.
- the complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID NOs: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human phenylalanine hydroxylase.
- Human phenylalanine hydroxylase is accession NM_000277.1.
- SEQ ID NO: 156 A ⁇ tilde over ( U ) ⁇ circumflex over ( G ) ⁇ tilde over ( U ) ⁇ CCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAGGAAACUCUCUCUGACUUUGGACA GGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGGUGCCAUAUCACUGAUCUUCU CACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGCGCUUAUUUGAGGAGAAUGAU GUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAAAGAAAGAUGAGUAUGAAUU UUUCACCCAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAAACAUCAUCAAGAUCUUGA GGCAUGACAUUGGUGCCACUGUCCUGACAAACAUCAUCAAGAUCUUGA GGCAUGACAUUGGUGCCACUGUCCUGACAAACA
- the 5′-UTR of tobacco etch virus is as follows:
- the base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 5′-UTR of tobacco etch virus (TEV).
- the complete mUNA molecule comprises a 5′ cap upstream of the sequence below (m7GpppGm), and a coding region (CDS) of a protein of interest, a 3′-UTR, and a polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of any native human mRNA.
- the translation enhancer is placed upstream of the AUG translation start site, and the enhancer region is not translated into the therapeutic protein.
- nGFP transcript having a polyA tail of 30 monomers in length is ligated to a donor poly ⁇ tail of 30 UNA Monomers in length to give an UNA-nGFP mRNA product having a polyA 30 ⁇ 30 tail of 60 monomers in length.
- the UNA-nGFP has an increased lifetime and markedly increased translational activity in fibroblasts.
- An mRNA encoding HIV-1 gag antigen having a polyA tail of 30 monomers in length is ligated to a donor poly ⁇ tail of 20 UNA Monomers in length to give an UNA-HIV-1 gag antigen mRNA product having a polyA 30 ⁇ 20 tail of 50 monomers in length.
- the UNA-HIV-1 gag antigen mRNA has an increased lifetime and markedly increased translational activity in fibroblasts.
- An mRNA encoding antigens overexpressed in lung cancers having a polyA tail of 30 monomers in length is ligated to a donor poly ⁇ tail of 10 UNA Monomers in length to give an UNA-mRNA product having a polyA 30 ⁇ 10 tail of 40 monomers in length.
- the UNA-mRNA has an increased lifetime and markedly increased translational activity in fibroblasts.
- An mRNA encoding malarial P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) having a polyA tail of 30 monomers in length is ligated to a donor poly ⁇ tail of 10 UNA Monomers in length to give an UNA-mRNA product having a polyA 30 ⁇ 10 tail of 40 monomers in length.
- the UNA-mRNA has an increased lifetime and markedly increased translational activity in fibroblasts.
- the UNA-mRNA is found to induce an antibody response in an animal model.
- An mRNA encoding malarial Plasmodium falciparum PfSEA-1, a 244 KD malaria antigen expressed in schizont-infected RBCs, having a polyA tail of 30 monomers in length is ligated to a donor poly ⁇ tail of 10 UNA Monomers in length to give an UNA-mRNA product having a polyA 30 ⁇ 10 tail of 40 monomers in length.
- the UNA-mRNA has an increased lifetime and markedly increased translational activity in fibroblasts.
- the UNA-mRNA is found to induce an antibody response in an animal model.
- FIG. 7 shows the primary structure of a functional mRNA transcript in the cytoplasm.
- the mRNA includes a 5′ methylguanosine cap, a protein coding sequence flanked by untranslated regions (UTRs), and a polyadenosine (polyA) tail bound by polyA binding proteins (PABPs).
- UTRs untranslated regions
- PABPs polyadenosine binding proteins
- FIG. 8 shows the 5′ cap and PABPs cooperatively interacting with proteins involved in translation to facilitate the recruitment and recycling of ribosome complexes.
- DNA splint oligomers were made for splint-mediated ligation of of a donor oligomer to an acceptor RNA. As shown in the scheme of FIG. 8 , a short mRNA acceptor oligomer and a 5′-monophosphate-bearing polyA donor oligomer can be ligated in the presence of a DNA splint oligomer.
- FIG. 9 shows the splint-mediated ligation scheme, in which an acceptor RNA with a 30-monomer stub polyA tail (A(30)) was ligated to a 30-monomer donor oligomer (A(30)).
- the splint-mediated ligation used a DNA oligomer splint which was complementary to the 3′ UTR sequence upstream of the stub polyA tail, and included a 60-monomer oligo(dT) 5′ heel (T(60)) to splint the ligation.
- the anchoring region of the splint was complementary to the UTR sequence to ensure that a 5′ dT 30 overhang was presented upon hybridization to the acceptor. This brings the donor oligomer into juxtaposition with the 3′ terminus of the stub tail, dramatically improving the kinetics of ligation.
- FIG. 10 shows the results of ligation using 2 ug of a 120-monomer acceptor with an A 30 stub tail that was ligated to a 5′-phosphorylated A 30 RNA donor oligomer using T4 RNA Ligase 2.
- the reaction was incubated overnight at 37° C.
- the ligation and a mock reaction done without enzyme were purified, treated with DNAse I for 1 hour to degrade and detach the splint oligomers, and re-purified in a volume of 30 uL.
- the ligation efficiency was nearly 100%.
- the absence of a size shift in the mock-reaction prep shows that the acceptor and donor were truly ligated and not simply held together by undigested splint oligomers.
- FIG. 11 shows the results of splint-mediated ligation using an acceptor RNA with a 30-monomer stub polyA tail (A(30)).
- the ligation reactions were performed with three different donor oligomer species: A(30), A(60), and A(120). Based on the gel shifts, the ligations attained nearly 100% efficiency.
- a protocol used for a 100 ul splint-mediated ligation reaction included the following materials, reagents, and steps.
- RNA Repurify the RNA using RNeasy spin columns, eluting in water or TE pH 7.0.
- the splint oligomer sequence includes an anchor that is specific to the 3′ UTR used for making mRNA.
- FIG. 12 shows the results of one-hour splint-mediated ligations that were performed on nGFP-A 30 transcripts. The resulting ligation products were compared to untreated transcripts and native nGFP-A 60 IVT products. The native nGFP-A 60 and the ligated products were up-shifted on the gel relative to the untreated nGFP-A 30 transcripts and mock-ligated material.
- a UNA-PolyA UNA Oligomer donor was made having the following structure:
- nGFP transcript with a polyA tail of 30-monomers in length was ligated to a donor polyA tail of 30-monomers in length to give an mRNA product having a polyA tail of 60-monomers in length (A 60 -bearing ligation product) by splint-mediated ligation.
- FIG. 13 shows increased lifetime and translational activity for the nGFP-A 60 ligation product.
- nuclearized transcripts were transfected into fibroblasts for comparison of nGFP-A 30 , mock-ligated nGFP-A 30 , and an nGFP-A 60 ligation product ( FIG. 13 , left to right).
- the significantly higher fluorescence signal observed for the nGFP-A 60 ligation product shows that it has markedly increased translational activity.
- a wild-type T4 RNA ligase was used to ligate a donor 5′ phosphorylated oligomer to a short IVT transcript.
- Short synthetic RNAs were generated by IVT, and the outcome of ligation reactions was evaluated on high-resolution 4% agarose gels. The increase in transcript size from ligation of a synthetic oligomer 30 monomers in length to a full-sized mRNA of 1-2 Kb is too small to clearly visualize on a gel.
- short synthetic RNAs of 100-180 monomers were generated by IVT.
- the 3′ terminal sequence of these short synthetic RNAs was identical to that in the 3′ UTRs of synthetic mRNAs.
- a synthetic oligomer having an adenylated 5′ end was prepared.
- the adenylated 5′ end normally formed as a catalytic intermediate by the ligase, pre-activated the synthetic oligomer for ligation.
- Use of the pre-adenylated synthetic oligomer obviated the need for ATP in the reactions, and allowed the use of a mutant ligase that was active exclusively on adenylated substrates.
- Pre-adenylation of the synthetic oligomer increased ligation efficiency and minimized side-product formation.
- a KQ mutant variant of T4 RNA Ligase 2 was used to ligate a pre-adenylated donor oligomer to a short IVT transcript.
- FIG. 14 shows the results of a ligation performed with a 100-monomer acceptor RNA that was treated for 3 hours at room temperature with T4 RNA Ligase 2 (truncated KQ mutant) using a 10 uM concentration of a polyA tail 30-monomer donor oligomer. 15% PEG 8000 was included in the reaction as a volume excluder to promote efficient ligation. The ligation reaction showed that a high molecular weight product was formed, having a size in between the 100-monomer acceptor RNA and a 180-monomer RNA transcript included as a size standard. These results show that the ligation reaction produced a predominant product having high molecular weight with nearly 100% ligation of the donor to the acceptor. Additional experiments performed with concentrations of the polyA tail at 10 uM, 20 uM , and 40 uM showed that at least half of the acceptor RNA was ligated in all cases.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Cell Biology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Virology (AREA)
- Enzymes And Modification Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
This invention provides a range of translatable messenger UNA (mUNA) molecules. The mUNA molecules can be translated in vitro and in vivo to provide an active polypeptide or protein, or to provide an immunization agent or vaccine component. The mUNA molecules can be used as an active agent to express an active polypeptide or protein in cells or subjects. Among other things, the mUNA molecules are useful in methods for treating rare diseases.
Description
- It has long been difficult to utilize messenger RNA molecules in medicines. Synthetic mRNA can be designed with inherent translational activity for making an active protein, which could be used in various therapeutic strategies. However, the expression of protein involves a number of steps that are localized and/or regulated. Further, plentiful RNase enzymes can degrade mRNA. Moreover, use of a synthetic mRNA requires clinical formulation and delivery to cells. These steps of mRNA delivery, partitioning and dynamics increase the need for stability and longevity of the synthetic mRNA.
- For efficient translation, natural mRNA transcripts incorporate a 5′ 7-methylguanosine cap and a 3′ polyA tail. PolyA binding proteins (PABPs) bind to the tail and cooperate with the 5′ cap via looping interactions to recruit the machinery of translation. A 3′ polyA tail of at least about 20 nucleotides is needed to activate the mRNA for translation. Translational activity can decrease to low levels in the absence of either the 5′ cap or the 3′ polyA tail.
- One drawback in using mRNA molecules in medicines is that the lifetime of the molecule in the cytoplasm of mammalian cells is relatively short. In general, ubiquitous mRNA degradation pathways actively clear out transcripts from the mRNA pool. The principle pathways for mRNA degradation involve deadenylation or trimming of the 3′ polyA tail by 3′-exoribonucleases and cleavage of the 5′-5′ triphosphate linkage that attaches the methylguanosine cap by a decapping complex.
- One way to increase mRNA longevity might be to increase 3′-nuclease resistance by incorporating nucleotide analogues or chemical modifications in either the phosphodiester backbone or the nucleotides, which are localized to the 3′ end to be compatible with enzymatic synthesis and efficient translation. A drawback of this approach is that it may not be possible to selectively incorporate such chemical modifications at 3′ termini, or to retain activity.
- There is an urgent need for molecules, structures and compositions having specific translational activity to provide active peptides and proteins, both in vitro and in vivo. Such new molecules having functional cytoplasmic half-life for producing active peptides and proteins can yield new drug molecules, therapeutic modalities, vaccines, and immunotherapies.
- What is needed are translatable molecules that have increased specific activity and/or lifetime over native mRNA, to be used in methods and compositions for producing and delivering active peptides and proteins in medicines.
- This invention relates to the fields of molecular biology and genetics, as well as to biopharmaceuticals and therapeutics generated from translatable molecules. More particularly, this invention relates to methods, structures and compositions for molecules having translational activity for making active peptides or proteins in vivo.
- This invention provides methods and compositions for novel molecules having translational activity, which can be used to provide active peptides and proteins.
- The molecules of this invention can have functional cytoplasmic half-life for producing peptides and proteins. The peptides and proteins can be active for therapeutic modalities, as well as in vaccines and immunotherapies.
- The molecules of this invention can be translatable messenger molecules, which can have long half-life, particularly in the cytoplasm of a cell. The longer duration of the translatable messenger molecules of this invention can be significant for providing a translation product that is active for ameliorating, preventing or treating various diseases. The diseases can be associated with undesirable modulation of protein concentration, or undesirable activity of a protein.
- This disclosure provides a range of structures for translatable molecules that have increased specific activity and/or lifetime over native mRNA. The translatable molecules of this invention can be used in medicines, and for methods and compositions for producing and delivering active peptides and proteins.
- Embodiments of this disclosure provide a wide range of novel, translatable messenger molecules. The translatable messenger molecules can contain monomers that are unlocked nucleomonomers (UNA monomers). The long duration of translatable messenger UNA molecules (mUNA molecules) of this invention can be useful for providing an active peptide or protein translation product. The mUNA molecules of this invention can be used in medicines for ameliorating, preventing or treating disease.
- The translatable mUNA molecules of this invention can be used to provide peptides or proteins in vitro, ex vivo, or in vivo.
- The translatable mUNA molecules of this invention can provide high-efficiency expression of virtually any protein.
- In some embodiments, the mUNA molecules of this invention have increased cytoplasmic half-life over a native, mature mRNA that provides the same peptide or protein. The mUNA structures and compositions of this invention can provide increased functional half-life with respect to native, mature mRNAs.
- In further aspects, a mUNA molecule of this invention can provide increased activity as a drug providing a peptide or protein product, as compared to a native, mature mRNA. In some embodiments, a mUNA molecule can reduce the expected dose level that would be required for efficacious therapy.
- Additional embodiments of this invention can provide vaccine compositions for immunization and immunotherapies using mUNA molecules.
- Embodiments of this invention include the following:
- A mUNA molecule, containing one or more UNA monomers, and containing nucleic acid monomers, wherein the mUNA molecule is translatable to express a polypeptide or protein. The molecule may have from 200 to 12,000 monomers, or from 200 to 4,000 monomers. In some embodiments, the molecule can have from 1 to 8,000 UNA monomers, or from 1 to 100 UNA monomers, or from 1 to 20 UNA monomers.
- A mUNA molecule can have one or more modified nucleic acid nucleotides, and/or one or more chemically-modified nucleic acid nucleotides.
- In some embodiments, a mUNA molecule can contain a 5′ cap, a 5′ untranslated region of monomers, a coding region of monomers, a 3′ untranslated region of monomers, and a tail region of monomers. In certain embodiments, the molecule can contain a translation enhancer in a 5′ or 3′ untranslated region.
- The mUNA molecules of this invention can be translatable in vivo, or in vitro, or in a mammalian cell, or in a human in vivo. In some embodiments, a translation product of a mUNA molecule can be an active peptide or protein.
- In certain embodiments, a translation product of a mUNA molecule is human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
- In another aspect, a mUNA molecule can exhibit at least 2-fold, 3-fold, 5-fold, or 10-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
- In certain embodiments, a mUNA molecule can have a cytoplasmic half-life in a cell at least 2-fold greater than a native mRNA of the cell that encodes the same translation product.
- Embodiments of this invention further contemplate therapeutic mUNA agents for a rare disease, a liver disease, or a cancer. A mUNA molecule can be an immunization agent or vaccine component for a rare disease, a liver disease, or a cancer.
- This invention further provides compositions containing a mUNA molecule and a pharmaceutically acceptable carrier, and vaccine or immunization compositions containing a mUNA molecule. The carrier can be a nanoparticle or liposome.
- In additional embodiments, this invention provides methods for ameliorating, preventing or treating a disease or condition in a subject comprising administering to the subject a composition containing a mUNA molecule. The disease or condition can be a rare disease, liver disease, or cancer.
- In certain embodiments, this invention provides methods for producing a polypeptide or protein in vivo, by administering to a mammal a composition containing a mUNA molecule. The polypeptide or protein may be deficient in a disease or condition of a subject or mammal. The protein can be human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
- This invention further provides methods for producing a polypeptide or protein in vitro, by transfecting a cell with a mUNA molecule. The polypeptide or protein can be deficient in a disease or condition of a subject or mammal. The protein can be human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
-
FIG. 1 shows the results of expressing human Factor IX (F9) in vivo using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of Factor IX.FIG. 1 shows that the translation efficiency of this mUNA molecule was doubled as compared to the native mRNA of F9. The mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human F9. -
FIG. 2 shows the results of expressing human Factor IX (F9) in vitro using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of Factor IX.FIG. 2 shows that the translation efficiency of this mUNA molecule was increased by 5-fold after 48 hours, as compared to the native mRNA of F9. The mUNA molecule of this embodiment was traslated in mouse hepatocyte cell line Hepa1-6 to produce human F9. -
FIG. 3 shows the results of expressing human Erythropoietin (EPO) in vitro using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of human EPO.FIG. 3 shows that the translation efficiency of this mUNA molecule was increased nearly 3-fold after 48 hours, as compared to the native mRNA of EPO. The mUNA molecule of this embodiment was translated in mouse hepatocyte cell line Hepa1-6 to produce human EPO. -
FIG. 4 shows the results of expressing mouse Erythropoietin (EPO) in vitro using several translatable mUNA molecules of this invention, as compared to expression of a native mRNA of mouse EPO.FIG. 4 shows that the translation efficiencies of the mUNA molecules (#2, 3, 4, 5, 6, 7, 8, 9, 10 and 11) were increased by up to 10-fold after 72 hours, as compared to the native mRNA of EPO. The mUNA molecules of this embodiment were translated in mouse hepatocyte cell line Hepa1-6 to produce mouse EPO. -
FIG. 5 shows the results of expressing human alpha-1-antitrypsin in vivo using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of human alpha-1-antitrypsin.FIG. 5 shows that the translation efficiency of this mUNA molecule at 72 hrs was increased more than 3-fold as compared to the native mRNA of human alpha-1-antitrypsin. The mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human alpha-1-antitrypsin. -
FIG. 6 shows the results of expressing human erythropoietin (EPO) in vivo using a translatable mUNA molecule of this invention, as compared to expression of a native mRNA of human EPO.FIG. 6 shows that the translation efficiency of this mUNA molecule at 72 hrs was increased more than 10-fold as compared to the native mRNA of human EPO. The mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human EPO. -
FIG. 7 shows the primary structure of a functional mRNA transcript in the cytoplasm. The mRNA includes a 5′ methylguanosine cap, a protein coding sequence flanked by untranslated regions (UTRs), and a polyadenosine (polyA) tail bound by polyA binding proteins (PABPs). -
FIG. 8 shows the 5′ cap and PABPs cooperatively interacting with proteins involved in translation to facilitate the recruitment and recycling of ribosome complexes. -
FIG. 9 shows the splint-mediated ligation scheme, in which an acceptor RNA with a 30-monomer stub polyA tail (A(30)) was ligated to a 30-monomer donor oligomer A(30). The splint-mediated ligation used a DNA oligomer splint which was complementary to the 3′ UTR sequence upstream of the stub polyA tail, and included a 60-monomer oligo(dT) 5′ heel (T(60)) to splint the ligation. The anchoring region of the splint was complementary to the UTR sequence to ensure that a 5′ dT30 overhang was presented upon hybridization to the acceptor. This brings the donor oligomer into juxtaposition with the 3′ terminus of the stub tail, dramatically improving the kinetics of ligation. -
FIG. 10 shows experimental results of splint-mediated ligation of a donor oligomer to an acceptor.FIG. 10 shows the results of ligation using 2 ug of a 120-monomer acceptor with an A30 stub tail that was ligated to a 5′-phosphorylated A30 RNA donor oligomer usingT4 RNA Ligase 2. The reaction was incubated overnight at 37° C. The ligation and a mock reaction done without enzyme were purified, treated with DNAse I for 1 hour to degrade and detach the splint oligomers, and re-purified in a volume of 30 uL. The ligation efficiency was nearly 100%. The absence of a size shift in the mock-reaction prep shows that the acceptor and donor were truly ligated and not simply held together by undigested splint oligomers. -
FIG. 11 shows the results of splint-mediated ligation using an acceptor RNA with a 30-monomer stub polyA tail (A(30)). The ligation reactions were performed with three different donor oligomer species: A(30), A(60), and A(120). Based on the gel shifts, the ligations have attained nearly 100% efficiency. -
FIG. 12 shows the results of one-hour splint-mediated ligations that were performed on nGFP-A30 transcripts. The resulting ligation products were compared to untreated transcripts and native nGFP-A60 IVT products. The native nGFP-A60 and the ligated products were up-shifted on the gel relative to the untreated nGFP-A30 transcripts and mock-ligated material, showing that the ligation yield was nearly 100%. -
FIG. 13 shows increased lifetime and translational activity for an nGFP-A60 ligation product. InFIG. 13 , nuclearized transcripts were transfected into fibroblasts, and a comparison of fluoresence signals was made for nGFP-A30, mock-ligated nGFP-A30, and an nGFP-A60 ligation product (FIG. 13 , left to right). The significantly higher fluorescence signal observed for the nGFP-A60 ligation product shows that it has markedly increased translational activity. -
FIG. 14 shows the results of a ligation performed with a 100-monomer acceptor RNA that was treated for 3 hours at room temperature with T4 RNA Ligase 2 (truncated KQ mutant) using a 10 uM concentration of a polyA tail 30-monomer donor oligomer. 15% PEG 8000 was included in the reaction as a volume excluder to promote efficient ligation. The ligation reaction showed that a high molecular weight product was formed, having a size in between the 100-monomer acceptor RNA and a 180-monomer RNA transcript included as a size standard. These results show that the ligation reaction produced a predominant product having high molecular weight with nearly 100% ligation of the donor to the acceptor. Additional experiments with concentrations of the polyA tail at 10 uM, 20 uM, and 40 uM showed that from about 50% to about 100% of the acceptor RNA was ligated. - This invention provides a range of novel agents and compositions to be used for therapeutic applications. The molecules and compositions of this invention can be used for ameliorating, preventing or treating various diseases associated with genomic functionalities.
- The molecules of this invention can be translatable messenger UNA molecules, which can have long half-life, particularly in the cytoplasm. The long duration mUNA molecules (mUNA molecules) can be used for ameliorating, preventing or treating various diseases associated with undesirable modulation of protein concentration, or activity of a protein.
- The properties of the mUNA compounds of this invention arise according to their molecular structure, and the structure of the molecule in its entirety, as a whole, can provide significant benefits based on those properties. Embodiments of this invention can provide mUNA molecules having one or more properties that advantageously provide enhanced effectiveness in regulating protein expression or concentration, or modulating protein activity. The molecules and compositions of this invention can provide formulations for therapeutic agents for various diseases and conditions, which can provide clinical agents.
- This invention provides a range of mUNA molecules that are surprisingly translatable to provide active peptide or protein, in vitro and in vivo.
- The mUNA structures and compositions can have increased translational activity and cytoplasmic half-life. In these embodiments, the mUNA structures and compositions can provide increased functional half-life in the cytoplasm of mammalian cells over native mRNA molecules. The inventive mUNA molecules can have increased half-life of activity with respect to a corresponding native mRNA.
- A wide range of novel mUNA molecules are provided herein, each of which can incorporate specialized linker groups. The linker groups can be attached in a chain in the mUNA molecule. Each linker group can also be attached to a nucleobase.
- In some aspects, a linker group can be a monomer. Monomers can be attached to form a chain molecule. In a chain molecule of this invention, a linker group monomer can be attached at any point in the chain.
- In certain aspects, linker group monomers can be attached in a chain molecule of this invention so that the linker group monomers reside near the ends of the chain, or at any position in the chain.
- As used herein, a chain molecule can also be referred to as an oligomer.
- In further aspects, the linker groups of a chain molecule can each be attached to a nucleobase. The presence of nucleobases in the chain molecule can provide a sequence of nucleobases in the chain molecule.
- In certain embodiments, this invention provides oligomer mUNA molecules having chain structures that incorporate novel combinations of the linker group monomers, along with certain natural nucleotides, or non-natural nucleotides, or modified nucleotides, or chemically-modified nucleotides.
- The oligomer mUNA molecules of this invention can display a sequence of nucleobases, and can be designed to express a polypeptide or protein, in vitro, ex vivo, or in vivo. The expressed polypeptide or protein can have activity in various forms, including activity corresponding to protein expressed from natural mRNA, or activity corresponding to a negative or dominant negative protein.
- In some aspects, this invention can provide active mUNA oligomer molecules having a base sequence that corresponds to at least a fragment of a native nucleic acid molecule of a cell.
- In some embodiments, the cell can be a eukaryotic cell, a mammalian cell, or a human cell.
- This invention provides structures, methods and compositions for oligomeric mUNA agents that incorporate the linker group monomers. The oligomeric molecules of this invention can be used as active agents in formulations for therapeutics.
- This invention provides a range of mUNA molecules that are useful for providing therapeutic effects because of their longevity of activity in providing an expressed peptide or protein.
- In certain embodiments, an active mUNA molecule can be structured as an oligomer composed of monomers. The oligomeric structures of this invention may contain one or more linker group monomers, along with certain nucleotides.
- An expressed peptide or protein can be modified or mutated as compared to a native variant, or can be a homolog or ortholog for enhanced expression in a eukaryotic cell. An active mUNA molecule can be human codon optimized. Methodologies for optimizing codons are known in the art.
- In certain embodiments, a mUNA molecule may contain a sequence of nucleobases, and can be designed to express a peptide or protein of any isoform, in part by having sufficient homology with a native polynucleotide sequence.
- In some embodiments, a mUNA molecule can be from about 200 to about 12,000 monomers in length, or more. In certain embodiments, a mUNA molecule can be from 200 to 12,000 monomers in length, or 200 to 10,000 monomers, or 200 to 8,000 monomers, or 200 to 6000 monomers, or 200 to 5000 monomers, or 200 to 4000 monomers, or 200 to 3600 monomers, or 200 to 3200 monomers, or 200 to 3000 monomers, or 200 to 2800 monomers, or 200 to 2600 monomers, or 200 to 2400 monomers, or 200 to 2200 monomers, or 600 to 3200 monomers, or 600 to 3000 monomers, or 600 to 2600 monomers.
- In some embodiments, a mUNA molecule can contain from 1 to about 8,000 UNA monomers. In certain embodiments, a mUNA molecule can contain from 1 to 8,000 UNA monomers, or 1 to 6,000 UNA monomers, or 1 to 4,000 UNA monomers, or 1 to 3,000 UNA monomers, or 1 to 2,000 UNA monomers, or 1 to 1,000 UNA monomers, or 1 to 500 UNA monomers, or 1 to 300 UNA monomers, or 1 to 200 UNA monomers, or 1 to 100 UNA monomers, or 1 to 50 UNA monomers, or 1 to 40 UNA monomers, or 1 to 30 UNA monomers, or 1 to 20 UNA monomers, or 1 to 10 UNA monomers, or 1 to 6 UNA monomers.
- In some embodiments, a mUNA molecule can be from about 200 to about 12,000 bases in length, or more. In certain embodiments, a mUNA molecule can be from 200 to 12,000 bases in length, or 200 to 10,000 bases, or 200 to 8,000 bases, or 200 to 6000 bases, or 200 to 5000 bases, or 200 to 4000 bases, or 200 to 3600 bases, or 200 to 3200 bases, or 200 to 3000 bases, or 200 to 2800 bases, or 200 to 2600 bases, or 200 to 2400 bases, or 200 to 2200 bases, or 600 to 3200 bases, or 600 to 3000 bases, or 600 to 2600 bases.
- A mUNA molecule of this invention may comprise a 5′ cap, a 5′ untranslated region of monomers, a coding region of monomers, a 3′ untranslated region of monomers, and a tail region of monomers. Any of these regions of monomers may comprise one or more UNA monomers.
- A mUNA molecule of this invention may comprise a 5′ untranslated region of monomers containing one or more UNA monomers.
- A mUNA molecule of this invention may comprise a coding region of monomers containing one or more UNA monomers.
- A mUNA molecule of this invention may comprise a 3′ untranslated region of monomers containing one or more UNA monomers.
- A mUNA molecule of this invention may comprise a tail region of monomers containing one or more UNA monomers.
- A mUNA molecule of this invention may comprise a 5′ cap containing one or more UNA monomers.
- A mUNA molecule of this invention can be translatable, and may comprise regions of sequences or structures that are operable for translation in a cell, or which have the functionality of regions of an mRNA including, for example, a 5′ cap, a 5′ untranslated region, a coding region, a 3′ untranslated region, and a polyA tail.
- This invention further contemplates methods for delivering one or more vectors, or one or more mUNA molecules to a cell.
- In some embodiments, one or more mUNA molecules can be delivered to a cell, in vitro, ex vivo, or in vivo. Viral and non-viral transfer methods as are known in the art can be used to introduce mUNA molecules in mammalian cells. mUNA molecules can be delivered with a pharmaceutically acceptable vehicle, or for example, encapsulated in a liposome.
- A peptide or protein expressed by a mUNA molecule can be any peptide or protein, endogenous or exogenous in nature with respect to a eukaryotic cell, and may be a synthetic or non-natural peptide or protein with activity or effect in the cell.
- In some embodiments, mUNA structures and compositions of this invention can reduce the number and frequency of transfections required for cell-fate manipulation in culture as compared to utilizing native compositions.
- In additional aspects, this invention provides increased activity for mUNA-based drugs as compared to utilizing native compositions, and can reduce the dose levels required for efficacious therapy.
- In further aspects, this invention provides increased activity for mUNA-based molecules, as compared to utilizing a native mRNA as active agent.
- In some aspects, this invention can provide mUNA molecules that may reduce the cellular innate immune response, as compared to that induced by a natural nucleic acid, peptide or protein.
- In further aspects, embodiments of this invention can provide increased efficacy for single-dose therapeutic modalities, including mUNA immunization and immunotherapies.
- This invention can provide synthetic mUNA molecules that are refractory to deadenylation as compared to native molecules.
- In certain embodiments, this invention can provide synthetic mUNA molecules with increased specific activity and longer functional half-life as compared to native molecules. The synthetic mUNA molecules of this invention can provide increased levels of ectopic protein expression. When using a mUNA molecule as a vector, cellular-delivery can be at increased levels, and cytotoxic innate immune responses can be restrained so that higher levels of ectopic protein expression can be achieved. The mUNA molecules of this invention can have increased specific activity and longer functional half-life than mRNAs.
- In certain aspects, a mUNA molecule may have a number of mutations from a native mRNA, or from a disease associated mRNA.
- In further embodiments, this invention can provide mUNA molecules having cleavable delivery and targeting moieties attached at the 3′ end.
- In general, the specific activity for a synthetic translatable molecule delivered by transfection can be viewed as the number of molecules of protein expressed per delivered transcript per unit time.
- As used herein, translation efficiency refers to a measure of the production of a protein or polypeptide by translation of a messenger molecule in vitro or in vivo.
- This invention provides a range of mUNA molecules, which can contain one or more UNA monomers, and a number of nucleic acid monomers, wherein the mUNA molecule can be translated to express a polypeptide or protein.
- In some embodiments, this invention includes a range of mUNA molecules, which contain one or more UNA monomers in one or more untranslated regions, and a number of nucleic acid monomers, wherein the mUNA molecule can be translated to express a polypeptide or protein.
- In some embodiments, this invention includes a range of mUNA molecules, which contain one or more UNA monomers in a tail region or monomers, and a number of nucleic acid monomers, wherein the mUNA molecule can be translated to express a polypeptide or protein.
- In some embodiments, a mUNA molecule can contain a modified 5′ cap.
- In some embodiments, a mUNA molecule can contain one ore more UNA monomers in a 5′ cap.
- In further embodiments, a mUNA molecule can contain a translation enhancing 5′ untranslated region of monomers.
- In further embodiments, a mUNA molecule can contain one or more UNA monomers in a 5′ untranslated region.
- In additional embodiments, a mUNA molecule can contain a translation enhancing 3′ untranslated region of monomers.
- In additional embodiments, a mUNA molecule can contain one or more UNA monomers in a 3′ untranslated region of monomers.
- In additional embodiments, a mUNA molecule can contain one or more UNA monomers in a tail region of monomers.
- In additional embodiments, a mUNA molecule can contain one or more UNA monomers in a polyA tail.
- In another aspect, a mUNA molecule can exhibit at least 2-fold, 3-fold, 5-fold, or 10-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
- In another aspect, a mUNA molecule can produce at least 2-fold, 3-fold, 5-fold, or 10-fold increased polypeptide or protein in vivo as compared to a native mRNA that encodes the same polypeptide or protein.
- In additional embodiments, this invention provides methods for treating a rare disease or condition in a subject by administering to the subject a composition containing a mUNA molecule.
- In additional embodiments, this invention provides methods for treating a liver disease or condition in a subject by administering to the subject a composition containing a mUNA molecule.
- Modalities for Peptides and Proteins
- A mUNA molecule of this invention may be used for ameliorating, preventing or treating a disease through enzyme modulation or replacement. In these embodiments, a mUNA molecule of this invention can be administered to regulate, modulate, increase, or decrease the concentration or effectiveness of a natural enzyme in a subject.
- In some aspects, the enzyme can be an unmodified, natural enzyme for which the patient has an abnormal quantity.
- In some embodiments, a mUNA molecule can be delivered to cells or subjects, and translated to supply increased levels of the natural enzyme.
- A mUNA molecule of this invention may be used for ameliorating, preventing or treating a disease through modulation or introduction of a peptide or protein. In these embodiments, a mUNA molecule of this invention can be administered to regulate, modulate, increase, or decrease the concentration or effectiveness of a peptide or protein in a subject, where the peptide or protein is non-natural or mutated, as compared to a native peptide or protein.
- In some aspects, the peptide or protein can be a modified, non-natural, exogenous, or synthetic peptide or protein, which has a pharmacological effect in a subject.
- In some embodiments, a mUNA molecule can be delivered to cells or subjects, and translated to supply a concentration of the peptide or protein.
- Examples of diseases for enzyme modulation include lysosomal diseases, for example, Gaucher disease, Fabry disease, Mucopolysaccharidoses (MPS) and related diseases including MPS I, MPS II (Hunter syndrome), and MPS VI, as well as Glycogen storage disease type II.
- Examples of diseases for enzyme modulation include hematologic diseases, for example, sickle-cell disease, thalassemia, methemoglobinemia, anemia due to deficiency of hemoglobin or B12 intrinsic factor, spherocytosis, glucose-6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency.
- Examples of diseases for enzyme modulation include hemophilia, Von Willebrand disease, Protein S deficiency, age-related macular degeneration, trinucleotide repeat disorders, muscular dystrophy, insertion mutation diseases, DNA repair-deficiency disorders, and deletion mutation diseases.
- Rare Diseases
- Examples of diseases and/or conditions for which the mUNA molecules of this invention can be translatable to provide an active agent include those in Table 1.
-
TABLE 1 Rare diseases RARE DISEASE DEFICIENCY Aminoacylase 1 deficiency Aminoacylase 1 Apo A-I deficiency Apo A-I Carbamoyl phosphate synthetase 1 Carbamoyl phosphate synthetase 1 deficiency Ornithine transcarbamylase Ornithine transcarbamylase deficiency Plasminogen activator inhibitor Plasminogen activator inhibitor type 1 type 1 deficiency Flaujeac factor deficiency Flaujeac factor (High-molecular-weight kininogen) High-molecular-weight kininogen High-molecular-weight kininogen (Flaujeac factor) deficiency congenital PEPCK 1 deficiency PEPCK 1 Pyruvate kinase deficiency liver Pyruvate kinase liver type type Alpha 1-antitrypsin deficiency Alpha 1-antitrypsin Anti-plasmin deficiency congenital Anti-plasmin Apolipoprotein C 2I deficiency Apolipoprotein C 2I Butyrylcholinesterase deficiency Butyrylcholinesterase Complement component 2 Complement component 2 deficiency Complement component 8 Complement component 8 type 2 deficiency type 2 Congenital antithrombin Antithrombin deficiency type 1 Congenital antithrombin Antithrombin, type 2 deficiency type 2 Congenital antithrombin Antithrombin, type 3 deficiency type 3 Cortisone reductase deficiency 1 Cortisone reductase Factor VII deficiency Factor VII Factor X deficiency Factor X Factor XI deficiency Factor XI Factor XII deficiency Factor XII Factor XIII deficiency Factor XIII Fibrinogen deficiency congenital Fibrinogen Fructose-1 6-bisphosphatase Fructose-1 6-bisphosphatase deficiency Gamma aminobutyric acid Gamma aminobutyric acid transaminase transaminase deficiency Gamma-cystathionase deficiency Gamma-cystathionase Glut2 deficiency Glut2 GTP cyclohydrolase I deficiency GTP cyclohydrolase I Isolated growth hormone Isolated growth hormone type 1B deficiency type 1B Molybdenum cofactor deficiency Molybdenum cofactor Prekallikrein deficiency congenital Prekallikrein Proconvertin deficiency congenital Proconvertin Protein S deficiency Protein S Pseudocholinesterase deficiency Pseudocholinesterase Stuart factor deficiency congenital Stuart factor Tetrahydrobiopterin deficiency Tetrahydrobiopterin Type 1 plasminogen deficiency Plasminogen Urocanase deficiency Urocanase Chondrodysplasia punctata with Chondrodysplasia punctata with steroid sulfatase/X- steroid sulfatase deficiency linked chondrodysplasia punctata 1 Homocystinuria due to CBS CBS deficiency Guanidinoacetate Guanidinoacetate methyltransferase methyltransferase deficiency Pulmonary surfactant protein B Pulmonary surfactant protein B deficiency Aminoacylase 1 deficiency Aminoacylase 1 Acid Sphingomyelinase Enzyme found in lysosomes, responsible for conversion of Deficiency lipid sphingomyelin into lipid ceramide Adenylosuccinate Lyase Neurological disorder, brain dysfunction (encephalopathy) Deficiency and to delayed development of mental and movement abilities, autistic behaviors and seizures Aggressive Angiomyxoma Myxoid tumor involving the blood vessels, may be a non- metastasizing benign tumor Albrights Hereditary Inherited in an autosomal dominant pattern, lack of Osteodystrophy responsiveness to parathyroid hormone, low serum calcium, high serum phosphate Carney Stratakis Syndrome Very rare syndrome characterized by gastrointestinal stromal tumors and paragangliomas. Carney Triad Syndrome Characterized by the coexistence of 3 types of neoplasms, mainly in young women, including gastric gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal paraganglioma CDKL5 Mutation Results in severe neurodevelopmental impairment and early onset, difficult to control seizures CLOVES Syndrome Complex vascular anomalies: Congenital, Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies Cockayne Syndrome Characterized by short stature and an appearance of premature aging, failure to gain weight, abnormally small head size, and impaired development of the nervous system Congenital Disorder of Rare inborn errors of metabolism involving deficient or Glycosylation type 1R defective glycosylation Cowden Syndrome Characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers DEND Syndrome Generally severe form of neonatal diabetes mellitus characterized by a triad of developmental delay, epilepsy, and neonatal diabetes Dercum's Disease Characterized by multiple, and painful lipomas. These lipomas mainly occur on the trunk, the upper arms and upper legs Febrile Infection-Related Epilepsy Explosive-onset, potentially fatal acute epileptic Syndrome encephalopathy, develops in previously healthy children and adolescents following the onset of a non-specific febrile illness Fibular Aplasia Tibial Campomelia Unknown genetic basis and inheritance with variable Oligosyndactyly Syndrome expressivity and penetrance Food Protein-Induced Enterocolitis A non-IgE mediated immune reaction in the gastrointestinal Syndrome system to one or more specific foods, commonly characterized by profuse vomiting and diarrhea Foreign Body Giant Cell Reactive Collection of fused macrophages which are generated in Tissue Disease response to the presence of a large foreign body; particularly evident with implants that cause the body chronic inflammation and foreign body response Galloway-Mowat Physical features may include an unusually small head and additional abnormalities of the head and facial area; damage to clusters of capillaries in the kidneys resulting in abnormal kidney function; and, in many cases, protrusion of part of the stomach through an abnormal opening in the diaphragm Gitelman syndrome Autosomal recessive kidney disorder characterized by hypokalemic metabolic alkalosis with hypocalciuria, and hypomagnesemia. Glycerol Kinase Deficiency X-linked recessive enzyme defect that is heterozygous in nature, responsible gene in a region containing genes in which deletions can cause DMD and adrenal hypoplasia congenita Glycogen Storage Disease type 9Caused by the inability to break down glycogen. The different forms of the condition can affect glycogen breakdown in liver cells, muscle cells or both gm1 gangliosidosis Autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes Hereditary spherocytosis Affects red blood cells, shortage of red blood cells, yellowing of the eyes and skin, and an enlarged spleen Hidradenitis Suppurativa Stage III Disorder of the terminal follicular epithelium in the apocrine gland-bearing skin, frequently causing keloids, contractures, and immobility. Stage III is defined as multiple lesions, with more extensive sinus tracts and scarring Horizonatal Gaze Palsy with Disorder that affects vision and also causes an abnormal Progressive Scoliosis curvature of the spine IMAGe syndrome The combination of intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (only about 20 cases reported in the medical literature) Isodicentric 15 Chromosome abnormality in which a child is born with extra genetic material from chromosome 15 isolated hemihyperplasia One side of the body grows more than other, causing asymmetry Juvenile Xanthogranuloma Usually benign and self-limiting. It occurs most often in the skin of the head, neck, and trunk but can also occur in the arms, legs, feet, and buttocks Kasabach-Merritt Syndrome A vascular tumor leads to decreased platelet counts and sometimes other bleeding problems Kniest Dysplasia Disorder of bone growth characterized by short stature (dwarfism) with other skeletal abnormalities and problems with vision and hearing Koolen de-Vries Syndrome Disorder characterized by developmental delay and mild to moderate intellectual disability. They usually have weak muscle tone in childhood. About half have recurrent seizures Lennox-Gastaut syndrome Type of epilepsy with multiple different types of seizures, particularly tonic (stiffening) and atonic (drop) seizures. Intellectual development is usually, but not always, impaired Lymphangiomatosis Congenital and can affect any of the body's systems except the central nervous system (including the brain) Lymphangiomiomytosis Can occur either sporadically or in association with the tuberous sclerosis complex (TSC) and is often considered a forme fruste of TSC MASA Syndrome X-linked recessive neurological disorder Mast Cell Activation disorder Condition with signs and symptoms involving the skin, gastrointestinal, cardiovascular, respiratory, and neurologic systems Mecp2 Duplication Syndrome Genetic neurodevelopmental disorder characterized by low muscle tone, potentially severe intellectual disability, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, and progressive spasticity Mucha Habermann Skin disorder Neonatal Hemochromatosis Severe liver disease of fetal or perinatal onset, associated with deposition of stainable iron in extrahepatic sites, disordered iron handling due to injury to the perinatal liver, as a form of fulminant hepatic failure N-glycanase deficiency The encoded enzyme may play a role in the proteasome- mediated degradation of misfolded glycoproteins Opsoclonus Myoclonus Syndrome Neurological disorder of unknown causes which appears to be the result of an autoimmune process involving the nervous system Persistent genital arousal disorder Results in a spontaneous, persistent, and uncontrollable genital arousal, with or without orgasm or genital engorgement, unrelated to any feelings of sexual desire Pompe Disease Inherited disorder caused by the buildup of glycogen in the body's cells. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally Progressive Familial Intrahepatic Disorder that causes progressive liver disease, which Cholestasis typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals Pseudohypoparathyroidism type 1a Characterized by renal resistance to parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia, and elevated PTH; resistance to other hormones including thydroid stimulating hormone, gonadotropins and growth- hormone-releasing hormone PTEN Hamartoma Tumor The gene was identified as a tumor suppressor that is Syndrome mutated in a large number of cancers at high frequency Schnitzler syndrome Characterised by chronic hives and periodic fever, bone pain and joint pain (sometimes with joint inflammation), weight loss, malaise, fatigue, swollen lymph glands and enlarged spleen and liver Scleroderma Chronic hardening and tightening of the skin and connective tissues Semi Lobar Holoprosencephany Holoprosencephany: birth defect of the brain, which often can also affect facial features, including closely spaced eyes, small head size, and sometimes clefts of the lip and roof of the mouth. Semilobar holoprosencephaly is a subtype of holoprosencephaly characterised by an incomplete forebrain division Sjogren's Syndrome Immune system disorder characterized by dry eyes and dry mouth Specific Antibody Deficiency Immune Disease SYNGAP 1 A ras GTPase-activating protein that is critical for the development of cognition and proper synapse function Trigeminal Trophic Syndrome This is the wing of tissue at the end of the nose above the nostril. Trigeminal trophic syndrome is due to damage to the trigeminal nerve Undiffentiated Connective Tissue Systemic autoimmune disease Disease X-linked hypophosphatemia X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that ingestion of vitamin D is relatively ineffective. It can cause bone deformity including short stature and genu varum - Modalities for Immune Modulation
- The mUNA molecules of this invention can be translatable to provide an active protein. In certain embodiments, a translatable mUNA molecule can provide an active mRNA immunization agent, or an mRNA vaccine component.
- A mUNA vaccine of this disclosure can advantageously provide a safe and efficacious genetic vaccine by inducing an immune response having both cellular and humoral components. In general, protein can be expressed using a mUNA vaccine of this invention.
- In some embodiments, a mUNA vaccine can advantageously provide protein synthesis in the cytoplasm. In certain embodiments, a mUNA vaccine of this invention can provide internalization, release and transport of an exogenous mRNA in the cytoplasm.
- In certain aspects, a mUNA vaccine of this invention can encode for a protein antigen that can be translated by host cells.
- In further aspects, some mUNA vaccines of this disclosure can encode for tumor antigens, viral antigens, or allergens.
- Modalities for administering a mUNA vaccine of this invention can include intravenous, intranodal, intradermal, subcutaneous and intrasplenic.
- Embodiments of this invention further provide mUNA vaccines having increased half-life of translation, which can be used to reduce the necessary dose and exposure to antigen, and reduce the risk of inducing tolerance.
- A mUNA vaccine of this invention can provide an immunological effect without the risk of integration of a component into the genome, and may reduce the risk of mutagenesis as compared to other genetic vaccines.
- Additional embodiments of this disclosure include mUNA molecules having translational activity, where the translational activity can be described by a cytoplasmic half-life in a mammalian cell. The half-life can be determined by the time required for 50% of the mUNA molecule to be degraded in the cell.
- A translatable mUNA molecule of this invention can be a precursor of an active molecule, which can be used in the treatment of a condition or disease in a subject.
- In some embodiments, a translatable mUNA molecule of this invention can be a pharmacologically active molecule having increased half-life in the cytoplasm of mammalian cells.
- Examples of mUNA molecules of this invention include a mUNA molecule that provides an mRNA encoding HIV-1 gag antigen, a mUNA molecule that provides an mRNA encoding antigens overexpressed in lung cancers, a mUNA molecule that provides an mRNA encoding malarial P. falciparum reticulocyte-binding protein homologue 5 (PfRHS), and a mUNA molecule that provides an mRNA encoding malarial Plasmodium falciparum PfSEA-1, a 244 KD malaria antigen expressed in schizont-infected RBCs.
- UNA Monomers and Oligomers
- In some embodiments, linker group monomers can be unlocked nucleomonomers (UNA monomers), which are small organic molecules based on a propane-1,2,3-tri-yl-trisoxy structure as shown below:
- where R1 and R2 are H, and R1 and R2 can be phosphodiester linkages, Base can be a nucleobase, and R3 is a functional group described below.
- In another view, the UNA monomer main atoms can be drawn in IUPAC notation as follows:
- where the direction of progress of the oligomer chain is from the 1-end to the 3-end of the propane residue.
- Examples of a nucleobase include uracil, thymine, cytosine, 5-methylcytosine, adenine, guanine, inosine, and natural and non-natural nucleobase analogues.
- Examples of a nucleobase include pseudouracil, 1-methylpseudouracil, and 5-methoxyuracil.
- In general, a UNA monomer, which is not a nucleotide, can be an internal linker monomer in an oligomer. An internal UNA monomer in an oligomer is flanked by other monomers on both sides.
- A UNA monomer can participate in base pairing when the oligomer forms a complex or duplex, for example, and there are other monomers with nucleobases in the complex or duplex.
- Examples of UNA monomer as internal monomers flanked at both the propane-1-yl position and the propane-3-yl position, where R3 is —OH, are shown below.
- A UNA monomer can be a terminal monomer of an oligomer, where the UNA monomer is attached to only one monomer at either the propane-1-yl position or the propane-3-yl position. Because the UNA monomers are flexible organic structures, unlike nucleotides, the terminal UNA monomer can be a flexible terminator for the oligomer.
- Examples of a UNA monomer as a terminal monomer attached at the propane-3-yl position are shown below.
- Because a UNA monomer can be a flexible molecule, a UNA monomer as a terminal monomer can assume widely differing conformations. An example of an energy minimized UNA monomer conformation as a terminal monomer attached at the propane-3-yl position is shown below.
- UNA-A terminal forms: the dashed bond shows the propane-3-yl attachment
- Among other things, the structure of the UNA monomer allows it to be attached to naturally-occurring nucleotides.
- A UNA oligomer can be a chain composed of UNA monomers, as well as various nucleotides that may be based on naturally-occurring nucleosides.
- In some embodiments, the functional group R3 of a UNA monomer can be —OR4, —SR4, —NR4 2, —NH(C═O)R4, morpholino, morpholin-1-yl, piperazin-1-yl, or 4-alkanoyl-piperazin-1-yl, where R4 is the same or different for each occurrence, and can be H, alkyl, a cholesterol, a lipid molecule, a polyamine, an amino acid, or a polypeptide.
- The UNA monomers are organic molecules. UNA monomers are not nucleic acid monomers or nucleotides, nor are they naturally-occurring nucleosides or modified naturally-occurring nucleosides.
- A UNA oligomer of this invention is a synthetic chain molecule.
- In some embodiments, as shown above, a UNA monomer can be UNA-A (designated Ã), UNA-U (designated Ũ), UNA-C (designated {hacek over (C)}) and UNA-G (designated {hacek over (G)}).
- Designations that may be used herein include mA, mG, mC, and mU, which refer to the 2′-O-Methyl modified ribonucleotides.
- Designations that may be used herein include dT, which refers to a 2′-deoxy T nucleotide.
- Additional Monomers for Oligomers
- As used herein, in the context of oligomer sequences, the symbol X represents a UNA monomer. When a mUNA oligomer is complexed or duplexed with a nucleic acid molecule, the UNA monomers of the mUNA oligomer can have any base attached that would be complementary to the monomer with which it is paired in the nucleic acid molecule.
- As used herein, in the context of oligomer sequences, the symbol N can represent any natural nucleotide monomer, or any modified nucleotide monomer. When a mUNA oligomer is complexed or duplexed with a nucleic acid molecule, an N monomer of the mUNA oligomer can have any base attached that would be complementary to the monomer with which it is paired in the nucleic acid molecule.
- As used herein, in the context of oligomer sequences, the symbol Q represents a non-natural, modified, or chemically-modified nucleotide monomer. When a mUNA oligomer is complexed or duplexed with a nucleic acid molecule, a Q monomer of the mUNA oligomer can have any base attached that would be complementary to the monomer with which it is paired in the nucleic acid molecule.
- Examples of nucleic acid monomers include non-natural, modified, and chemically-modified nucleotides, including any such nucleotides known in the art.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include any such nucleotides known in the art, for example, 2′-O-methyl ribonucleotides, 2′-O-methyl purine nucleotides, 2′-deoxy-2′-fluoro ribonucleotides, 2′-deoxy-2′-fluoro pyrimidine nucleotides, 2′-deoxy ribonucleotides, 2′-deoxy purine nucleotides, universal base nucleotides, 5-C-methyl-nucleotides, and inverted deoxyabasic monomer residues.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include 3′-end stabilized nucleotides, 3′-glyceryl nucleotides, 3′-inverted abasic nucleotides, and 3′-inverted thymidine.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include locked nucleic acid nucleotides (LNA), 2′-O,4′-C-methylene-(D-ribofuranosyl) nucleotides, 2′-methoxyethoxy (MOE) nucleotides, 2′-methyl-thio-ethyl, 2′-deoxy-2′-fluoro nucleotides, and 2′-O-methyl nucleotides.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include 2′, 4′-Constrained 2′-O-Methoxyethyl (cMOE) and 2′-O-Ethyl (cEt) Modified DNAs.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include 2′-amino nucleotides, 2′-O-amino nucleotides, 2′-C-allyl nucleotides, and 2′-O-allyl nucleotides.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include N6-methyladenosine nucleotides.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include nucleotide monomers with modified bases 5-(3-amino)propyluridine, 5-(2-mercapto)ethyluridine, 5-bromouridine; 8-bromoguanosine, or 7-deazaadenosine.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include 2′-O-aminopropyl substituted nucleotides.
- Examples of non-natural, modified, and chemically-modified nucleotide monomers include replacing the 2′-OH group of a nucleotide with a 2′-R, a 2′-OR, a 2′-halogen, a 2′-SR, or a 2′-amino, where R can be H, alkyl, alkenyl, or alkynyl.
- Examples of nucleotide monomers include pseudouridine (psi-Uridine) and 1-methylpseudouridine.
- Some examples of modified nucleotides are given in Saenger, Principles of Nucleic Acid Structure, Springer-Verlag, 1984.
- mUNA Compounds
- Aspects of this invention provide structures and compositions for mUNA molecules that are oligomeric compounds. The mUNA compounds can be active agents for pharmaceutical compositions.
- An oligomeric mUNA agent of this invention may contain one or more UNA monomers. Oligomeric molecules of this invention can be used as active agents in formulations for supplying peptide and protein therapeutics.
- In some embodiments, this invention provides oligomeric mUNA compounds having a structure that incorporates novel combinations of UNA monomers with certain natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides.
- Oligomeric mUNA compounds of this invention can have a length of from about 200 to about 12,000 bases in length. Oligomeric mUNA compounds of this invention can have a length of about 1800, or about 1900, or about 2000, or about 2100, or about 2200, or about 2300, or about 2400, or about 2500 bases.
- In further aspects, the oligomeric mUNA compounds of this invention can be pharmacologically active molecules. A mUNA molecule can be used as an active pharmaceutical ingredient for generating a peptide or protein active agent in vitro, in vivo, or ex vivo.
- A mUNA molecule of this invention can have the structure of Formula I
- wherein L1 is a linkage, n is from 200 to 12,000, and for each occurrence L2 is a UNA linker group having the formula —C1—C2—C3—, where R is attached to C2 and has the formula —OCH(CH2R3)R5, where R3 is —OR4, —SR4, —NR4 2, —NH(C═O)R4, morpholino, morpholin-1-yl, piperazin-1-yl, or 4-alkanoyl-piperazin-1-yl, where R4 is the same or different for each occurrence and is H, alkyl, a cholesterol, a lipid molecule, a polyamine, an amino acid, or a polypeptide, and where R5 is a nucleobase, or L2(R) is a sugar such as a ribose and R is a nucleobase, or L2 is a modified sugar such as a modified ribose and R is a nucleobase. In certain embodiments, a nucleobase can be a modified nucleobase. L1 can be a phosphodiester linkage.
- The base sequence of a mUNA molecule can be any sequence of nucleobases.
- In some aspects, a mUNA molecule of this invention can have any number of phosphorothioate intermonomer linkages in any intermonomer location.
- In some embodiments, any one or more of the intermonomer linkages of a mUNA molecule can be a phosphodiester, a phosphorothioate including dithioates, a chiral phosphorothioate, and other chemically modified forms.
- When a mUNA molecule terminates in a UNA monomer, the terminal position has a 1-end, or the terminal position has a 3-end, according to the positional numbering shown above.
- mUNA Molecules with Enhanced Translation
- A mUNA molecule of this invention can incorporate a region that enhances the translational efficiency of the mUNA molecule.
- In general, translational enhancer regions as known in the art can be incorporated into the structure of a mUNA molecule to increase peptide or protein yields.
- A mUNA molecule containing a translation enhancer region can provide increased production of peptide or protein.
- In some embodiments, a translation enhancer region can comprise, or be located in a 5′ or 3′ untranslated region of a mUNA molecule.
- Examples of translation enhancer regions include naturally-occurring enhancer regions from
TEV 5′UTR and Xenopus beta-globin 3′UTR. - mUNA Molecular Structure and Sequences
- A mUNA molecule can be designed to express a target peptide or protein. In some embodiments, the target peptide or protein can be associated with a condition or disease in a subject.
- In some aspects, the base sequence of a mUNA molecule can include a portion that is identical to at least an effective portion or domain of a base sequence of an mRNA, where an effective portion is sufficient to impart a therapeutic activity to a translation product of the mUNA molecule.
- In some aspects, this invention provides active mUNA oligomer molecules having a base sequence identical to at least a fragment of a native nucleic acid molecule of a cell.
- In certain embodiments, the base sequence of a mUNA molecule can include a portion that is identical to a base sequence of an mRNA, except for one or more base mutations. The number of mutations for the mUNA molecule should not exceed an amount that would produce a translation product of the mUNA molecule having substantially less activity than the mRNA.
- The oligomer mUNA molecules of this invention can display a sequence of nucleobases, and can be designed to express a peptide or protein, in vitro, ex vivo, or in vivo. The expressed peptide or protein can have activity in various forms, including activity corresponding to protein expressed from a native or natural mRNA.
- In some embodiments, a mUNA molecule of this invention may have a chain length of about 400 to 15,000 monomers, where any monomer that is not a UNA monomer can be a Q monomer.
- mUNA Molecular Cap Structure
- A mUNA molecule of this invention may have a 5′-end capped with various groups and their analogues as are known in the art. The 5′ cap may be a m7GpppGm cap. The 5′ cap may be an ARCA cap (3′-OMe-m7G(5′)pppG). The 5′ cap may be an mCAP (m7G(5′)ppp(5′)G, N7-Methyl-Guanosine-5′-Triphosphate-5′-Guanosine). The 5′ cap may be resistant to hydrolysis.
- Some examples of 5′ cap structures are given in WO2015/051169A2.
- Genetic Basis for mUNA Molecules
- In some embodiments, the mUNA molecules of this invention can be structured to provide peptides or proteins that are nominally expressed by any portion of a genome. Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein are set forth below.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neoplasia, PTEN; ATM; ATR; EGFR; ERBB2; ERBB3; ERBB4; Notch1; Notch2; Notch3; Notch4; AKT; AKT2; AKT3; HIF; HIF1a; HIF3a; Met; HRG; Bc12; PPAR alpha; PPAR gamma; WT1 (Wilms Tumor); FGF Receptor Family members (5 members: 1, 2, 3, 4, 5); CDKN2a; APC; RB (retinoblastoma); MEN1; VHL; BRCA1; BRCA2; AR (Androgen Receptor); TSG101; IGF; IGF Receptor; Igf1 (4 variants); Igf2 (3 variants);
Igf 1 Receptor;Igf 2 Receptor; Bax; Bc12; caspases family (9 members: 1, 2, 3, 4, 6, 7, 8, 9, 12); Kras; Apc. - Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Age-related Macular Degeneration, Schizophrenia, Aber; Cc12; Cc2; cp (ceruloplasmin); Timp3; cathepsinD; Vldlr; Ccr2 Neuregulin1 (Nrg 1); Erb4 (receptor for Neuregulin); Complexin1 (Cplx1); Tph1 Tryptophan hydroxylase;
Tph2 Tryptophan hydroxylase 2;Neurexin 1; GSK3; GSK3a; GSK3b. - Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: 5-HTT (Slc6a4); COMT; DRD (Drd1a); SLC6A3; DAOA; DTNBP1; Dao (Dao1).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Trinucleotide Repeat Disorders, HTT (Huntington's Dx); SBMA/SMAX1/AR (Kennedy's Dx); FXN/X25 (Friedrich's Ataxia); ATX3 (Machado-Joseph's Dx); ATXN1 and ATXN2 (spinocerebellar ataxias); DMPK (myotonic dystrophy); Atrophin-1 and Atn 1 (DRPLA Dx); CBP (Creb-BP-global instability); VLDLR (Alzheimer's); Atxn7; Atxn10.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fragile X Syndrome, FMR2; FXR1; FXR2; mGLUR5.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Secretase Related Disorders, APH-1 (alpha and beta); Presenilin (Psen1); nicastrin (Ncstn); PEN-2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nos1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Parp1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nat1; Nat2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Prion-related disorders, Prp.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: ALS disease, SOD1; ALS2; STEX; FUS; TARDBP; VEGF (VEGF-a; VEGF-b; VEGF-c).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Drug addiction, Prkce (alcohol); Drd2; Drd4; ABAT (alcohol); GRIA2; Grm5; Grin1; Htr1b; Grin2a; Drd3; Pdyn; Gria1 (alcohol).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Autism, Mecp2; BZRAP1; MDGA2; Sema5A;
Neurexin 1; Fragile X (FMR2 (AFF2); FXR1; FXR2; Mglur5). - Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Alzheimer's Disease, E1; CHIP; UCH; UBB; Tau; LRP; PICALM; Clusterin; PS1; SORL1; CR1; Vld1r; Uba1; Uba3; CHIP28 (Aqp1, Aquaporin 1); Uch11; Uch13; APP.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inflammation, 1L-10; IL-1 (1L-1a; IL-1b); 1L-13; IL-17 (IL-17a (CTLA8); IL-17b; IL-17c; IL-17d; IL-17f); II-23; Cx3er1; ptpn22; TNFa; NOD2/CARD15 for IBD; IL-6; 1L-12 (1L-12a; 1L-12b); CTLA4; Cx3cl1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Parkinson's Disease, x-Synuclein; DJ-1; LRRK2; Parkin; PINK1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Blood and coagulation diseases and disorders, Anemia (CDAN1, CDA1, RPS19, DBA, PKLR, PK1, NT5C3, UMPH1, PSN1, RHAG, RH50A, NRAMP2, SPTB, ALAS2, ANH1, ASB, ABCB7, ABC7, ASAT); Bare lymphocyte syndrome (TAPBP, TPSN, TAP2, ABCB3, PSF2, RING11, MHC2TA, C2TA, RFX5, RFXAP, RFX5), Bleeding disorders (TBXA2R, P2RX1, P2X1); Factor H and factor H-like 1 (HF1, CFH, HUS); Factor V and factor VIII (MCFD2); Factor VII deficiency (F7); Factor X deficiency (F10); Factor XI deficiency (F11); Factor XII deficiency (F12, HAF); Factor XIIIA deficiency (F13A1, F13A); Factor XIIIB deficiency (F13B); Fanconi anemia (FANCA, FACA, FA1, FA, FAA, FAAP95, FAAP90, FLJ34064, FANCB, FANCC, FACC, BRCA2, FANCD1, FANCD2, FANCD, FACD, FAD, FANCE, FACE, FANCF, XRCC9, FANCG, BRIP1, BACH1, FANCJ, PHF9, FANCL, FANCM, KIAA1596); Hemophagocytic lymphohistiocytosis disorders (PRF1, HPLH2, UNC13D, MUNC13-4, HPLH3, HLH3, FHL3); Hemophilia A (F8, F8C, HEMA); Hemophilia B (F9 Factor IX, HEMB), Hemorrhagic disorders (PI, ATT, F5); Leukocyde deficiencies and disorders (ITGB2, CD18, LCAMB, LAD, EIF2B1, EIF2BA, EIF2B2, EIF2B3, EIF2B5, LVWM, CACH, CLE, EIF2B4); Sickle cell anemia (HBB); Thalassemia (HBA2, HBB, HBD, LCRB, HBA1).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cell dysregulation and oncology diseases and disorders, B-cell non-Hodgkin lymphoma (BCL7A, BCL7); Leukemia (TAL1 TCL5, SCL, TAL2, FLT3, NBS1, NBS, ZNFN1A1, IK1, LYF1, HOXD4, HOX4B, BCR, CML, PHL, ALL, ARNT, KRAS2, RASK2, GMPS, AF10, ARHGEF12, LARG, KIAA0382, CALM, CLTH, CEBPA, CEBP, CHIC2, BTL, FLT3, KIT, PBT, LPP, NPM1, NUP214, D9S46E, CAN, CAIN, RUNX1, CBFA2, AML1, WHSC1L1, NSD3, FLT3, AF1Q, NPM1, NUMA1, ZNF145, PLZF, PML, MYL, STAT5B, AF10, CALM, CLTH, ARL11, ARLTS1, P2RX7, P2X7, BCR, CML, PHL, ALL, GRAF, NF1, VRNF, WSS, NFNS, PTPN11, PTP2C, SHP2, NS1, BCL2, CCND1, PRAD1, BCL1, TCRA, GATA1, GF1, ERYF1, NFE1, ABL1, NQO1, DIA4, NMOR1, NUP214, D9S46E, CAN, CAIN).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inflammation and immune related diseases and disorders, AIDS (KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1, IFNG, CXCL12, SDF1); Autoimmune lymphoproliferative syndrome (TNFRSF6, APT1, FAS, CD95, ALPS1A); Combined immuno-deficiency, (IL2RG, SCIDX1, SCIDX, IMD4); HIV-1 (CCL5, SCYA5, D17S136E, TCP228), HIV susceptibility or infection (IL10, CSIF, CMKBR2, CCR2, CMKBR5, CCCKR5 (CCR5)); Immuno-deficiencies (CD3E, CD3G, AICDA, AID, HIGM2, TNFRSF5, CD40, UNG, DGU, HIGM4, TNFSF5, CD40LG, HIGM1, IGM, FOXP3, IPEX, AIID, XPID, PIDX, TNFRSF14B, TACI); Inflammation (IL-10, IL-1 (IL-1a, IL-1b), IL-13, IL-17 (IL-17a (CTLA8), IL-17b, IL-17c, IL-17d, IL-17f, II-23, Cx3cr1, ptpn22, TNFa, NOD2/CARD15 for IBD, IL-6, IL-12 (IL-12a, IL-12b), CTLA4, Cx3c11); Severe combined immunodeficiencies (SCIDs) (JAK3, JAKL, DCLRE1C, ARTEMIS, SCIDA, RAG1, RAG2, ADA, PTPRC, CD45, LCA, IL7R, CD3D, T3D, IL2RG, SCIDX1, SCIDX, IMD4).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Metabolic, liver, kidney and protein diseases and disorders, Amyloid neuropathy (TTR, PALB); Amyloidosis (APOA1, APP, AAA, CVAP, AD1, GSN, FGA, LYZ, TTR, PALB); Cirrhosis (KRT18, KRT8, CIRH1A, NAIC, TEX292, KIAA1988); Cystic fibrosis (CFTR, BG213071, ABCC7, CF, MRP7); Glycogen storage diseases (SLC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM); Hepatic adenoma, 142330 (TCF1, HNF1A, MODY3), Hepatic failure, early onset, and neurologic disorder (SCOD1, SCO1), Hepatic lipase deficiency (LIPC), Hepato-blastoma, cancer and carcinomas (CTNNB1, PDGFRL, PDGRL, PRLTS, AXIN1, AXIN, CTNNB1, TP53, P53, LFS1, IGF2R, MPRI, MET, CASP8, MCH5; Medullary cystic kidney disease (UMOD, HNFJ, FJHN, MCKD2, ADMCKD2); Phenylketonuria (PAH, PKU1, QDPR, DHPR, PTS); Polycystic kidney and hepatic disease (FCYT, PKHD1, ARPKD, PKD1, PKD2, PKD4, PKDTS, PRKCSH, G19P1, PCLD, SEC63).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Lipoprotein lipase, APOA1, APOC3 and APOA4.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Muscular/skeletal diseases and disorders, Becker muscular dystrophy (DMD, BMD, MYF6), Duchenne Muscular Dystrophy (DMD, BMD); Emery-Dreifuss muscular dystrophy (LMNA, LMN1, EMD2, FPLD, CMD1A, HGPS, LGMD1B, LMNA, LMN1, EMD2, FPLD, CMD1A); Facio-scapulohumeral muscular dystrophy (FSHMD1A, FSHD1A); Muscular dystrophy (FKRP, MDC1C, LGMD2I, LAMA2, LAMM, LARGE, KIAA0609, MDC1D, FCMD, TTID, MYOT, CAPN3, CANP3, DYSF, LGMD2B, SGCG, LGMD2C, DMDA1, SCG3, SGCA, ADL, DAG2, LGMD2D, DMDA2, SGCB, LGMD2E, SGCD, SGD, LGMD2F, CMD1L, TCAP, LGMD2G, CMD1N, TRIM32, HT2A, LGMD2H, FKRP, MDC1C, LGMD2I, TTN, CMD1G, TMD, LGMD2J, POMT1, CAV3, LGMD1C, SEPN1, SELN, RSMD1, PLEC1, PLTN, EBS1); Osteopetrosis (LRP5, BMND1, LRP7, LR3, OPPG, VBCH2, CLCN7, CLC7, OPTA2, OSTM1, GL, TCIRG1, TIRC7, OC116, OPTB1); Muscular atrophy (VAPB, VAPC, ALS8, SMN1, SMA1, SMA2, SMA3, SMA4, BSCL2, SPG17, GARS, SMAD1, CMT2D, HEXB, IGHMBP2, SMUBP2, CATF1, SMARD1).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neurological and neuronal diseases and disorders, ALS (SOD1, ALS2, STEX, FUS, TARDBP, VEGF (VEGF-a, VEGF-b, VEGF-c); Alzheimer's Disease (APP, AAA, CVAP, AD1, APOE, AD2, PSEN2, AD4, STM2, APBB2, FE65L1, NOS3, PLAU, URK, ACE, DCP1, ACE1, MPO, PACIP1, PAXIP1L, PTIP, A2M, BLMH, BMH, PSEN1, AD3); Autism (Mecp2, BZRAP1, MDGA2, Sema5A, Neurexin 1, GLO1, MECP2, RTT, PPMX, MRX16, MRX79, NLGN3, NLGN4, KIAA1260, AUTSX2); Fragile X Syndrome (FMR2, FXR1, FXR2, mGLUR5); Huntington's disease and disease like disorders (HD, IT15, PRNP, PRIP, JPH3, JP3, HDL2, TBP, SCA17); Parkinson disease (NR4A2, NURR1, NOT, TINUR, SNCAIP, TBP, SCA17, SNCA, NACP, PARK1, PARK4, DJ1, PARK7, LRRK2, PARK8, PINK1, PARK6, UCHL1, PARK5, SNCA, NACP, PARK1, PARK4, PRKN, PARK2, PDJ, DBH, NDUFV2); Rett syndrome (MECP2, RTT, PPMX, MRX16, MRX79, CDKL5, STK9, MECP2, RTT, PPMX, MRX16, MRX79, x-Synuclein, DJ-1); Schizo-phrenia (Neuregulin1 (Nrg1), Erb4 (receptor for Neuregulin), Complexin1 (Cplx1), Tph1 Trypto-phan hydroxylase, Tph2, Tryptophan hydroxylase 2, Neurexin 1, GSK3, GSK3a, GSK3b, 5-HTT (S1c6a4), COMT, DRD (Drd1a), SLC6A3, DAOA, DTNBP1, Dao (Dao1)); Secretase Related Dis-orders (APH-1 (alpha and beta), Presenilin (Psen1), nicastrin, (Ncstn), PEN-2, Nos1, Parp1, Nat1, Nat2); Trinucleotide Repeat Disorders (HTT (Huntington's Dx), SBMA/SMAX1/AR (Kennedy's Dx), FXN/X25 (Friedrich's Ataxia), ATX3 (Machado-Joseph's Dx), ATXN1 and ATXN2 (spinocerebellar ataxias), DMPK (myotonic dystrophy), Atrophin-1 and Atn1 (DRPLA Dx), CBP (Creb-BP—global instability), VLDLR (Alzheimer's), Atxn7, Atxn10).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Occular diseases and disorders, Age-related macular degeneration (Aber, Cc12, Cc2, cp (ceruloplasmin), Timp3, cathepsinD, Vldlr, Ccr2); Cataract (CRYAA, CRYA1, CRYBB2, CRYB2, PITX3, BFSP2, CP49, CP47, CRYAA, CRYA1, PAX6, AN2, MGDA, CRYBA1, CRYB1, CRYGC, CRYG3, CCL, LIM2, MP19, CRYGD, CRYG4, BFSP2, CP49, CP47, HSF4, CTM, HSF4, CTM, MIP, AQP0, CRYAB, CRYA2, CTPP2, CRYBB1, CRYGD, CRYG4, CRYBB2, CRYB2, CRYGC, CRYG3, CCL, CRYAA, CRYA1, GJA8, CX50, CAE1, GJA3, CX46, CZP3, CAE3, CCM1, CAM, KRIT1); Corneal clouding and dystrophy (APOA1, TGFBI, CSD2, CDGG1, CSD, BIGH3, CDG2, TACSTD2, TROP2, M1S1, VSX1, RINX, PPCD, PPD, KTCN, COL8A2, FECD, PPCD2, PIP5K3, CFD); Cornea plana congenital (KERA, CNA2); Glaucoma (MYOC, TIGR, GLC1A, JOAG, GPOA, OPTN, GLC1E, FIP2, HYPL, NRP, CYP1B1, GLC3A, OPA1, NTG, NPG, CYP1B1, GLC3A); Leber congenital amaurosis (CRB1, RP12, CRX, CORD2, CRD, RPGRIP1, LCA6, CORD9, RPE65, RP20, AIPL1, LCA4, GUCY2D, GUC2D, LCA1, CORD6, RDH12, LCA3); Macular dystrophy (ELOVL4, ADMD, STGD2, STGD3, RDS, RP7, PRPH2, PRPH, AVMD, AOFMD, VMD2).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Epilepsy, myoclonic, EPM2A, MELF, EPM2 Lafora type, 254780 Epilepsy, myoclonic, NHLRC1, EPM2A, EPM2B Lafora type, 254780.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Duchenne muscular DMD, BMD dystrophy, 310200 (3) AIDS, delayed/rapid KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1 progression to (3).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: AIDS, delayed/rapid KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1 progression to (3) AIDS, rapid IFNG progression to, 609423 (3) AIDS, resistance to CXCL12, SDF1 (3).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Alpha-1-Antitrypsin Deficiency, SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1]; SERPINA2 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 2]; SERPINA3 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3]; SERPINA5 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 5]; SERPINA6 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 6]; SERPINA7 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 7];” AND “SERPLNA6 (serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 6).
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PI3K/AKT Signaling, PRKCE; ITGAM; ITGA5; IRAK1; PRKAA2; EIF2AK2; PTEN; EIF4E; PRKCZ; GRK6; MAPK1; TSC1; PLK1; AKT2; IKBKB; PIK3CA; CDK8; CDKN1B; NFKB2; BCL2; PIK3CB; PPP2R1A; MAPK8; BCL2L1; MAPK3; TSC2; ITGA1; KRAS; EIF4EBP1; RELA; PRKCD; NOS3; PRKAA1; MAPK9; CDK2; PPP2CA; PIM1; ITGB7; YWHAZ; ILK; TP53; RAF1.; IKBKG; RELB; DYRK1A; CDKN1A; ITGB1; MAP2K2; JAK1; AKT1; JAK2; PIK3R1; CHUK; PDPK1; PPP2R5C; CTNNB1.; MAP2K1; NFKB1; PAK3; ITGB3; CCND1; GSK3A; FRAP1; SFN; ITGA2; TTK; CSNK1A1; BRAF; GSK3B; AKT3; FOXO1; SGK; HSP90AA1; RPS6KB1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: ERK/MAPK Signaling, PRKCE; ITGAM; ITGA5; HSPB1; IRAK1; PRKAA2; EIF2AK2; RAC1; RAP1A; TLN1; EIF4E; ELK1; GRK6; MAPK1; RAC2; PLK1; AKT2; PIK3CA; CDK8; CREB1; PRKCI; PTK2; FOS; RPS6KA4; PIK3CB; PPP2R1A; PIK3C3; MAPK8; MAPK3; ITGA1; ETS1; KRAS; MYCN; EIF4EBP1; PPARG; PRKCD; PRKAA1; MAPK9; SRC; CDK2; PPP2CA; PIM1; PIK3C2A; ITGB7; YWHAZ; PPP1CC; KSR1; PXN; RAF1; FYN; DYRK1A; ITGB1; MAP2K2; PAK4; PIK3R1; STAT3; PPP2R5C; MAP2K1; PAK3; ITGB3; ESR1; ITGA2; MYC; TTK; CSNK1A1; CRKL; BRAF; ATF4; PRKCA; SRF; STAT1; SGK.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Serine/Threonine-Protein Kinase, CDK16; PCTK1; CDK5R1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glucocorticoid Receptor Signaling, RAC1; TAF4B; EP300; SMAD2; TRAF6; PCAF; ELK1; MAPK1; SMAD3; AKT2; IKBKB; NCOR2; UBE2I; PIK3CA; CREB1; FOS; HSPA5; NFKB2; BCL2; MAP3K14; STAT5B; PIK3CB; PIK3C3; MAPK8; BCL2L1; MAPK3; TSC22D3; MAPK10; NRIP1; KRAS; MAPK13; RELA; STAT5A; MAPK9; NOS2A; PBX1; NR3C1; PIK3C2A; CDKN1C; TRAF2; SERPINE1; NCOA3; MAPK14; TNF; RAF1; IKBKG; MAP3K7; CREBBP; CDKN1A; MAP2K2; JAK1; IL8; NCOA2; AKT1; JAK2; PIK3R1; CHUK; STAT3; MAP2K1; NFKB1; TGFBR1; ESR1; SMAD4; CEBPB; JUN; AR; AKT3; CCL2; MMP1; STAT1; IL6; HSP90AA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Axonal Guidance Signaling, PRKCE; ITGAM; ROCK1; ITGA5; CXCR4; ADAM12; IGF1; RAC1; RAP1A; E1F4E; PRKCZ; NRP1; NTRK2; ARHGEF7; SMO; ROCK2; MAPK1; PGF; RAC2; PTPN11; GNAS; AKT2; PIK3CA; ERBB2; PRKC1; PTK2; CFL1; GNAQ; PIK3CB; CXCL12; PIK3C3; WNT11; PRKD1; GNB2L1; ABL1; MAPK3; ITGA1; KRAS; RHOA; PRKCD; PIK3C2A; ITGB7; GLI2; PXN; VASP; RAF1; FYN; ITGB1; MAP2K2; PAK4; ADAM17; AKT1; PIK3R1; GLI1; WNT5A; ADAM10; MAP2K1; PAK3; ITGB3; CDC42; VEGFA; ITGA2; EPHA8; CRKL; RND1; GSK3B; AKT3; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Ephrin Receptor Signaling, PRKCE; ITGAM; ROCK1; ITGA5; CXCR4; IRAK1; PRKAA2; EIF2AK2; RAC1; RAP1A; GRK6; ROCK2; MAPK1; PGF; RAC2; PTPN11; GNAS; PLK1; AKT2; DOK1; CDK8; CREB1; PTK2; CFL1; GNAQ; MAP3K14; CXCL12; MAPK8; GNB2L1; ABL1; MAPK3; ITGA1; KRAS; RHOA; PRKCD; PRKAA1; MAPK9; SRC; CDK2; PIM1; ITGB7; PXN; RAF1; FYN; DYRK1A; ITGB1; MAP2K2; PAK4, AKT1; JAK2; STAT3; ADAM10; MAP2K1; PAK3; ITGB3; CDC42; VEGFA; ITGA2; EPHA8; TTK; CSNK1A1; CRKL; BRAF; PTPN13; ATF4; AKT3; SGK.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Actin Cytoskeleton Signaling, ACTN4; PRKCE; ITGAM; ROCK1; ITGA5; IRAK1; PRKAA2; EIF2AK2; RAC1; INS; ARHGEF7; GRK6; ROCK2; MAPK1; RAC2; PLK1; AKT2; PIK3CA; CDK8; PTK2; CFL1; PIK3CB; MYH9; DIAPH1; PIK3C3; MAPK8; F2R; MAPK3; SLC9A1; ITGA1; KRAS; RHOA; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; PIK3C2A; ITGB7; PPP1CC; PXN; VIL2; RAF1; GSN; DYRK1A; ITGB1; MAP2K2; PAK4; PIP5K1A; PIK3R1; MAP2K1; PAK3; ITGB3; CDC42; APC; ITGA2; TTK; CSNK1A1; CRKL; BRAF; VAV3; SGK.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Huntington's Disease Signaling, PRKCE; IGF1; EP300; RCOR1.; PRKCZ; HDAC4; TGM2; MAPK1; CAPNS1; AKT2; EGFR; NCOR2; SP1; CAPN2; PIK3CA; HDAC5; CREB1; PRKC1; HSPA5; REST; GNAQ; PIK3CB; PIK3C3; MAPK8; IGF1R; PRKD1; GNB2L1; BCL2L1; CAPN1; MAPK3; CASP8; HDAC2; HDAC7A; PRKCD; HDAC11; MAPK9; HDAC9; PIK3C2A; HDAC3; TP53; CASP9; CREBBP; AKT1; PIK3R1; PDPK1; CASP1; APAF1; FRAP1; CASP2; JUN; BAX; ATF4; AKT3; PRKCA; CLTC; SGK; HDAC6; CASP3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Apoptosis Signaling, PRKCE; ROCK1; BID; IRAK1; PRKAA2; EIF2AK2; BAK1; BIRC4; GRK6; MAPK1; CAPNS1; PLK1; AKT2; IKBKB; CAPN2; CDK8; FAS; NFKB2; BCL2; MAP3K14; MAPK8; BCL2L1; CAPN1; MAPK3; CASP8; KRAS; RELA; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; TP53; TNF; RAF1; IKBKG; RELB; CASP9; DYRK1A; MAP2K2; CHUK; APAF1; MAP2K1; NFKB1; PAK3; LMNA; CASP2; BIRC2; TTK; CSNK1A1; BRAF; BAX; PRKCA; SGK; CASP3; BIRC3; PARP1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: B Cell Receptor Signaling, RAC1; PTEN; LYN; ELK1; MAPK1; RAC2; PTPN11; AKT2; IKBKB; PIK3CA; CREB1; SYK; NFKB2; CAMK2A; MAP3K14; PIK3CB; PIK3C3; MAPK8; BCL2L1; ABL1; MAPK3; ETS1; KRAS; MAPK13; RELA; PTPN6; MAPK9; EGR1; PIK3C2A; BTK; MAPK14; RAF1; IKBKG; RELB; MAP3K7; MAP2K2; AKT1; PIK3R1; CHUK; MAP2K1; NFKB1; CDC42; GSK3A; FRAP1; BCL6; BCL10; JUN; GSK3B; ATF4; AKT3; VAV3; RPS6KB1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Leukocyte Extravasation Signaling, ACTN4; CD44; PRKCE; ITGAM; ROCK1; CXCR4; CYBA; RAC1; RAP1A; PRKCZ; ROCK2; RAC2; PTPN11; MMP14; PIK3CA; PRKCI; PTK2; PIK3CB; CXCL12; PIK3C3; MAPK8; PRKD1; ABL1; MAPK10; CYBB; MAPK13; RHOA; PRKCD; MAPK9; SRC; PIK3C2A; BTK; MAPK14; NOX1; PXN; VIL2; VASP; ITGB1; MAP2K2; CTNND1; PIK3R1; CTNNB1; CLDN1; CDC42; F11R; ITK; CRKL; VAV3; CTTN; PRKCA; MMP1; MMP9.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Integrin Signaling, ACTN4; ITGAM; ROCK1; ITGA5; RAC1; PTEN; RAP1A; TLN1; ARHGEF7; MAPK1; RAC2; CAPNS1; AKT2; CAPN2; P1K3CA; PTK2; PIK3CB; PIK3C3; MAPK8; CAV1; CAPN1; ABL1; MAPK3; ITGA1; KRAS; RHOA; SRC; PIK3C2A; ITGB7; PPP1CC; ILK; PXN; VASP; RAF1; FYN; ITGB1; MAP2K2; PAK4; AKT1; PIK3R1; TNK2; MAP2K1; PAK3; ITGB3; CDC42; RND3; ITGA2; CRKL; BRAF; GSK3B; AKT3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Acute Phase Response Signaling, IRAK1; SOD2; MYD88; TRAF6; ELK1; MAPK1; PTPN11; AKT2; IKBKB; PIK3CA; FOS; NFKB2; MAP3K14; PIK3CB; MAPK8; RIPK1; MAPK3; IL6ST; KRAS; MAPK13; IL6R; RELA; SOCS1; MAPK9; FTL; NR3C1; TRAF2; SERPINE1; MAPK14; TNF; RAF1; PDK1; IKBKG; RELB; MAP3K7; MAP2K2; AKT1; JAK2; PIK3R1; CHUK; STAT3; MAP2K1; NFKB1; FRAP1; CEBPB; JUN; AKT3; IL1R1; IL6.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PTEN Signaling, ITGAM; ITGA5; RAC1; PTEN; PRKCZ; BCL2L11; MAPK1; RAC2; AKT2; EGFR; IKBKB; CBL; PIK3CA; CDKN1B; PTK2; NFKB2; BCL2; PIK3CB; BCL2L1; MAPK3; ITGA1; KRAS; ITGB7; ILK; PDGFRB; INSR; RAF1; IKBKG; CASP9; CDKN1A; ITGB1; MAP2K2; AKT1; PIK3R1; CHUK; PDGFRA; PDPK1; MAP2K1; NFKB1; ITGB3; CDC42; CCND1; GSK3A; ITGA2; GSK3B; AKT3; FOXO1; CASP3; RPS6KB1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: p53 Signaling, PTEN; EP300; BBC3; PCAF; FASN; BRCA1; GADD45A; BIRC5; AKT2; PIK3CA; CHEK1; TP53INP1; BCL2; PIK3CB; PIK3C3; MAPK8; THBS1; ATR; BCL2L1; E2F1; PMAIP1; CHEK2; TNFRSF10B; TP73; RBI; HDAC9; CDK2; PIK3C2A; MAPK14; TP53; LRDD; CDKN1A; HIPK2; AKT1; RIK3R1; RRM2B; APAF1; CTNNB1; SIRT1; CCND1; PRKDC; ATM; SFN; CDKN2A; JUN; SNAI2; GSK3B; BAX; AKT3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Aryl Hydrocarbon Receptor Signaling, HSPB1; EP300; FASN; TGM2; RXRA; MAPK1; NQO1; NCOR2; SP1; ARNT; CDKN1B; FOS; CHEK1; SMARCA4; NFKB2; MAPK8; ALDH1A1; ATR; E2F1; MAPK3; NRIP1; CHEK2; RELA; TP73; GSTP1; RB1; SRC; CDK2; AHR; NFE2L2; NCOA3; TP53; TNF; CDKN1A; NCOA2; APAF1; NFKB1; CCND1; ATM; ESR1; CDKN2A; MYC; JUN; ESR2; BAX; IL6; CYP1B1; HSP90AA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Xenobiotic Metabolism Signaling, PRKCE; EP300; PRKCZ; RXRA; MAPK1; NQO1; NCOR2; PIK3CA; ARNT; PRKCI; NFKB2; CAMK2A; PIK3CB; PPP2R1A; PIK3C3; MAPK8; PRKD1; ALDH1A1; MAPK3; NRIP1; KRAS; MAPK13; PRKCD; GSTP1; MAPK9; NOS2A; ABCB1; AHR; PPP2CA; FTL; NFE2L2; PIK3C2A; PPARGC1A; MAPK14; TNF; RAF1; CREBBP; MAP2K2; PIK3R1; PPP2R5C; MAP2K1; NFKB1; KEAP1; PRKCA; EIF2AK3; IL6; CYP1B1; HSP90AA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: SAPK/JNK Signaling, PRKCE; IRAK1; PRKAA2; EIF2AK2; RAC1; ELK1; GRK6; MAPK1; GADD45A; RAC2; PLK1; AKT2; PIK3CA; FADD; CDK8; PIK3CB; PIK3C3; MAPK8; RIPK1; GNB2L1; IRS1; MAPK3; MAPK10; DAXX; KRAS; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; PIK3C2A; TRAF2; TP53; LCK; MAP3K7; DYRK1A; MAP2K2; PIK3R1; MAP2K1; PAK3; CDC42; JUN; TTK; CSNK1A1; CRKL; BRAF; SGK.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PPAr/RXR Signaling, PRKAA2; EP300; INS; SMAD2; TRAF6; PPARA; FASN; RXRA; MAPK1; SMAD3; GNAS; IKBKB; NCOR2; ABCA1; GNAQ; NFKB2; MAP3K14; STAT5B; MAPK8; IRS1; MAPK3; KRAS; RELA; PRKAA1; PPARGC1A; NCOA3; MAPK14; INSR; RAF1; IKBKG; RELB; MAP3K7; CREBBP; MAP2K2; JAK2; CHUK; MAP2K1; NFKB1; TGFBR1; SMAD4; JUN; IL1R1; PRKCA; IL6; HSP90AA1; ADIPOQ.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: NF-KB Signaling, IRAK1; EIF2AK2; EP300; INS; MYD8; PRKCZ: TRAF6; TBK1; AKT2; EGFR; IKBKB; PIK3CA; BTRC; NFKB2; MAP3K14; PIK3CB; PIK3C3; MAPK8; RIPK1; HDAC2; KRAS; RELA; PIK3C2A; TRAF2; TLR4: PDGFRB; TNF; INSR; LCK; IKBKG; RELB; MAP3K7; CREBBP; AKT1; PIK3R1; CHUK; PDGFRA; NFKB1; TLR2; BCL10; GSK3B; AKT3; TNFAIP3; IL1R1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neuregulin Signaling, ERBB4; PRKCE; ITGAM; ITGA5: PTEN; PRKCZ; ELK1; MAPK1; PTPN11; AKT2; EGFR; ERBB2; PRKCI; CDKN1B; STAT5B; PRKD1; MAPK3; ITGA1; KRAS; PRKCD; STAT5A; SRC; ITGB7; RAF1; ITGB1; MAP2K2; ADAM17; AKT1; PIK3R1; PDPK1; MAP2K1; ITGB3; EREG; FRAP1; PSEN1; ITGA2; MYC; NRG1; CRKL; AKT3; PRKCA; HSP90AA1; RPS6KB1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Wnt & Beta catenin Signaling, CD44; EP300; LRP6; DVL3; CSNK1E; GJA1; SMO; AKT2; PIN1; CDH1; BTRC; GNAQ; MARK2; PPP2R1A; WNT11; SRC; DKK1; PPP2CA; SOX6; SFRP2: ILK; LEF1; SOX9; TP53; MAP3K7; CREBBP; TCF7L2; AKT1; PPP2R5C; WNT5A; LRP5; CTNNB1; TGFBR1; CCND1; GSK3A; DVL1; APC; CDKN2A; MYC; CSNK1A1; GSK3B; AKT3; SOX2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Insulin Receptor Signaling, PTEN; INS; EIF4E; PTPN1; PRKCZ; MAPK1; TSC1; PTPN11; AKT2; CBL; PIK3CA; PRKCI; PIK3CB; PIK3C3; MAPK8; IRS1; MAPK3; TSC2; KRAS; EIF4EBP1; SLC2A4; PIK3C2A; PPP1CC; INSR; RAF1; FYN; MAP2K2; JAK1; AKT1; JAK2; PIK3R1; PDPK1; MAP2K1; GSK3A; FRAP1; CRKL; GSK3B; AKT3; FOXO1; SGK; RPS6KB1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-6 Signaling, HSPB1; TRAF6; MAPKAPK2; ELK1; MAPK1; PTPN11; IKBKB; FOS; NFKB2: MAP3K14; MAPK8; MAPK3; MAPK10; IL6ST; KRAS; MAPK13; IL6R; RELA; SOCS1; MAPK9; ABCB1; TRAF2; MAPK14; TNF; RAF1; IKBKG; RELB; MAP3K7; MAP2K2; IL8; JAK2; CHUK; STAT3; MAP2K1; NFKB1; CEBPB; JUN; IL1R1; SRF; IL6.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Hepatic Cholestasis, PRKCE; IRAK1; INS; MYD8; PRKCZ; TRAF6; PPARA; RXRA; IKBKB; PRKCI; NFKB2; MAP3K14; MAPK8; PRKD1; MAPK10; RELA; PRKCD; MAPK9; ABCB1; TRAF2; TLR4; TNF; INSR; IKBKG; RELB; MAP3K7; IL8; CHUK; NR1H2; TJP2; NFKB1; ESR1; SREBF1; FGFR4; JUN; IL1R1; PRKCA; IL6.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IGF-1 Signaling, IGF1; PRKCZ; ELK1; MAPK1; PTPN11; NEDD4; AKT2; PIK3CA; PRKC1; PTK2; FOS; PIK3CB; PIK3C3; MAPK8; 1GF1R; IRS1; MAPK3; IGFBP7; KRAS; PIK3C2A; YWHAZ; PXN; RAF1; CASP9; MAP2K2; AKT1; PIK3R1; PDPK1; MAP2K1; IGFBP2; SFN; JUN; CYR61; AKT3; FOXO1; SRF; CTGF; RPS6KB1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: NRF2-mediated Oxidative Stress Response, PRKCE; EP300; SOD2; PRKCZ; MAPK1; SQSTM1; NQO1; PIK3CA; PRKC1; FOS; PIK3CB; P1K3C3; MAPK8; PRKD1; MAPK3; KRAS; PRKCD; GSTP1; MAPK9; FTL; NFE2L2; PIK3C2A; MAPK14; RAF1; MAP3K7; CREBBP; MAP2K2; AKT1; PIK3R1; MAP2K1; PPIB; JUN; KEAP1; GSK3B; ATF4; PRKCA; EIF2AK3; HSP90AA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Hepatic, Fibrosis/Hepatic Stellate Cell Activation, EDN1; IGF1; KDR; FLT1; SMAD2; FGFR1; MET; PGF; SMAD3; EGFR; FAS; CSF1; NFKB2; BCL2; MYH9; IGF1R; IL6R; RELA; TLR4; PDGFRB; TNF; RELB; IL8; PDGFRA; NFKB1; TGFBR1; SMAD4; VEGFA; BAX; IL1R1; CCL2; HGF; MMP1; STAT1; IL6; CTGF; MMP9.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PPAR Signaling, EP300; INS; TRAF6; PPARA; RXRA; MAPK1; IKBKB; NCOR2; FOS; NFKB2; MAP3K14; STAT5B; MAPK3; NRIP1; KRAS; PPARG; RELA; STAT5A; TRAF2; PPARGC1A; PDGFRB; TNF; INSR; RAF1; IKBKG; RELB; MAP3K7; CREBBP; MAP2K2; CHUK; PDGFRA; MAP2K1; NFKB1; JUN; IL1R1; HSP90AA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fc Epsilon RI Signaling, PRKCE; RAC1; PRKCZ; LYN; MAPK1; RAC2; PTPN11; AKT2; PIK3CA; SYK; PRKCI; PIK3CB; PIK3C3; MAPK8; PRKD1; MAPK3; MAPK10; KRAS; MAPK13; PRKCD; MAPK9; PIK3C2A; BTK; MAPK14; TNF; RAF1; FYN; MAP2K2; AKT1; PIK3R1; PDPK1; MAP2K1; AKT3; VAV3; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: G-Protein Coupled Receptor Signaling, PRKCE; RAP1A; RGS16; MAPK1; GNAS; AKT2; IKBKB; PIK3CA; CREB1; GNAQ; NFKB2; CAMK2A; PIK3CB; PIK3C3; MAPK3; KRAS; RELA; SRC; PIK3C2A; RAF1; IKBKG; RELB; FYN; MAP2K2; AKT1; PIK3R1; CHUK; PDPK1; STAT3; MAP2K1; NFKB1; BRAF; ATF4; AKT3; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inositol Phosphate Metabolism, PRKCE; IRAK1; PRKAA2; EIF2AK2; PTEN; GRK6; MAPK1; PLK1; AKT2; PIK3CA; CDK8; PIK3CB; PIK3C3; MAPK8; MAPK3; PRKCD; PRKAA1; MAPK9; CDK2; PIM1; PIK3C2A; DYRK1A; MAP2K2; PIP5K1A; PIK3R1; MAP2K1; PAK3; ATM; TTK; CSNK1A1; BRAF; SGK.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: PDGF Signaling, EIF2AK2; ELK1; ABL2; MAPK1; PIK3CA; FOS; PIK3CB;PIK3C3; MAPK8; CAV1; ABL1; MAPK3; KRAS; SRC; PIK3C2A; PDGFRB; RAF1; MAP2K2; JAK1; JAK2; PIK3R1; PDGFRA; STAT3; SPHK1; MAP2K1; MYC; JUN; CRKL; PRKCA; SRF; STAT1; SPHK2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: VEGF Signaling, ACTN4; ROCK1; KDR; FLT1; ROCK2; MAPK1; PGF; AKT2; PIK3CA; ARNT; PTK2; BCL2; PIK3CB; PIK3C3; BCL2L1; MAPK3; KRAS; HIF1A; NOS3; PIK3C2A; PXN; RAF1; MAP2K2; ELAVL1; AKT1; PIK3R1; MAP2K1; SFN; VEGFA; AKT3; FOXO1; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Natural Killer Cell Signaling, PRKCE; RAC1; PRKCZ; MAPK1; RAC2; PTPN11; KIR2DL3; AKT2; PIK3CA; SYK; PRKCI; PIK3CB; PIK3C3; PRKD1; MAPK3; KRAS; PRKCD; PTPN6; PIK3C2A; LCK; RAF1; FYN; MAP2K2; PAK4; AKT1; PIK3R1; MAP2K1; PAK3; AKT3; VAV3; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cell Cycle: G1/S Checkpoint Regulation, HDAC4; SMAD3; SUV39H1; HDAC5; CDKN1B; BTRC; ATR; ABL1; E2F1; HDAC2; HDAC7A; RB1; HDAC11; HDAC9; CDK2; E2F2; HDAC3; TP53; CDKN1A; CCND1; E2F4; ATM; RBL2; SMAD4; CDKN2A; MYC; NRG1; GSK3B; RBL1; HDAC6.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: T Cell Receptor Signaling, RAC1; ELK1; MAPK1; IKBKB; CBL; PIK3CA; FOS; NFKB2; PIK3CB; PIK3C3; MAPK8; MAPK3; KRAS; RELA, PIK3C2A; BTK; LCK; RAF1; IKBKG; RELB, FYN; MAP2K2; PIK3R1; CHUK; MAP2K1; NFKB1; ITK; BCL10; JUN; VAV3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Death Receptor Signaling, CRADD; HSPB1; BID; BIRC4; TBK1; IKBKB; FADD; FAS; NFKB2; BCL2; MAP3K14; MAPK8; RIPK1; CASP8; DAXX; TNFRSF10B; RELA; TRAF2; TNF; IKBKG; RELB; CASP9; CHUK; APAF1; NFKB1; CASP2; BIRC2; CASP3; BIRC3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: FGF Signaling RAC1; FGFR1; MET; MAPKAPK2; MAPK1; PTPN11; AKT2; PIK3CA; CREB1; PIK3CB; PIK3C3; MAPK8; MAPK3; MAPK13; PTPN6; PIK3C2A; MAPK14; RAF1; AKT1; PIK3R1; STAT3; MAP2K1; FGFR4; CRKL; ATF4; AKT3; PRKCA; HGF.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: GM-CSF Signaling, LYN; ELK1; MAPK1; PTPN11; AKT2; PIK3CA; CAMK2A; STAT5B; PIK3CB; PIK3C3; GNB2L1; BCL2L1; MAPK3; ETS1; KRAS; RUNX1; PIM1; PIK3C2A; RAF1; MAP2K2; AKT1; JAK2; PIK3R1; STAT3; MAP2K1; CCND1; AKT3; STAT1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Amyotrophic Lateral Sclerosis Signaling, BID; IGF1; RAC1; BIRC4; PGF; CAPNS1; CAPN2; PIK3CA; BCL2; PIK3CB; PIK3C3; BCL2L1; CAPN1; PIK3C2A; TP53; CASP9; PIK3R1; RAB5A; CASP1; APAF1; VEGFA; BIRC2; BAX; AKT3; CASP3; BIRC3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: JAK/Stat Signaling, PTPN1; MAPK1; PTPN11; AKT2; PIK3CA; STAT5B; PIK3CB; PIK3C3; MAPK3; KRAS; SOCS1; STAT5A; PTPN6; PIK3C2A; RAF1; CDKN1A; MAP2K2; JAK1; AKT1; JAK2; PIK3R1; STAT3; MAP2K1; FRAP1; AKT3; STAT1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nicotinate and Nicotinamide Metabolism, PRKCE; IRAK1; PRKAA2; EIF2AK2; GRK6; MAPK1; PLK1; AKT2; CDK8; MAPK8; MAPK3; PRKCD; PRKAA1; PBEF1; MAPK9; CDK2; PIM1; DYRK1A; MAP2K2; MAP2K1; PAK3; NT5E; TTK; CSNK1A1; BRAF; SGK.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Chemokine Signaling, CXCR4; ROCK2; MAPK1; PTK2; FOS; CFL1; GNAQ; CAMK2A; CXCL12; MAPK8; MAPK3; KRAS; MAPK13; RHOA; CCR3; SRC; PPP1CC; MAPK14; NOXI; RAF1; MAP2K2; MAP2K1; JUN; CCL2; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-2 Signaling, ELK1; MAPK1; PTPN11; AKT2; PIK3CA; SYK; FOS; STAT5B; PIK3CB; PIK3C3; MAPK8; MAPK3; KRAS; SOCS1; STAT5A; PIK3C2A: LCK; RAF1; MAP2K2; JAK1; AKT1; PIK3R1; MAP2K1; JUN; AKT3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Synaptic Long Term Depression, PRKCE; IGF1; PRKCZ; PRDX6; LYN; MAPK1; GNAS; PRKC1; GNAQ; PPP2R1A; IGF1R; PRKID1; MAPK3; KRAS; GRN; PRKCD; NOS3; NOS2A; PPP2CA; YWHAZ; RAF1; MAP2K2; PPP2R5C; MAP2K1; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Estrogen Receptor Signaling, TAF4B; EP300; CARM1; PCAF; MAPK1; NCOR2; SMARCA4; MAPK3; NRIP1; KRAS; SRC; NR3C1; HDAC3; PPARGC1A; RBM9; NCOA3; RAF1; CREBBP; MAP2K2; NCOA2; MAP2K1; PRKDC; ESR1; ESR2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Protein Ubiquitination Pathway, TRAF6; SMURF1; BIRC4; BRCA1; UCHL1; NEDD4; CBL; UBE2I; BTRC; HSPA5; USP7; USP10; FBXW7; USP9X; STUB1; USP22; B2M; BIRC2; PARK2; USPS; USP1; VHL; HSP90AA1; BIRC3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-10 Signaling, TRAF6; CCR1; ELK1; IKBKB; SP1; FOS; NFKB2; MAP3K14; MAPK8; MAPK13; RELA; MAPK14; TNF; IKBKG; RELB; MAP3K7; JAK1; CHUK; STAT3; NFKB1; JUN; IL1R1; IL6.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: VDR/RXR Activation, PRKCE; EP300; PRKCZ; RXRA; GADD45A; HEST; NCOR2; SP1; PRKC1; CDKN1B; PRKD1; PRKCD; RUNX2; KLF4; YY1; NCOA3; CDKN1A; NCOA2; SPP1; LRP5; CEBPB; FOXO1; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: TGF-beta Signaling, EP300; SMAD2; SMURF1; MAPK1; SMAD3; SMAD1; FOS; MAPK8; MAPK3; KRAS; MAPK9; RUNX2; SERPINE1; RAF1; MAP3K7; CREBBP; MAP2K2; MAP2K1; TGFBR1; SMAD4; JUN; SMAD5.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Toll-like Receptor Signaling, IRAK1; EIF2AK2; MYD8; TRAF6; PPARA; ELK1; IKBKB; FOS; NFKB2; MAP3K14; MAPK8; MAPK13; RELA; TLR4; MAPK14; IKBKG; RELB; MAP3K7; CHUK; NFKB1; TLR2; JUN.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: p38 MAPK Signaling, HSPB1; IRAK1; TRAF6; MAPKAPK2; ELK1; FADD; FAS; CREB1; DDIT3; RPS6KA4; DAXX; MAPK13; TRAF2; MAPK14; TNF; MAP3K7; TGFBR1; MYC; ATF4; IL1R1; SRF;
STAT 1. - Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Neurotrophin/TRK Signaling, NTRK2; MAPK1; PTPN11; PIK3CA; CREB1; FOS; PIK3CB; PIK3C3; MAPK8; MAPK3; KRAS; PIK3C2A; RAF1; MAP2K2; AKT1; PIK3R1; PDPK1; MAP2K1; CDC42; JUN; ATF4.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: FXR/RXR Activation, INS; PPARA; FASN; RXRA; AKT2; SDC1; MAPK8; APOB; MAPK10; PPARG; MTTP; MAPK9; PPARGC1A; TNF; CREBBP; AKT1; SREBF1; FGFR4; AKT3; FOXO1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Synaptic Long Term Potentiation, PRKCE; RAP1A; EP300; PRKCZ; MAPK1; CREB1; PRKC1; GNAQ; CAMK2A; PRKD1; MAPK3; KRAS; PRKCD; PPP1CC; RAF1; CREBBP; MAP2K2; MAP2K1; ATF4; PRKCA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Calcium Signaling, RAP1A; EP300; HDAC4; MAPK1; HDAC5; CREB1; CAMK2A; MYH9; MAPK3; HDAC2; HDAC7A; HDAC11; HDAC9; HDAC3; CREBBP; CALR; CAMKK2; ATF4; HDAC6.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: EGF Signaling, ELK1; MAPK1; EGFR; PIK3CA; FOS; PIK3CB; PIK3C3; MAPK8; MAPK3; PIK3C2A; RAF1; JAK1; PIK3R1; STAT3; MAP2K1; JUN; PRKCA; SRF; STAT1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Hypoxia Signaling in the Cardiovascular System, EDN1; PTEN; EP300; NQO1; UBE21; CREB1; ARNT; HIF1A; SLC2A4; NOS3; TP53; LDHA; AKT1; ATM; VEGFA; JUN; ATF4; VHL; HSP90AA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: LPS/IL-1 Mediated Inhibition of RXR Function, IRAK1; MYD88; TRAF6; PPARA; RXRA; ABCA1, MAPK8; ALDH1A1; GSTP1; MAPK9; ABCB1; TRAF2; TLR4; TNF; MAP3K7; NR1H2; SREBF1; JUN; IL1R1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: LXR/RXR Activation, FASN; RXRA; NCOR2; ABCA1; NFKB2; IRF3; RELA; NOS2A; TLR4; TNF; RELB; LDLR; NR1H2; NFKB1; SREBF1; IL1R1; CCL2; IL6; MMP9.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Amyloid Processing, PRKCE; CSNK11E; MAPK1; CAPNS1; AKT2; CAPN2; CAPN1; MAPK3; MAPK13; MAPT; MAPK14; AKT1; PSEN1; CSNK1A1; GSK3B; AKT3; APP.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: IL-4 Signaling, AKT2; PIK3CA; PIK3CB; PIK3C3; IRS1; KRAS; SOCS1; PTPN6; NR3C1; PIK3C2A; JAK1; AKT1; JAK2; PIK3R1; FRAP1; AKT3; RPS6KB1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cell Cycle: G2/M DNA Damage Checkpoint Regulation, EP300; PCAF; BRCA1; GADD45A; PLK1; BTRC; CHEK1; ATR; CHEK2; YWHAZ; TP53; CDKN1A; PRKDC; ATM; SFN; CDKN2A.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nitric Oxide Signaling in the Cardiovascular System, KDR; FLT1; PGF; AKT2; PIK3CA; PIK3CB; PIK3C3; CAV1; PRKCD; NOS3; PIK3C2A; AKT1; PIK3R1; VEGFA; AKT3; HSP90AA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Purine Metabolism NME2; SMARCA4; MYH9; RRM2; ADAR; EIF2AK4; PKM2; ENTPD1; RAD51; RRM2B; TJP2; RAD51C; NT5E; POLD1; NME1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: cAMP-mediated Signaling, RAP1A; MAPK1; GNAS; CREB1; CAMK2A; MAPK3; SRC; RAF1; MAP2K2; STAT3; MAP2K1; BRAF; ATF4.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Mitochondrial Dysfunction Notch Signaling, SOD2; MAPK8; CASP8; MAPK10; MAPK9; CASP9; PARK7; PSEN1; PARK2; APP; CASP3 HES1; JAG1; NUMB; NOTCH4; ADAM17; NOTCH2; PSEN1; NOTCH3; NOTCH1; DLL4.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Endoplasmic Reticulum Stress Pathway, HSPA5; MAPK8; XBP1; TRAF2; ATF6; CASP9; ATF4; EIF2AK3; CASP3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pyrimidine Metabolism, NME2; AICDA; RRM2; EIF2AK4; ENTPD1; RRM2B; NT5E; POLD1; NME1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Parkinson's Signaling, UCHL1; MAPK8; MAPK13; MAPK14; CASP9; PARK7; PARK2; CASP3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cardiac & Beta Adrenergic Signaling, GNAS; GNAQ; PPP2R1A; GNB2L1; PPP2CA; PPP1CC; PPP2R5C.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycolysis/Gluco-neogenesis, HK2; GCK; GPI; ALDH1A1; PKM2; LDHA; HK1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Interferon Signaling, IRF1; SOCS1; JAK1; JAK2; IFITM1; STAT1; IFIT3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Sonic Hedgehog Signaling, ARRB2; SMO; GLI2; DYRK1A; GLI1; GSK3B; DYRKIB.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycerophospholipid Metabolism, PLD1; GRN; GPAM; YWHAZ; SPHK1; SPHK2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Phospholipid Degradation, PRDX6; PLD1; GRN; YWHAZ; SPHK1; SPHK2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Tryptophan Metabolism, SIAH2; PRMT5; NEDD4; ALDH1A1; CYP1B1; SIAH1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Lysine Degradation, SUV39H1; EHMT2; NSD1; SETD7; PPP2R5C.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Nucleotide Excision, ERCC5; ERCC4; XPA; XPC; ERCC1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Repair Pathway Starch and Sucrose Metabolism, UCHL1; HK2; GCK; GPI; HK1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Aminosugars Metabolism, NQO1; HK2; GCK; HK1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Arachidonic Acid Metabolism, PRDX6; GRN; YWHAZ; CYP1B1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Circadian Rhythm Signaling, CSNK1E; CREB1; ATF4; NR1D1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Coagulation System, BDKRB1; F2R; SERPINE1; F3.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Dopamine Receptor Signaling, PPP2R1A; PPP2CA; PPP1CC; PPP2R5C.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glutathione Metabolism, IDH2; GSTP1; ANPEP; IDH1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycerolipid Metabolism, ALDH1A1; GPAM; SPHK1; SPHK2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Linoleic Acid Metabolism, PRDX6; GRN; YWHAZ; CYP1B1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Methionine Metabolism, DNMT1; DNMT3B; AHCY; DNMT3A.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pyruvate Metabolism, GLO1; ALDH1A1; PKM2; LDHA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Arginine and Proline Metabolism, ALDH1A1; NOS3; NOS2A.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Eicosanoid Signaling, PRDX6; GRN; YWHAZ.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fructose and Mannose Metabolism, HK2; GCK; HK1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Galactose Metabolism, HK2; GCK; HK1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Stilbene, Coumarine and Lignin Biosynthesis, PRDX6; PRDX1; TYR.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Antigen Presentation Pathway, CALR; B2M.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Biosynthesis of Steroids, NQO1; DHCR7.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Butanoate Metabolism, ALDH1A1; NLGN1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Citrate Cycle, IDH2; IDH1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fatty Acid Metabolism, ALDH1A1; CYP1B1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycerophospholipid Metabolism, PRDX6; CHKA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Histidine Metabolism, PRMT5; ALDH1A1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Inositol Metabolism, ERO1L; APEX1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Metabolism of Xenobiotics by Cytochrome p450, GSTP1; CYP1B1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Methane Metabolism, PRDX6; PRDX1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Phenylalanine Metabolism, PRDX6; PRDX1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Propanoate Metabolism, ALDH1A1; LDHA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Selenoamino Acid Metabolism, PRMT5; AHCY.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Sphingolipid Metabolism, SPHK1; SPHK2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Aminophosphonate Metabolism, PRMT5.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Androgen and Estrogen Metabolism, PRMT5.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Ascorbate and Aldarate Metabolism, ALDH1A1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Bile Acid Biosynthesis, ALDH1A1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Cysteine Metabolism, LDHA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Fatty Acid Biosynthesis, FASN.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glutamate Receptor Signaling, GNB2L1.
- Examples of genes and/or polynucleotides that can be edited with the guide molecules of this invention include: NRF2-mediated Oxidative Stress Response, PRDX1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pentose Phosphate Pathway, GPI.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pentose and Glucuronate Interconversions, UCHL1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Retinol Metabolism, ALDH1A1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Riboflavin Metabolism, TYR.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Tyrosine Metabolism, PRMT5, TYR.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Ubiquinone Biosynthesis, PRMT5.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Valine, Leucine and Isoleucine Degradation, ALDH1A1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Glycine, Serine and Threonine Metabolism, CHKA.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Lysine Degradation, ALDH1A1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pain/Taste, TRPM5; TRPA1.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Pain, TRPM7; TRPC5; TRPC6; TRPC1; Cnr1; cnr2; Grk2; Trpa1; Pomc; Cgrp; Crf; Pka; Era; Nr2b; TRPM5; Prkaca; Prkacb; Prkar1a; Prkar2a.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Mitochondrial Function, AIF; CytC; SMAC (Diablo); Aifm-1; Aifm-2.
- Examples of genes for which a mUNA molecule can be used to express the corresponding peptide or protein include: Developmental Neurology, BMP-4; Chordin (Chrd); Noggin (Nog); WNT (Wnt2; Wnt2b; Wnt3a; Wnt4; Wnt5a; Wnt6; Wnt7b; Wnt8b; Wnt9a; Wnt9b; Wnt10a; Wnt10b; Wnt16); beta-catenin; Dick-1; Frizzled related proteins; Otx-2; Gbx2; FGF-8; Reelin; Dab1; unc-86 (Pou4f1 or Brn3a); Numb; Reln.
- mUNA Methods
- In various aspects, this invention provides methods for synthesis of mUNA messenger UNA oligomer molecules.
- mUNA oligomer molecules of this invention can be synthesized and isolated using methods disclosed herein, as well as any pertinent techniques known in the art.
- Some methods for preparing nucleic acids are given in, for example, Merino, Chemical Synthesis of Nucleoside Analogues, (2013); Gait, Oligonucleotide synthesis: a practical approach (1984); Herdewijn, Oligonucleotide Synthesis, Methods in Molecular Biology, Vol. 288 (2005).
- In some embodiments, a ligase can be used to link a synthetic oligomer to the 3′ end of an RNA molecule or an RNA transcript to form a mUNA molecule. The synthetic oligomer that is ligated to the 3′ end can provide the functionality of a polyA tail, and advantageously provide resistance to its removal by 3′-exoribonucleases. The ligated product mUNA molecule can have increased specific activity and provide increased levels of ectopic protein expression.
- In certain embodiments, ligated product mUNA molecules of this invention can be made with an RNA transcript that has native specificity. The ligated product can be a synthetic molecule that retains the structure of the RNA transcript at the 5′ end to ensure compatibility with the native specificity.
- In further embodiments, ligated product mUNA molecules of this invention can be made with an exogenous RNA transcript or non-natural RNA. The ligated product can be a synthetic molecule that retains the structure of the RNA.
- In general, the canonical mRNA degradation pathway in cells includes the steps: (i) the polyA tail is gradually cut back to a stub by 3′ exonucleases, shutting down the looping interaction required for efficient translation and leaving the cap open to attack; (ii) decapping complexes remove the 5′ cap; (iii) the unprotected and translationally incompetent residuum of the transcript is degraded by 5′ and 3′ exonuclease activity.
- Embodiments of this invention involve new mUNA structures which can have increased translational activity over a native transcript. The mUNA molecules can prevent exonucleases from trimming back the polyA tail in the process of de-adenylation.
- Embodiments of this invention provide structures, compositions and methods for translatable mUNA molecules. Embodiments of this invention can provide translatable mUNA molecules containing one or more UNA monomers and having increased functional half-life.
- It has been found that ligation of a synthetic oligomer to the 3′ end of an mRNA transcript can surprisingly be accomplished with high conversion of the mRNA transcript to the ligation product. The ligase can catalyze the joining of the 3′-hydroxyl terminus of the RNA transcript to a synthetic oligomer bearing a 5′ monophosphate group. The 3′ end of the synthetic oligomer can be blocked to prevent circularization and concatemerization, while the presence of a triphosphate or cap moiety at the 5′ terminus of the mRNA transcript can prevent its entry into undesired side reactions.
- In some embodiments, the yield of conversion of the mRNA transcript to the ligation product mUNA molecule can be from 70% to 100%. In some embodiments, the yield of conversion of the mRNA transcript to the ligation product can be 70%, 80%, 90%, 95%, 99%, or 100%.
- As used herein, the terms polyA tail and polyA oligomer refer to an oligomer of monomers, wherein the monomers can include nucleotides based on adenine, UNA monomers, naturally-occurring nucelotides, modified nucleotides, or nucleotide analogues.
- A modified nucleotide can be base-modified, sugar-modified, or linkage modified.
- Splint Ligation Methods
- Embodiments of this invention can employ splint ligation to synthesize mUNA molecules.
- In some aspects, ligation of a tail oligomer to the 3′ end of an RNA molecule can surprisingly be accomplished with high conversion of the RNA molecule to the ligation product by using a DNA splint oligomer. Splint ligation of specific RNA molecules can be done with a DNA ligase and a bridging DNA splint oligomer that is complementary to the RNAs.
- As used herein, a molecule to which a tail oligomer is added can be referred to as an acceptor oligomer, and a tail oligomer to be ligated to an acceptor oligomer can be referred to as a donor oligomer.
- A donor oligomer of this invention may contain one or more UNA monomers. In some embodiments, a donor oligomer may be composed of UNA monomers and adenylate nucleotides.
- A donor oligomer of this invention may include any number of UNA monomers within its total length.
- An acceptor oligomer of this invention can be a RNA of any length, an mRNA, or a mammalian gene transcript.
- In some aspects, ligation of a donor oligomer of any length to the 3′ end of an acceptor RNA molecule can surprisingly be accomplished with high conversion to the ligation product mUNA molecule by using a DNA splint oligomer.
- In certain embodiments, a DNA splint oligomer can hybridize to the end of an mRNA having a short polyA tail, anchored in a specific position based on a region complementary to the end of the mRNA's 3′ UTR. The polyA tail can be about 30 monomers or less in length. The DNA splint oligomer can incorporate a poly(dT) tail that overhangs beyond the native polyA tail of the mRNA transcript. The poly(dT) tail can bring a polyA oligomer into position for efficient ligation to the synthetic mRNA.
- Embodiments of this invention can employ splint ligation to introduce UNA monomers, modified nucleotides, or nucleotide analogues into RNA molecules.
- In certain embodiments, in splint ligation the DNA ligase can be used to join RNA molecules in an RNA:DNA hybrid.
- In some embodiments, the donor can be from 2 to 120 monomers in length, or from 3 to 120 monomers, or from 4 to 120 monomers, or from 5 to 120 monomers, or from 6 to 120 monomers, or longer.
- The splint oligomer can be removed from the ligation product using a DNAse treatment, which can be required post-IVT to remove the DNA template for transcription.
- Cohesive End Ligation
- In some embodiments, a wild-type T4 RNA ligase can be used to join the 3′ hydroxyl terminus of an RNA transcript to a tail oligomer bearing a 5′ monophosphate group.
- In further embodiments, a KQ mutant variant of
T4 RNA Ligase 2, which requires a pre-adenylated donor, was used to join the 3′ hydroxyl terminus of an RNA transcript to a pre-adenylated tail oligomer. - In these embodiments, a preponderance of the tail can advantageously be incorporated co-transcriptionally in the IVT synthetic RNA transcript, and the donor oligomer can be correspondingly shortened.
- Post-Ligation Treatment
- In some aspects, a 3′-exonuclease treatment can be used to remove the unligated fraction of the product of the ligation reaction. Examples of a 3′-exonuclease include Exonuclease T, Ribonuclease R, and analogs thereof.
- In certain embodiments, Ribonuclease R can be used with high processivity, and the ligation can be insensitive to sequence content and variations, as well as secondary structure.
- Tail Oligomers
- In some embodiments, the 100% bulk ligation of a tail oligomer to the 3′ end of an RNA has been achieved.
- Donor oligomers of this invention for ligation to the 3′ end of an mRNA may be from 2 to 120 monomers in length, or from 3 to 120 monomers in length, or from 4 to 120 monomers in length, or from 5 to 120 monomers in length, or longer.
- In further embodiments, a donor oligomer may have a 3′-terminal modification to block circularization or oligimerization of the synthetic oligomer in ligation reactions. Examples of a 3′-terminal modification include a 3′-terminal C3 spacer.
- A donor oligomer of this invention may contain one or more UNA monomers.
- A donor oligomer can include one or more nucleic acid monomers that are naturally-occurring nucleotides, modified naturally-occurring nucleotides, or non-naturally-occurring nucleotides.
- A donor oligomer can include a nucleic acid monomer that is base-modified, sugar-modified, or linkage modified.
- Pharmaceutical Compositions
- In some aspects, this invention provides pharmaceutical compositions containing a mUNA oligomeric compound and a pharmaceutically acceptable carrier.
- A pharmaceutical composition can be capable of local or systemic administration. In some aspects, a pharmaceutical composition can be capable of any modality of administration. In certain aspects, the administration can be intravenous, subcutaneous, pulmonary, intramuscular, intraperitoneal, dermal, oral, or nasal administration.
- Embodiments of this invention include pharmaceutical compositions containing an oligomeric compound in a lipid formulation.
- In some embodiments, a pharmaceutical composition may comprise one or more lipids selected from cationic lipids, anionic lipids, sterols, pegylated lipids, and any combination of the foregoing.
- In certain embodiments, a pharmaceutical composition can be substantially free of liposomes.
- In further embodiments, a pharmaceutical composition can include liposomes or nanoparticles.
- Some examples of lipids and lipid compositions for delivery of an active molecule of this invention are given in WO/2015/074085, which is hereby incorporated by reference in its entirety.
- In additional embodiments, a pharmaceutical composition can contain an oligomeric compound within a viral or bacterial vector.
- A pharmaceutical composition of this disclosure may include carriers, diluents or excipients as are known in the art. Examples of pharmaceutical compositions and methods are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro ed. 1985), and Remington, The Science and Practice of Pharmacy, 21st Edition (2005).
- Examples of excipients for a pharmaceutical composition include antioxidants, suspending agents, dispersing agents, preservatives, buffering agents, tonicity agents, and surfactants.
- An effective dose of an agent or pharmaceutical formulation of this invention can be an amount that is sufficient to cause translation of a mUNA molecule in a cell.
- A therapeutically effective dose can be an amount of an agent or formulation that is sufficient to cause a therapeutic effect. A therapeutically effective dose can be administered in one or more separate administrations, and by different routes.
- A therapeutically effective dose, upon administration, can result in serum levels of an active agent of 1-1000 pg/ml, or 1-1000 ng/ml, or 1-1000 μg/ml, or more.
- A therapeutically effective dose of an active agent in vivo can be a dose of 0.001-0.01 mg/kg body weight, or 0.01-0.1 mg/kg, or 0.1-1 mg/kg, or 1-10 mg/kg, or 10-100 mg/kg.
- A therapeutically effective dose of an active agent in vivo can be a dose of 0.001 mg/kg body weight, or 0.01 mg/kg, or 0.1 mg/kg, or 1 mg/kg, or 2 mg/kg, or 3 mg/kg, or 4 mg/kg, or 5 mg/kg, or more.
- A subject can be an animal, or a human subject or patient.
- Base sequences show herein are from left to right, 5′ to 3′, unless stated otherwise.
- For the examples below, the mUNA transfection protocol in vitro was as follows:
-
- 1Plate mouse hepatocyte Hepa1-6
cells 5000 cells per well in 96 well plate at least 8 hours before transfection. - 2 Replace 90 uL DMEM medium containing 10% FBS and Non-essential amino acid) adding 90 uL into each well of 96 well plate immediately before beginning the transfection experiment.
- 3 Prepare Messenger Max transfection reagent (Life Technologies) mUNA complex according to manufacturer's instruction.
- 4 Transfer 10 uL of the complex into a well containing the cells in the 96-well plate.
- 5 Collect the medium after desired time points and add 100 uL fresh medium into each well. Medium will be kept at −80° C. until ELISA assay is performed using the standard manufacturer protocol.
- 1Plate mouse hepatocyte Hepa1-6
- For the examples below, the mUNA transfection protocol in vivo was as follows:
-
- 1 The mUNA is formulated with Lipid nanoparticle (LNP).
- 2 Inject the LNP-formulated mUNA (1 mg/kg mUNA) into BL57BL/c mice (4-6 week-old) via standard i.v. injection in the lateral tail vein.
- 3 Collect approximately 50 uL of blood in a Heparin-coated microcentrifuge tube.
- 4 Centrifuge at 3,000×g for 10 minutes at 4° C.
- 5 Transfer the supernatant (plasma) into a fresh microcentrifuge tube. Plasma will be kept at −80° C. until ELISA assay is performed using the standard manufacturer protocol.
- All of the comparative mUNA and mRNA molecules in the examples below were synthesized with the 5′ cap being a m7GpppGm cap. Unless otherwise specified, the mUNA molecules in the examples below contained a 5′-UTR of TEV, and a 3′ UTR of xenopus beta-globin.
- In this example, a translatable mUNA molecule was made and used for expressing human Factor IX (FT9) in vivo with advantageously increased efficiency of translation, as compared to the mRNA of Factor IX. The translatable mUNA molecule expressing human Factor IX in vivo exhibited activity suitable for use in methods for ameliorating or treating hemophilia B. In this embodiment, the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a F9 CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- The translation efficiency of this mUNA molecule is shown in
FIG. 1 , as compared to the mRNA of F9. - The mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human F9.
-
FIG. 1 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of F9. In particular, after 55 hours, the translation efficiency of this mUNA molecule was increased by more than 2-fold (827/388) as compared to the mRNA of F9. - Details of the base structure of this translatable mUNA molecule are as follows:
-
(SEQ ID NO: 1) (m7GpppGm)GGGAAACAUAAGUCAACACAACAUAUACAAAACAAACGAA UCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUC UUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUA GCCAUGGCCCAGCGCGUGAACAUGAUCAUGGCAGAAUCACCAGGCCUCAU CACCAUCUGCCUUUUAGGAUAUCUACUCAGUGCUGAAUGUACAGUUUUUC UUGAUCAUGAAAACGCCAACAAAAUUCUGAAUCGGCCAAAGAGGUAUAAU UCAGGUAAAUUGGAAGAGUUUGUUCAAGGGAACCUUGAGAGAGAAUGUAU GGAAGAAAAGUGUAGUUUUGAAGAAGCACGAGAAGUUUUUGAAAACACUG AAAGAACAACUGAAUUUUGGAAGCAGUAUGUUGAUGGAGAUCAGUGUGAG UCCAAUCCAUGUUUAAAUGGCGGCAGUUGCAAGGAUGACAUUAAUUCCUA UGAAUGUUGGUGUCCCUUUGGAUUUGAAGGAAAGAACUGUGAAUUAGAUG UAACAUGUAACAUUAAGAAUGGCAGAUGCGAGCAGUUUUGUAAAAAUAGU GCUGAUAACAAGGUGGUUUGCUCCUGUACUGAGGGAUAUCGACUUGCAGA AAACCAGAAGUCCUGUGAACCAGCAGUGCCAUUUCCAUGUGGAAGAGUUU CUGUUUCACAAACUUCUAAGCUCACCCGUGCUGAGACUGUUUUUCCUGAU GUGGACUAUGUAAAUUCUACUGAAGCUGAAACCAUUUUGGAUAACAUCAC UCAAAGCACCCAAUCAUUUAAUGACUUCACUCGGGUUGUUGGUGGAGAAG AUGCCAAACCAGGUCAAUUCCCUUGGCAGGUUGUUUUGAAUGGUAAAGUU GAUGCAUUCUGUGGAGGCUCUAUCGUUAAUGAAAAAUGGAUUGUAACUGC UGCCCACUGUGUUGAAACUGGUGUUAAAAUUACAGUUGUCGCAGGUGAAC AUAAUAUUGAGGAGACAGAACAUACAGAGCAAAAGCGAAAUGUGAUUCGA AUUAUUCCUCACCACAACUACAAUGCAGCUAUUAAUAAGUACAACCAUGA CAUUGCCCUUCUGGAACUGGACGAACCCUUAGUGCUAAACAGCUACGUUA CACCUAUUUGCAUUGCUGACAAGGAAUACACGAACAUCUUCCUCAAAUUU GGAUCUGGCUAUGUAAGUGGCUGGGGAAGAGUCUUCCACAAAGGGAGAUC AGCUUUAGUUCUUCAGUACCUUAGAGUUCCACUUGUUGACCGAGCCACAU GUCUUCGAUCUACAAAGUUCACCAUCUAUAACAACAUGUUCUGUGCUGGC UUCCAUGAAGGAGGUAGAGAUUCAUGUCAAGGAGAUAGUGGGGGACCCCA UGUUACUGAAGUGGAAGGGACCAGUUUCUUAACUGGAAUUAUUAGCUGGG GUGAAGAGUGUGCAAUGAAAGGCAAAUAUGGAAUAUAUACCAAGGUAUCC CGGUAUGUCAACUGGAUUAAGGAAAAAACAAAGCUCACUUGACUAGUGAC UGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGA GUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCA AAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAU AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAÃÃAA - In this example, the translatable mUNA molecule of Example 1 (SEQ ID NO: 1) was made and used for expressing human Factor IX (F9) in vitro with advantageously increased efficiency of translation, as compared to the mRNA of Factor IX. The translatable mUNA molecule expressing human Factor IX exhibited activity suitable for use in methods for ameliorating or treating hemophilia B.
- The translation efficiency of this mUNA molecule (SEQ ID NO: 1) is shown in
FIG. 2 , as compared to the mRNA of F9. - The mUNA molecule of this embodiment was traslated in mouse hepatocyte cell line Hepa1-6 to produce human F9.
-
FIG. 2 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of F9. In particular, after 48 hours, the translation efficiency of this mUNA molecule was increased by 5-fold (91/16) as compared to the mRNA of F9. - In this example, a translatable mUNA molecule was made and used for expressing human Erythropoietin (EPO) in vitro with advantageously increased efficiency of translation, as compared to the mRNA of EPO. The translatable mUNA molecule expressing human EPO exhibited activity suitable for use in methods for ameliorating or treating certain anemias, inflammatory bowel disease, and/or certain myelodysplasias. In this embodiment, the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a human EPO CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- The translation efficiency of this mUNA molecule is shown in
FIG. 3 , as compared to the mRNA of EPO. - The mUNA molecule of this embodiment was translated in mouse hepatocyte cell line Hepa1-6 to produce human EPO.
-
FIG. 3 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of F9. In particular, after 48 hours, the translation efficiency of this mUNA molecule was more than doubled (4500/1784) as compared to the mRNA of EPO. - Details of the base structure of this translatable mUNA molecule are as follows:
-
(SEQ ID NO: 2) (m7GpppGm)GGGAAACAUAAGUCAACACAACAUAUACAAAACAAACGAA UCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUC UUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUA GCCAUGGGGGUGCACGAAUGUCCUGCCUGGCUGUGGCUUCUCCUGUCCCU GCUGUCGCUCCCUCUGGGCCUCCCAGUCCUGGGCGCCCCACCACGCCUCA UCUGUGACAGCCGAGUCCUGGAGAGGUACCUCUUGGAGGCCAAGGAGGCC GAGAAUAUCACGACGGGCUGUGCUGAACACUGCAGCUUGAAUGAGAAUAU CACUGUCCCAGACACCAAAGUUAAUUUCUAUGCCUGGAAGAGGAUGGAGG UCGGGCAGCAGGCCGUAGAAGUCUGGCAGGGCCUGGCCCUGCUGUCGGAA GCUGUCCUGCGGGGCCAGGCCCUGUUGGUCAACUCUUCCCAGCCGUGGGA GCCCCUGCAGCUGCAUGUGGAUAAAGCCGUCAGUGGCCUUCGCAGCCUCA CCACUCUGCUUCGGGCUCUGGGAGCCCAGAAGGAAGCCAUCUCCCCUCCA GAUGCGGCCUCAGCUGCUCCACUCCGAACAAUCACUGCUGACACUUUCCG CAAACUCUUCCGAGUCUACUCCAAUUUCCUCCGGGGAAAGCUGAAGCUGU ACACAGGGGAGGCCUGCAGGACAGGGGACAGAUGACUAGUGACUGACUAG GAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUA AGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUA GCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAÃ ÃAA - In this example, several translatable mUNA molecules were made and used for expressing mouse Erythropoietin (EPO) in vitro with advantageously increased efficiency of translation, as compared to the mRNA of EPO. In this embodiment, the translatable mUNA molecules each comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a mouse EPO CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- The translation efficiency of these mUNA molecules (#2, 3, 4, 5, 6, 7, 8, 9, 10 and 11) are shown in
FIG. 4 , as compared to the mRNA of EPO (#1). - The mUNA molecules of this embodiment were translated in mouse hepatocyte cell line Hepa1-6 to produce mouse EPO.
-
FIG. 4 shows that the translation efficiency of the mUNA molecules (#2, 3, 4, 5, 6, 7, 8, 9, 10 and 11) was advantageously and surprisingly increased as compared to the mRNA of EPO (#1). In particular, after 72 hours, the translation efficiency of the mUNA molecules was increased by up to 8-fold (0.203/0.025) as compared to the mRNA of EPO, and the translation efficiency of every mUNA molecule (#2, 3, 4, 5, 6, 7, 8, 9, 10 and 11) was increased as compared to the mRNA of EPO (#1). - Details of the base structure of the translatable
mUNA molecule # 2 are as follows: -
(SEQ ID NO: 3) (m7GpppGm)GGGAAACAUAAGUCAACACAACAUAUACAAAACAAACGAA UCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUC UUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUA GCCAUGGGGGUGCCCGAACGUCCCACCCUGCUGCUUUUACUCUCCUUGCU ACUGAUUCCUCUGGGCCUCCCAGUCCUCUGUGCUCCCCCACGCCUCAUCU GCGACAGUCGAGUUCUGGAGAGGUACAUCUUAGAGGCCAAGGAGGCAGAA AAUGUCACGAUGGGUUGUGCAGAAGGUCCCAGACUGAGUGAAAAUAUUAC AGUCCCAGAUACCAAAGUCAACUUCUAUGCUUGGAAAAGAAUGGAGGUGG AAGAACAGGCCAUAGAAGUUUGGCAAGGCCUGUCCCUGCUCUCAGAAGCC AUCCUGCAGGCCCAGGCCCUGCUAGCCAAUUCCUCCCAGCCACCAGAGAC CCUUCAGCUUCAUAUAGACAAAGCCAUCAGUGGUCUACGUAGCCUCACUU CACUGCUUCGGGUACUGGGAGCUCAGAAGGAAUUGAUGUCGCCUCCAGAU ACCACCCCACCUGCUCCACUCCGAACACUCACAGUGGAUACUUUCUGCAA GCUCUUCCGGGUCUACGCCAACUUCCUCCGGGGGAAACUGAAGCUGUACA CGGGAGAGGUCUGCAGGAGAGGGGACAGGTGACUAGUGACUGACUAGGAU CUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGC UACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCC AUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA{tilde over (ÃA)} - Details of the base structure of the translatable
mUNA molecules # 3 through #11 that were made are the same asmolecule # 2, except that the 3′ terminal tail regions, the last 40 monomers are as follows: -
mUNA molecule #3 (SEQ ID NO: 4) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAÃÃAA mUNA molecule #4 (SEQ ID NO: 5) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAÃÃAAAA mUNA molecule #5 (SEQ ID NO: 6) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAÃÃAAAAAA mUNA molecule #6 (SEQ ID NO: 7) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAÃÃAAAAAAAA mUNA molecule #7 (SEQ ID NO: 8) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAÃÃAAAAAAAAAA mUNA molecule #8 (SEQ ID NO: 9) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAÃÃAAAAAAAAAAAA mUNA molecule #9 (SEQ ID NO: 10) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAÃÃAAAAAAAAAAAAAA mUNA molecule #10 (SEQ ID NO: 11) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAÃÃAAAAAAAAAAAAAAAA mUNA molecule #11 (SEQ ID NO: 12) AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAÃÃAAAAAAAAAAAAAAAAAA - In this example, a translatable mUNA molecule was made and used for expressing human alpha-1-Antitrypsin in vivo with advantageously increased efficiency of translation, as compared to the mRNA of human alpha-1-Antitrypsin. The translatable mUNA molecule expressing human alpha-1-Antitrypsin exhibited activity suitable for use in methods for ameliorating or treating alpha-1-Antitrypsin deficiency. In this embodiment, the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a human alpha-1-Antitrypsin CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- The translation efficiency of this mUNA molecule is shown in
FIG. 5 , as compared to the mRNA of human alpha-1-Antitrypsin. - The mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human alpha-1-Antitrypsin.
-
FIG. 5 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of human alpha-1-Antitrypsin. In particular, after 72 hours, the translation efficiency of this mUNA molecule was increased by more than 3-fold (87.8/25.4) as compared to the mRNA of human alpha-1-Antitrypsin. - Details of the base structure of this translatable mUNA molecule were as follows:
-
(SEQ ID NO: 13) (m7GpppGm)GGGAAACAUAAGUCAACACAACAUAUACAAAACAAACGAA UCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUC UUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUA GCCAUGCCGUCUUCUGUCUCGUGGGGCAUCCUCCUGCUGGCAGGCCUGUG CUGCCUGGUCCCUGUCUCCCUGGCUGAGGAUCCCCAGGGAGAUGCUGCCC AGAAGACAGAUACAUCCCACCAUGAUCAGGAUCACCCAACCUUCAACAAG AUCACCCCCAACCUGGCUGAGUUCGCCUUCAGCCUAUACCGCCAGCUGGC ACACCAGUCCAACAGCACCAAUAUCUUCUUCUCCCCAGUGAGCAUCGCUA CAGCCUUUGCAAUGCUCUCCCUGGGGACCAAGGCUGACACUCACGAUGAA AUCCUGGAGGGCCUGAAUUUCAACCUCACGGAGAUUCCGGAGGCUCAGAU CCAUGAAGGCUUCCAGGAACUCCUCCGUACCCUCAACCAGCCAGACAGCC AGCUCCAGCUGACCACCGGCAAUGGCCUGUUCCUCAGCGAGGGCCUGAAG CUAGUGGAUAAGUUUUUGGAGGAUGUUAAAAAGUUGUACCACUCAGAAGC CUUCACUGUCAACUUCGGGGACACCGAAGAGGCCAAGAAACAGAUCAACG AUUACGUGGAGAAGGGUACUCAAGGGAAAAUUGUGGAUUUGGUCAAGGAG CUUGACAGAGACACAGUUUUUGCUCUGGUGAAUUACAUCUUCUUUAAAGG CAAAUGGGAGAGACCCUUUGAAGUCAAGGACACCGAGGAAGAGGACUUCC ACGUGGACCAGGUGACCACCGUGAAGGUGCCUAUGAUGAAGCGUUUAGGC AUGUUUAACAUCCAGCACUGUAAGAAGCUGUCCAGCUGGGUGCUGCUGAU GAAAUACCUGGGCAAUGCCACCGCCAUCUUCUUCCUGCCUGAUGAGGGGA AACUACAGCACCUGGAAAAUGAACUCACCCACGAUAUCAUCACCAAGUUC CUGGAAAAUGAAGACAGAAGGUCUGCCAGCUUACAUUUACCCAAACUGUC CAUUACUGGAACCUAUGAUCUGAAGAGCGUCCUGGGUCAACUGGGCAUCA CUAAGGUCUUCAGCAAUGGGGCUGACCUCUCCGGGGUCACAGAGGAGGCA CCCCUGAAGCUCUCCAAGGCCGUGCAUAAGGCUGUGCUGACCAUCGACGA GAAAGGGACUGAAGCUGCUGGGGCCAUGUUUUUAGAGGCCAUACCCAUGU CUAUCCCCCCCGAGGUCAAGUUCAACAAACCCUUUGUCUUCUUAAUGAUU GAACAAAAUACCAAGUCUCCCCUCUUCAUGGGAAAAGUGGUGAAUCCCAC CCAAAAAUAACUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCU CAAGAACACCCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUU ACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAA AAGAAAGUUUCUUCACAUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAÃÃAAAA - In this example, a translatable mUNA molecule was made and used for expressing human Erythropoietin (EPO) in vivo with advantageously increased efficiency of translation, as compared to the mRNA of EPO. The translatable mUNA molecule expressing human EPO exhibited activity suitable for use in methods for ameliorating or treating certain anemias, inflammatory bowel disease, and/or certain myelodysplasias. In this embodiment, the translatable mUNA molecule comprised a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a human EPO CDS, a 3′UTR of xenopus beta-globin, and a tail region.
- The translation efficiency of this mUNA molecule is shown in
FIG. 6 , as compared to the mRNA of EPO. - The mUNA molecule of this embodiment was translated in C57BL/c mouse to produce human EPO.
-
FIG. 6 shows that the translation efficiency of this mUNA molecule was advantageously and surprisingly increased as compared to the mRNA of EPO. In particular, after 72 hours, the translation efficiency of this mUNA molecule was increased by more than 10-fold (1517/143) as compared to the mRNA of EPO. - Details of the base structure of this translatable mUNA molecule were as follows:
-
(SEQ ID NO: 14) (m7GpppGm)GGGAAACAUAAGUCAACACAACAUAUACAAAACAAACGA AUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAAUCAUU UCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACG AUAGCCAUGGGGGUGCACGAAUGUCCUGCCUGGCUGUGGCUUCUCCUGU CCCUGCUGUCGCUCCCUCUGGGCCUCCCAGUCCUGGGCGCCCCACCACG CCUCAUCUGUGACAGCCGAGUCCUGGAGAGGUACCUCUUGGAGGCCAAG GAGGCCGAGAAUAUCACGACGGGCUGUGCUGAACACUGCAGCUUGAAUG AGAAUAUCACUGUCCCAGACACCAAAGUUAAUUUCUAUGCCUGGAAGAG GAUGGAGGUCGGGCAGCAGGCCGUAGAAGUCUGGCAGGGCCUGGCCCUG CUGUCGGAAGCUGUCCUGCGGGGCCAGGCCCUGUUGGUCAACUCUUCCC AGCCGUGGGAGCCCCUGCAGCUGCAUGUGGAUAAAGCCGUCAGUGGCCU UCGCAGCCUCACCACUCUGCUUCGGGCUCUGGGAGCCCAGAAGGAAGCC AUCUCCCCUCCAGAUGCGGCCUCAGCUGCUCCACUCCGAACAAUCACUG CUGACACUUUCCGCAAACUCUUCCGAGUCUACUCCAAUUUCCUCCGGGG AAAGCUGAAGCUGUACACAGGGGAGGCCUGCAGGACAGGGGACAGAUGA CUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACAC CCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUG UUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAG UUUCUUCACAUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAÃÃAAAA - In this example, a translatable mUNA molecule is made for use in expressing human CFTR in vivo. The translatable mUNA molecule expressing human CFTR in vivo is suitable for use in methods for ameliorating or treating cystic fibrosis. In this embodiment, the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a CFTR CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human CFTR is accession NM_000492.3.
- In this example, a translatable mUNA molecule is made for use in expressing human argininosuccinate lyase (ASL) in vivo. The translatable mUNA molecule expressing human ASL in vivo is suitable for use in methods for ameliorating or treating ASL deficiency. In this embodiment, the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a ASL CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human ASL is accession NM_001024943.1.
- In this example, a translatable mUNA molecule is made for use in expressing human Phenylalanine-4-hydroxylase (PAH) in vivo. The translatable mUNA molecule expressing human PAH in vivo is suitable for use in methods for ameliorating or treating Phenylketonuria (PKU). In this embodiment, the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a PAH CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human PAH is accession NM_000277.1.
- In this example, a translatable mUNA molecule is made for use in expressing human Sodium/iodide cotransporter (NIS) in vivo. The translatable mUNA molecule expressing human NIS in vivo is suitable for use in methods for ameliorating or treating thyroid disease. In this embodiment, the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a NIS CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human NIS is accession BC105047.
- In this example, a translatable mUNA molecule is made for use in expressing human Sodium/iodide cotransporter (NIS) in vivo. The translatable mUNA molecule expressing human NIS in vivo is suitable for use in methods for ameliorating or treating thyroid disease. In this embodiment, the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a NIS CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human NIS is accession BC105047.
- In this example, a translatable mUNA molecule is made for use in expressing human Hepcidin in vivo. The translatable mUNA molecule expressing human Hepcidin in vivo is suitable for use in methods for ameliorating or treating iron deficiency disease. In this embodiment, the translatable mUNA molecule comprises a 5′ cap (m7GpppGm), a 5′ UTR of TEV, a Hepcidin CDS, a 3′UTR of xenopus beta-globin, and a tail region shown in Example 4.
- Human Hepcidin is accession NM_021175.3.
- In this example, the structures of mUNA molecules for use in expressing Factor IX are shown.
- Factor IX (F9) is associated with hemophilia B.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Factor IX. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Factor IX.
-
Human Factor IX is accession NM_000133.3. (SEQ ID NO: 15) AU{circumflex over (G)}CAGCGCGUGAACAUGAUCAUGGCAGAAUC{tilde over (A)}CCAGGCCUCAUCACCA UCUGCCUUUUAGG{tilde over (A)}UAUCUACUCAGUGCUGAAUGUACAGUUUU{tilde over (U)}CUUGA UCAUGAAAACGCCAACAAAAUUCU{circumflex over (G)}AAUCGGCCAAAGAGGUAUAAUUCA GGUAA{tilde over (A)}UUGGAAGAGUUUGUUCAAGGGAACCUUGA{circumflex over (G)}AGAGAAUGUAUGG AAGAAAAGUGUAGUUU{tilde over (U)}GAAGAAGCACGAGAAGUUUUUGAAAACAC{tilde over (U)}GA AAGAACAACUGAAUUUUGGAAGCAGUA{tilde over (U)}GUUGAUGGAGAUCAGUGUGAG UCCAAUCC{tilde over (A)}UGUUUAAAUGGCGGCAGUUGCAAGGAUGA{circumflex over (C)}AUUAAUUCCU AUGAAUGUUGGUGUCCCUU{tilde over (U)}GGAUUUGAAGGAAAGAACUGUGAAUUAGA {tilde over (U)}GUAACAUGUAACAUUAAGAAUGGCAGAUG{circumflex over (C)}GAGCAGUUUUGUAAAAAU AGUGCUGAUAA{circumflex over (C)}AAGGUGGUUUGCUCCUGUACUGAGGGAUA{tilde over (U)}CGACUUG CAGAAAACCAGAAGUCCUGUGA{tilde over (A)}CCAGCAGUGCCAUUUCCAUGUGGAAG AGU{tilde over (U)}UCUGUUUCACAAACUUCUAAGCUCACCCG{tilde over (U)}GCUGAGACUGUUUUU CCUGAUGUGGACUA{tilde over (U)}GUAAAUUCUACUGAAGCUGAAACCAUUUUG{circumflex over (G)}AUA ACAUCACUCAAAGCACCCAAUCAUU{tilde over (U)}AAUGACUUCACUCGGGUUGUUGG UGGAGA{tilde over (A)}GAUGCCAAACCAGGUCAAUUCCCUUGGCA{circumflex over (G)}GUUGUUUUGAAU GGUAAAGUUGAUGCAUU{circumflex over (C)}UGUGGAGGCUCUAUCGUUAAUGAAAAAUG{circumflex over (G)}A UUGUAACUGCUGCCCACUGUGUUGAAAC{tilde over (U)}GGUGUUAAAAUUACAGUUGU CGCAGGUGA{tilde over (A)}CAUAAUAUUGAGGAGACAGAACAUACAGA{circumflex over (G)}CAAAAGCGA AAUGUGAUUCGAAUUAUUCC{tilde over (U)}CACCACAACUACAAUGCAGCUAUUAAUA A{circumflex over (G)}UACAACCAUGACAUUGCCCUUCUGGAACU{circumflex over (G)}GACGAACCCUUAGUGCU AAACAGCUACGU{tilde over (U)}ACACCUAUUUGCAUUGCUGACAAGGAAUA{circumflex over (C)}ACGAAC AUCUUCCUCAAAUUUGGAUCUGG{circumflex over (C)}UAUGUAAGUGGCUGGGGAAGAGUCU UCCA{circumflex over (C)}AAAGGGAGAUCAGCUUUAGUUCUUCAGUA{circumflex over (C)}CUUAGAGUUCCACU UGUUGACCGAGCCAC{tilde over (A)}UGUCUUCGAUCUACAAAGUUCACCAUCUA{tilde over (U)}AAC AACAUGUUCUGUGCUGGCUUCCAUGA{tilde over (A)}GGAGGUAGAGAUUCAUGUCAAG GAGAUAG{tilde over (U)}GGGGGACCCCAUGUUACUGAAGUGGAAGG{circumflex over (G)}ACCAGUUUCUU AACUGGAAUUAUUAGCUG{circumflex over (G)}GGUGAAGAGUGUGCAAUGAAAGGCAAAUA{tilde over (U)} GGAAUAUAUACCAAGGUAUCCCGGUAUGU{circumflex over (C)}AACUGGAUUAAGGAAAAAA CAAAGCUCAC{tilde over (U)}UAA (SEQ ID NO: 16) A{tilde over (U)}{circumflex over (G)}{circumflex over (C)}AGCGCGUGAACAUGAUCAUGGCAGAAUCACCAGGCCUCAUCACCA UCUGCCUUUUAGGAUAUCUACUCAGUGCUGAAUGUACAGUUUUUCUUGA UCAUGAAAACGCCAACAAAAUUCUGAAUCGGCCAAAGAGGUAUAAUUCA GGUAAAUUGGAAGAGUUUGUUCAAGGGAACCUUGAGAGAGAAUGUAUGG AAGAAAAGUGUAGUUUUGAAGAAGCACGAGAAGUUUUUGAAAACACUGA AAGAACAACUGAAUUUUGGAAGCAGUAUGUUGAUGGAGAUCAGUGUGAG UCCAAUCCAUGUUUAAAUGGCGGCAGUUGCAAGGAUGACAUUAAUUCCU AUGAAUGUUGGUGUCCCUUUGGAUUUGAAGGAAAGAACUGUGAAUUAGA UGUAACAUGUAACAUUAAGAAUGGCAGAUGCGAGCAGUUUUGUAAAAAU AGUGCUGAUAACAAGGUGGUUUGCUCCUGUACUGAGGGAUAUCGACUUG CAGAAAACCAGAAGUCCUGUGAACCAGCAGUGCCAUUUCCAUGUGGAAG AGUUUCUGUUUCACAAACUUCUAAGCUCACCCGUGCUGAGACUGUUUUU CCUGAUGUGGACUAUGUAAAUUCUACUGAAGCUGAAACCAUUUUGGAUA CACAUCACUCAAAGCACCCAAUCAUUUAAUGACUUCACUCGGGUUGUUG GUGGAGAAGAUGCCAAACCAGGUCAAUUCCCUUGGCAGGUUGUUUUGAA UGGUAAAGUUGAUGCAUUCUGUGGAGGCUCUAUGUUAAUGAAAAAUGGA UUGUAACUGCUGCCCACUGUGUUGAAACUGGUGUUAAAAUUACAGUUGU CGCAGGUGAACAUAAUAUUGAGGAGACAGAACAUACAGAGCAAAAGCGA AAUGUGAUUCGAAUUAUUCCUCACCACAACUACAAUGCAGCUAUUAAUA AGUACAACCAUGACAUUGCCCUUCUGGAACUGGACGAACCCUUAGUGCU AAACAGCUACGUUACACCUAUUUGCAUUGCUGACAAGGAAUACACGAAC AUCUUCCUCAAAUUUGGAUCUGGCUAUGUAAGUGGCUGGGGAAGAGUCU UCCACAAAGGGAGAUCAGCUUUAGUUCUUCAGUACCUUAGAGUUCCACU UGUUGACCGAGCCACAUGUCUUCGAUCUACAAAGUUCACCAUCUAUAAC AACAUGUUCUGUGCUGGCUUCCAUGAAGGAGGUAGAGAUUCAUGUCAAG GAGAUAGUGGGGGACCCCAUGUUACUGAAGUGGAAGGGACCAGUUUCUU AACUGGAAUUAUUAGCUGGGGUGAAGAGUGUGCAAUGAAAGGCAAAUAU GGAAUAUAUACCAAGGUAUCCCGGUAUGUCAACUGGAUUAAGGAAAAAA CAAAGCUCAC{tilde over (U)}{tilde over (U)}{tilde over (A)}A (SEQ ID NO: 17) A{tilde over (U)}GCAGCGCG{tilde over (U)}GAACA{tilde over (U)}GA{tilde over (U)}CAGGCAGAA{tilde over (U)}CACCAGGCC{tilde over (U)}CA{tilde over (U)}CACCA{tilde over (U)} C{tilde over (U)}GCC{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}AGGA{tilde over (U)}A{tilde over (U)}C{tilde over (U)}AC{tilde over (U)}CAG{tilde over (U)}GC{tilde over (U)}GAA{tilde over (U)}G{tilde over (U)}ACAG{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}GA{tilde over (U)} CA{tilde over (U)}GAAAACGCCAACAAAA{tilde over (U)}{tilde over (U)}C{tilde over (U)}GAA{tilde over (U)}CGGCCAAAGAGG{tilde over (U)}A{tilde over (U)}AA{tilde over (U)}{tilde over (U)}CAG G{tilde over (U)}AAA{tilde over (U)}{tilde over (U)}GGAAGAG{tilde over (U)}{tilde over (U)}{tilde over (U)}G{tilde over (U)}{tilde over (U)}CAAGGGAACC{tilde over (U)}{tilde over (U)}GAGAGAGAA{tilde over (U)}G{tilde over (U)}A{tilde over (U)}GGA AGAAAAG{tilde over (U)}G{tilde over (U)}AG{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GAAGAAGCACGAGAAG{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GAAAACAC{tilde over (U)}GAA AGAACAAC{tilde over (U)}GAA{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GGAAGCAG{tilde over (U)}A{tilde over (U)}G{tilde over (U)}{tilde over (U)}GA{tilde over (U)}GGAGA{tilde over (U)}CAG{tilde over (U)}G{tilde over (U)}GAG{tilde over (U)} CCAA{tilde over (U)}CCA{tilde over (U)}G{tilde over (U)}{tilde over (U)}{tilde over (U)}AAA{tilde over (U)}GGCGGCAG{tilde over (U)}{tilde over (U)}GCAAGGA{tilde over (U)}GACA{tilde over (U)}{tilde over (U)}AA{tilde over (U)}{tilde over (U)}CC{tilde over (U)}A {tilde over (U)}GAA{tilde over (U)}G{tilde over (U)}{tilde over (U)}GG{tilde over (U)}G{tilde over (U)}CCC{tilde over (U)}{tilde over (U)}{tilde over (U)}GGA{tilde over (U)}{tilde over (U)}{tilde over (U)}GAAGGAAAGAAC{tilde over (U)}G{tilde over (U)}GAA{tilde over (U)}{tilde over (U)}AGA{tilde over (U)} G{tilde over (U)}AACA{tilde over (U)}G{tilde over (U)}AACA{tilde over (U)}{tilde over (U)}AAGAA{tilde over (U)}GGCAGA{tilde over (U)}GCGAGCAG{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}G{tilde over (U)}AAAAA{tilde over (U)}A G{tilde over (U)}GC{tilde over (U)}GA{tilde over (U)}AACAAGG{tilde over (U)}GG{tilde over (U)}{tilde over (U)}{tilde over (U)}GC{tilde over (U)}CC{tilde over (U)}G{tilde over (U)}AC{tilde over (U)}GAGGGA{tilde over (U)}A{tilde over (U)}CGAC{tilde over (U)}{tilde over (U)}GC AGAAAACCAGAAG{tilde over (U)}CC{tilde over (U)}G{tilde over (U)}GAACCAGCAG{tilde over (U)}GCCA{tilde over (U)}{tilde over (U)}{tilde over (U)}CCA{tilde over (U)}G{tilde over (U)}GGAAGA G{tilde over (U)}{tilde over (U)}{tilde over (U)}C{tilde over (U)}G{tilde over (U)}{tilde over (U)}{tilde over (U)}CACAAAC{tilde over (U)}{tilde over (U)}C{tilde over (U)}AAGC{tilde over (U)}CACCCG{tilde over (U)}GC{tilde over (U)}GAGAC{tilde over (U)}G{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}C C{tilde over (U)}GA{tilde over (U)}G{tilde over (U)}GGAC{tilde over (U)}A{tilde over (U)}G{tilde over (U)}AAA{tilde over (U)}{tilde over (U)}C{tilde over (U)}AC{tilde over (U)}GAAGC{tilde over (U)}GAAACCA{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GGA{tilde over (U)}AA CA{tilde over (U)}CAC{tilde over (U)}CAAAGCACCCAA{tilde over (U)}CA{tilde over (U)}{tilde over (U)}{tilde over (U)}AA{tilde over (U)}GAC{tilde over (U)}{tilde over (U)}CAC{tilde over (U)}CGGG{tilde over (U)}{tilde over (U)}G{tilde over (U)}{tilde over (U)}GG{tilde over (U)} GGAGAAGA{tilde over (U)}GCCAAACCAGG{tilde over (U)}CAA{tilde over (U)}{tilde over (U)}CCC{tilde over (U)}{tilde over (U)}GGCAGG{tilde over (U)}{tilde over (U)}G{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GAA{tilde over (U)}G G{tilde over (U)}AAAG{tilde over (U)}{tilde over (U)}GA{tilde over (U)}GCA{tilde over (U)}{tilde over (U)}C{tilde over (U)}G{tilde over (U)}GGAGGC{tilde over (U)}C{tilde over (U)}A{tilde over (U)}CG{tilde over (U)}{tilde over (U)}AA{tilde over (U)}GAAAAA{tilde over (U)}GGA{tilde over (U)} {tilde over (U)}G{tilde over (U)}AAC{tilde over (U)}GC{tilde over (U)}GCCCAC{tilde over (U)}G{tilde over (U)}G{tilde over (U)}{tilde over (U)}GAAAC{tilde over (U)}GG{tilde over (U)}G{tilde over (U)}{tilde over (U)}AAAA{tilde over (U)}{tilde over (U)}ACAG{tilde over (U)}{tilde over (U)}G{tilde over (U)}C GCAGG{tilde over (U)}GAACA{tilde over (U)}AA{tilde over (U)}A{tilde over (U)}{tilde over (U)}GAGGAGACAGAACA{tilde over (U)}ACAGAGCAAAAGCGAA A{tilde over (U)}G{tilde over (U)}GA{tilde over (U)}{tilde over (U)}CGAA{tilde over (U)}{tilde over (U)}A{tilde over (U)}{tilde over (U)}CC{tilde over (U)}CACCACAAC{tilde over (U)}ACAA{tilde over (U)}GCAGC{tilde over (U)}A{tilde over (U)}{tilde over (U)}AA{tilde over (U)}AA G{tilde over (U)}ACAACCA{tilde over (U)}GACA{tilde over (U)}{tilde over (U)}GCCC{tilde over (U)}{tilde over (U)}C{tilde over (U)}GGAAC{tilde over (U)}GGACGAACCC{tilde over (U)}{tilde over (U)}AG{tilde over (U)}GC{tilde over (U)}A AACAGC{tilde over (U)}ACG{tilde over (U)}{tilde over (U)}ACACC{tilde over (U)}A{tilde over (U)}{tilde over (U)}{tilde over (U)}GCA{tilde over (U)}{tilde over (U)}GC{tilde over (U)}GACAAGGAA{tilde over (U)}ACACGAACA {tilde over (U)}C{tilde over (U)}{tilde over (U)}CC{tilde over (U)}CAAA{tilde over (U)}{tilde over (U)}{tilde over (U)}GGA{tilde over (U)}C{tilde over (U)}GGC{tilde over (U)}A{tilde over (U)}G{tilde over (U)}AAG{tilde over (U)}GGC{tilde over (U)}GGGGAAGAG{tilde over (U)}C{tilde over (U)}{tilde over (U)} CCACAAAGGGAGA{tilde over (U)}CAGC{tilde over (U)}{tilde over (U)}{tilde over (U)}AG{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}CAG{tilde over (U)}ACC{tilde over (U)}{tilde over (U)}AGAG{tilde over (U)}{tilde over (U)}CCAC{tilde over (U)}{tilde over (U)} G{tilde over (U)}{tilde over (U)}GACCGAGCCACA{tilde over (U)}G{tilde over (U)}C{tilde over (U)}{tilde over (U)}CGA{tilde over (U)}C{tilde over (U)}ACAAAG{tilde over (U)}{tilde over (U)}CACCA{tilde over (U)}C{tilde over (U)}A{tilde over (U)}AACA ACA{tilde over (U)}G{tilde over (U)}{tilde over (U)}C{tilde over (U)}G{tilde over (U)}GC{tilde over (U)}GGC{tilde over (U)}{tilde over (U)}CCA{tilde over (U)}GAAGGAGG{tilde over (U)}AGAGA{tilde over (U)}{tilde over (U)}CA{tilde over (U)}G{tilde over (U)}CAAGG AGA{tilde over (U)}AG{tilde over (U)}GGGGGACCCCA{tilde over (U)}G{tilde over (U)}{tilde over (U)}AC{tilde over (U)}GAAG{tilde over (U)}GGAAGGGACCAG{tilde over (U)}{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}A AC{tilde over (U)}GGAA{tilde over (U)}{tilde over (U)}A{tilde over (U)}{tilde over (U)}AGC{tilde over (U)}GGGG{tilde over (U)}GAAGAG{tilde over (U)}G{tilde over (U)}GCAA{tilde over (U)}GAAAGGCAAA{tilde over (U)}A{tilde over (U)}G GAA{tilde over (U)}A{tilde over (U)}A{tilde over (U)}ACCAAGG{tilde over (U)}A{tilde over (U)}CCCGG{tilde over (U)}A{tilde over (U)}G{tilde over (U)}CAAC{tilde over (U)}GGA{tilde over (U)}{tilde over (U)}AAGGAAAAAAC AAAGC{tilde over (U)}CAC{tilde over (U)}{tilde over (U)}AA - In this example, the structures of mUNA molecules for use in expressing alpha-1-Antitrypsin are shown.
- Alpha-1-Antitrypsin is associated with alpha-1-Antitrypsin deficiency disease, cystic fibrosis, interstitial lung disease, and pulmonary arterial hypertension.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of alpha-1-Antitrypsin. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of alpha-1-Antitrypsin.
-
Human alpha-1-antitrypsin mRNA is accession NM_000295.4. (SEQ ID NO: 18) AU{circumflex over (G)}CCGUCUUCUGUCUCGUGGGGCAUCCUCCU{circumflex over (G)}CUGGCAGGCCUGUGCU GCCUGGUCCCUGU{circumflex over (C)}UCCCUGGCUGAGGAUCCCCAGGGAGAUGC{tilde over (U)}GCCCA GAAGACAGAUACAUCCCACCAUGA{tilde over (U)}CAGGAUCACCCAACCUUCAACAAG AUCA{circumflex over (C)}CCCCAACCUGGCUGAGUUCGCCUUCAGCCU{tilde over (A)}UACCGCCAGCUGG CACACCAGUCCAACAG{circumflex over (C)}ACCAAUAUCUUCUUCUCCCCAGUGAGCAU{circumflex over (C)}GC UACAGCCUUUGCAAUGCUCUCCCUGGG{circumflex over (G)}ACCAAGGCUGACACUCACGAU GAAAUCCU{circumflex over (G)}GAGGGCCUGAAUUUCAACCUCACGGAGAU{tilde over (U)}CCGGAGGCUC AGAUCCAUGAAGGCUUCCA{circumflex over (G)}GAACUCCUCCGUACCCUCAACCAGCCAGA {circumflex over (C)}AGCCAGCUCCAGCUGACCACCGGCAAUGG{circumflex over (C)}CUGUUCCUCAGCGAGGGC CUGAAGCUAGU{circumflex over (G)}GAUAAGUUUUUGGAGGAUGUUAAAAAGUU{circumflex over (G)}UACCACU CAGAAGCCUUCACUGUCAACUU{circumflex over (C)}GGGGACACCGAAGAGGCCAAGAAACA GAU{circumflex over (C)}AACGAUUACGUGGAGAAGGGUACUCAAGG{circumflex over (G)}AAAAUUGUGGAUUUG GUCAAGGAGCUUGA{circumflex over (C)}AGAGACACAGUUUUUGCUCUGGUGAAUUA{circumflex over (C)}AUCU UCUUUAAAGGCAAAUGGGAGAGACC{circumflex over (C)}UUUGAAGUCAAGGACACCGAGGA AGAGGA{circumflex over (C)}UUCCACGUGGACCAGGUGACCACCGUGAA{circumflex over (G)}GUGCCUAUGAUG AAGCGUUUAGGCAUGUU{tilde over (U)}AACAUCCAGCACUGUAAGAAGCUGUCCAG{circumflex over (C)}U GGGUGCUGCUGAUGAAAUACCUGGGCAA{tilde over (U)}GCCACCGCCAUCUUCUUCCU GCCUGAUGA{circumflex over (G)}GGGAAACUACAGCACCUGGAAAAUGAACU{circumflex over (C)}ACCCACGAU AUCAUCACCAAGUUCCUGGA{tilde over (A)}AAUGAAGACAGAAGGUCUGCCAGCUUAC A{tilde over (U)}UUACCCAAACUGUCCAUUACUGGAACCUA{tilde over (U)}GAUCUGAAGAGCGUCCU GGGUCAACUGGG{circumflex over (C)}AUCACUAAGGUCUUCAGCAAUGGGGCUGA{circumflex over (C)}CUCUCC GGGGUCACAGAGGAGGCACCCCU{circumflex over (G)}AAGCUCUCCAAGGCCGUGCAUAAGG CUGU{circumflex over (G)}CUGACCAUCGACGAGAAAGGGACUGAAGC{tilde over (U)}GCUGGGGCCAUGUU UUUAGAGGCCAUACC{circumflex over (C)}AUGUCUAUCCCCCCCGAGGUCAAGUUCAA{circumflex over (C)}AAA CCCUUUGUCUUCUUAAUGAUUGAACA{tilde over (A)}AAUACCAAGUCUCCCCUCUUCA UGGGAAA{tilde over (A)}GUGGUGAAUCCCACCCAAAAAU{tilde over (A)}A (SEQ ID NO: 19) A{tilde over (U)}{circumflex over (G)}{circumflex over (C)}CGUCUUCUGUCUCGUGGGGCAUCCUCCUGCUGGCAGGCCUGUGCU GCCUGGUCCCUGUCUCCCUGGCUGAGGAUCCCCAGGGAGAUGCUGCCCA GAAGACAGAUACAUCCCACCAUGAUCAGGAUCACCCAACCUUCAACAAG AUCACCCCCAACCUGGCUGAGUUCGCCUUCAGCCUAUACCGCCAGCUGG CACACCAGUCCAACAGCACCAAUAUCUUCUUCUCCCCAGUGAGCAUCGC UACAGCCUUUGCAAUGCUCUCCCUGGGGACCAAGGCUGACACUCACGAU GAAAUCCUGGAGGGCCUGAAUUUCAACCUCACGGAGAUUCCGGAGGCUC AGAUCCAUGAAGGCUUCCAGGAACUCCUCCGUACCCUCAACCAGCCAGA CAGCCAGCUCCAGCUGACCACCGGCAAUGGCCUGUUCCUCAGCGAGGGC CUGAAGCUAGUGGAUAAGUUUUUGGAGGAUGUUAAAAAGUUGUACCACU CAGAAGCCUUCACUGUCAACUUCGGGGACACCGAAGAGGCCAAGAAACA GAUCAACGAUUACGUGGAGAAGGGUACUCAAGGGAAAAUUGUGGAUUUG GUCAAGGAGCUUGACAGAGACACAGUUUUUGCUCUGGUGAAUUACAUCU UCUUUAAAGGCAAAUGGGAGAGACCCUUUGAAGUCAAGGACACCGAGGA AGAGGACUUCCACGUGGACCAGGUGACCACCGUGAAGGUGCCUAUGAUG AAGCGUUUAGGCAUGUUUAACAUCCAGCACUGUAAGAAGCUGUCCAGCU GGGUGCUGCUGAUGAAAUACCUGGGCAAUGCCACCGCCAUCUUCUUCCU GCCUGAUGAGGGGAAACUACAGCACCUGGAAAAUGAACUCACCCACGAU AUCAUCACCAAGUUCCUGGAAAAUGAAGACAGAAGGUCUGCCAGCUUAC AUUUACCCAAACUGUCCAUUACUGGAACCUAUGAUCUGAAGAGCGUCCU GGGUCAACUGGGCAUCACUAAGGUCUUCAGCAAUGGGGCUGACCUCUCC GGGGUCACAGAGGAGGCACCCCUGAAGCUCUCCAAGGCCGUGCAUAAGG CUGUGCUGACCAUCGACGAGAAAGGGACUGAAGCUGCUGGGGCCAUGUU UUUAGAGGCCAUACCCAUGUCUAUCCCCCCCGAGGUCAAGUUCAACAAA CCCUUUGUCUUCUUAAUGAUUGAACAAAAUACCAAGUCUCCCCUCUUCA UGGGAAAAGUGGUGAAUCCCACCCAAAA{tilde over (A)}{tilde over (U)}{tilde over (A)}A (SEQ ID NO: 20) A{tilde over (U)}GCCG{tilde over (U)}C{tilde over (U)}{tilde over (U)}C{tilde over (U)}G{tilde over (U)}C{tilde over (U)}CG{tilde over (U)}GGGGCA{tilde over (U)}CC{tilde over (U)}CC{tilde over (U)}GC{tilde over (U)}GGCAGGCC{tilde over (U)}G{tilde over (U)}GC{tilde over (U)} GCC{tilde over (U)}GG{tilde over (U)}CCC{tilde over (U)}G{tilde over (U)}C{tilde over (U)}CCC{tilde over (U)}GGC{tilde over (U)}GAGGA{tilde over (U)}CCCCAGGGAGA{tilde over (U)}GC{tilde over (U)}GCCCA GAAGACAGA{tilde over (U)}ACA{tilde over (U)}CCCACCA{tilde over (U)}GA{tilde over (U)}CAGGA{tilde over (U)}CACCCAACC{tilde over (U)}{tilde over (U)}CAACAAG A{tilde over (U)}CACCCCCAACC{tilde over (U)}GGC{tilde over (U)}GAG{tilde over (U)}{tilde over (U)}CGCC{tilde over (U)}{tilde over (U)}CAGCC{tilde over (U)}A{tilde over (U)}ACCGCCAGC{tilde over (U)}GG CACACCAG{tilde over (U)}CCAACAGCACCAA{tilde over (U)}A{tilde over (U)}C{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}C{tilde over (U)}CCCCAG{tilde over (U)}GAGCA{tilde over (U)}CGC {tilde over (U)}ACAGCC{tilde over (U)}{tilde over (U)}{tilde over (U)}GCAA{tilde over (U)}GC{tilde over (U)}C{tilde over (U)}CCC{tilde over (U)}GGGGACCAAGGC{tilde over (U)}GACAC{tilde over (U)}CACGA{tilde over (U)} GAAA{tilde over (U)}CC{tilde over (U)}GGAGGGCC{tilde over (U)}GAA{tilde over (U)}{tilde over (U)}{tilde over (U)}CAACC{tilde over (U)}CACGGAGA{tilde over (U)}{tilde over (U)}CCGGAGGC{tilde over (U)}C AGA{tilde over (U)}CCA{tilde over (U)}GAAGGC{tilde over (U)}{tilde over (U)}CCAGGAAC{tilde over (U)}CC{tilde over (U)}CCG{tilde over (U)}ACCC{tilde over (U)}CAACCAGCCAGA CAGCCAGC{tilde over (U)}CCAGC{tilde over (U)}GACCACCGGCAA{tilde over (U)}GGCC{tilde over (U)}G{tilde over (U)}{tilde over (U)}CC{tilde over (U)}CAGCGAGGGC C{tilde over (U)}GAAGC{tilde over (U)}AG{tilde over (U)}GGA{tilde over (U)}AAG{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GGAGGA{tilde over (U)}G{tilde over (U)}{tilde over (U)}AAAAAG{tilde over (U)}{tilde over (U)}G{tilde over (U)}ACCAC{tilde over (U)} CAGAAGCC{tilde over (U)}{tilde over (U)}CAC{tilde over (U)}G{tilde over (U)}CAAC{tilde over (U)}{tilde over (U)}CGGGGACACCGAAGAGGCCAAGAAACA GA{tilde over (U)}CAACGA{tilde over (U)}{tilde over (U)}ACG{tilde over (U)}GGAGAAGGG{tilde over (U)}AC{tilde over (U)}CAAGGGAAAA{tilde over (U)}{tilde over (U)}G{tilde over (U)}GGA{tilde over (U)}{tilde over (U)}{tilde over (U)}G G{tilde over (U)}CAAGGAGC{tilde over (U)}{tilde over (U)}GACAGAGACACAG{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GC{tilde over (U)}C{tilde over (U)}GG{tilde over (U)}GAA{tilde over (U)}{tilde over (U)}ACA{tilde over (U)}C{tilde over (U)} {tilde over (U)}C{tilde over (U)}{tilde over (U)}{tilde over (U)}AAAGGCAAA{tilde over (U)}GGGAGAGACCC{tilde over (U)}{tilde over (U)}{tilde over (U)}GAAG{tilde over (U)}CAAGGACACCGAGGA AGAGGAC{tilde over (U)}{tilde over (U)}CCACG{tilde over (U)}GGACCAGG{tilde over (U)}GACCACCG{tilde over (U)}GAAGG{tilde over (U)}GCC{tilde over (U)}A{tilde over (U)}GA{tilde over (U)}G AAGCG{tilde over (U)}{tilde over (U)}{tilde over (U)}AGGCA{tilde over (U)}G{tilde over (U)}{tilde over (U)}{tilde over (U)}AACA{tilde over (U)}CCAGCAC{tilde over (U)}G{tilde over (U)}AAGAAGC{tilde over (U)}G{tilde over (U)}CCAGC{tilde over (U)} GGG{tilde over (U)}GC{tilde over (U)}GC{tilde over (U)}GA{tilde over (U)}GAAA{tilde over (U)}ACC{tilde over (U)}GGGCAA{tilde over (U)}GCCACCGCCA{tilde over (U)}C{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}CC{tilde over (U)} GCC{tilde over (U)}GA{tilde over (U)}GAGGGGAAAC{tilde over (U)}ACAGCACC{tilde over (U)}GGAAAA{tilde over (U)}GAAC{tilde over (U)}CACCCACGA{tilde over (U)} A{tilde over (U)}CA{tilde over (U)}CACCAAG{tilde over (U)}{tilde over (U)}CC{tilde over (U)}GGAAAA{tilde over (U)}GAAGACAGAAGG{tilde over (U)}C{tilde over (U)}GCCAGC{tilde over (U)}{tilde over (U)}AC A{tilde over (U)}{tilde over (U)}{tilde over (U)}ACCCAAAC{tilde over (U)}G{tilde over (U)}CCA{tilde over (U)}{tilde over (U)}AC{tilde over (U)}GGAACC{tilde over (U)}A{tilde over (U)}GA{tilde over (U)}C{tilde over (U)}GAAGAGCG{tilde over (U)}CC{tilde over (U)} GGG{tilde over (U)}CAAC{tilde over (U)}GGGCA{tilde over (U)}CAC{tilde over (U)}AAGG{tilde over (U)}C{tilde over (U)}{tilde over (U)}CAGCAA{tilde over (U)}GGGGC{tilde over (U)}GACC{tilde over (U)}C{tilde over (U)}CC GGGG{tilde over (U)}CACAGAGGAGGCACCCC{tilde over (U)}GAAGC{tilde over (U)}C{tilde over (U)}CCAAGGCCG{tilde over (U)}GCA{tilde over (U)}AAGG C{tilde over (U)}G{tilde over (U)}GC{tilde over (U)}GACCA{tilde over (U)}CGACGAGAAAGGGAC{tilde over (U)}GAAGC{tilde over (U)}GC{tilde over (U)}GGGGCCA{tilde over (U)}G{tilde over (U)}{tilde over (U)} {tilde over (U)}{tilde over (U)}{tilde over (U)}AGAGGCCA{tilde over (U)}ACCCA{tilde over (U)}G{tilde over (U)}C{tilde over (U)}A{tilde over (U)}CCCCCCCGAGG{tilde over (U)}CAAG{tilde over (U)}{tilde over (U)}CAACAAA CCC{tilde over (U)}{tilde over (U)}{tilde over (U)}G{tilde over (U)}C{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}AA{tilde over (U)}GA{tilde over (U)}{tilde over (U)}GAACAAAA{tilde over (U)}ACCAAG{tilde over (U)}C{tilde over (U)}CCCC{tilde over (U)}C{tilde over (U)}{tilde over (U)}CA {tilde over (U)}GGGAAAAG{tilde over (U)}GG{tilde over (U)}GAA{tilde over (U)}CCCACCCAAAAA{tilde over (U)}AA - In this example, the structures of mUNA molecules for use in expressing alpha-1-Antitrypsin are shown.
- Alpha-1-Antitrypsin is associated with alpha-1-Antitrypsin deficiency disease, cystic fibrosis, interstitial lung disease, and pulmonary arterial hypertension.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 5′-UTR of the native mRNA of alpha-1-Antitrypsin. The complete mUNA molecule comprises a 5′ cap (m7GpppGm) upstream of the sequence below, and coding region (CDS) for human alpha-1-Antitrypsin, a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of alpha-1-Antitrypsin.
-
Human alpha-1-antitrypsin mRNA is accession NM_000295.4. (SEQ ID NO: 21) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 22) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGCCGA{circumflex over (C)}{circumflex over (C)} (SEQ ID NO: 23) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGCC{circumflex over (G)}{tilde over (A)}CC (SEQ ID NO: 24) GGCACCACCACUGACCUGGGACAGUGAAUCGACAG{circumflex over (C)}{circumflex over (C)}GACC (SEQ ID NO: 25) GGCACCACCACUGACCUGGGACAGUGAAUCGAC{tilde over (A)}{circumflex over (G)}CCGACC (SEQ ID NO: 26) GGCACCACCACUGACCUGGGACAGUGAAUCG{tilde over (A)}{circumflex over (C)}AGCCGACC (SEQ ID NO: 27) GGCACCACCACUGACCUGGGACAGUGAAU{circumflex over (C)}{circumflex over (G)}ACAGCCGACC (SEQ ID NO: 28) GGCACCACCACUGACCUGGGACAGUGA{tilde over (A)}{tilde over (U)}CGACAGCCGACC (SEQ ID NO: 29) GGCACCACCACUGACCUGGGACAGU{circumflex over (G)}{tilde over (A)}AUCGACAGCCGACC (SEQ ID NO: 30) GGCACCACCACUGACCUGGGACA{circumflex over (G)}{tilde over (U)}GAAUCGACAGCCGACC (SEQ ID NO: 31) GGCACCACCACUGACCUGGGA{circumflex over (C)}{tilde over (A)}GUGAAUCGACAGCCGACC (SEQ ID NO: 32) GGCACCACCACUGACCUGG{circumflex over (G)}{tilde over (A)}CAGUGAAUCGACAGCCGACC (SEQ ID NO: 33) GGCACCACCACUGACCU{circumflex over (G)}{circumflex over (G)}GACAGUGAAUCGACAGCCGACC (SEQ ID NO: 34) GGCACCACCACUGAC{circumflex over (C)}{tilde over (U)}GGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 35) GGCACCACCACUG{tilde over (A)}{circumflex over (C)}UGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 36) GGCACCACCAC{tilde over (U)}{circumflex over (G)}ACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 37) GGCACCACC{tilde over (A)}{circumflex over (C)}CUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 38) GGCACCA{circumflex over (C)}{circumflex over (C)}ACUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 39) GGCAC{circumflex over (C)}{tilde over (A)}CCACUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 40) GGC{tilde over (A)}{circumflex over (C)}CACCACUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 41) G{circumflex over (G)}{circumflex over (C)}ACCACCACUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 42) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGCCG{tilde over (A)}C{circumflex over (C)} (SEQ ID NO: 43) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGCC{circumflex over (G)}AC{circumflex over (C)} (SEQ ID NO: 44) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGC{circumflex over (C)}AC{circumflex over (C)} (SEQ ID NO: 45) GGCACCACCACUGACCUGGGACAGUGAAUCGACAG{circumflex over (C)}CGAC{circumflex over (C)} (SEQ ID NO: 46) GGCACCACCACUGACCUGGGACAGUGAAUCGACA{circumflex over (G)}CCGAC{circumflex over (C)} (SEQ ID NO: 47) GGCACCACCACUGACCUGGGACAGUGAAUCGAC{tilde over (A)}GCCGAC{circumflex over (C)} (SEQ ID NO: 48) GGCACCACCACUGACCUGGGACAGUGAAUCGA{circumflex over (C)}AGCCGAC{circumflex over (C)} (SEQ ID NO: 49) GGCACCACCACUGACCUGGGACAGUGAAUCG{tilde over (A)}CAGCCGAC{circumflex over (C)} (SEQ ID NO: 50) GGCACCACCACUGACCUGGGACAGUGAAUC{circumflex over (G)}ACAGCCGAC{circumflex over (C)} (SEQ ID NO: 51) GGCACCACCACUGACCUGGGACAGUGAAU{circumflex over (C)}GACAGCCGAC{circumflex over (C)} (SEQ ID NO: 52) GGCACCACCACUGACCUGGGACAGUGAA{tilde over (U)}CGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 53) GGCACCACCACUGACCUGGGACAGUGA{tilde over (A)}UCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 54) GGCACCACCACUGACCUGGGACAGUG{tilde over (A)}AUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 55) GGCACCACCACUGACCUGGGACAGU{circumflex over (G)}AAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 56) GGCACCACCACUGACCUGGGACAG{tilde over (U)}GAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 57) GGCACCACCACUGACCUGGGACA{circumflex over (G)}UGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 58) GGCACCACCACUGACCUGGGAC{tilde over (A)}GUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 59) GGCACCACCACUGACCUGGGA{circumflex over (C)}AGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 60) GGCACCACCACUGACCUGGG{tilde over (A)}CAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 61) GGCACCACCACUGACCUGG{circumflex over (G)}ACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 62) GGCACCACCACUGACCUG{circumflex over (G)}GACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 63) GGCACCACCACUGACCU{circumflex over (G)}GGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 64) GGCACCACCACUGACC{tilde over (U)}GGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 65) GGCACCACCACUGAC{circumflex over (C)}UGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 66) GGCACCACCACUGA{circumflex over (C)}UUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 67) GGCACCACCACUG{tilde over (A)}CCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 68) GGCACCACCACU{circumflex over (G)}ACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 69) GGCACCACCAC{tilde over (U)}GACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 70) GGCACCACCA{circumflex over (C)}UGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 71) GGCACCACC{tilde over (A)}CUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 72) GGCACCAC{circumflex over (C)}ACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 73) GGCACCA{circumflex over (C)}CACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 74) GGCACC{tilde over (A)}CCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 75) GGCAC{circumflex over (C)}ACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 76) GGCA{circumflex over (C)}CACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 77) GGC{tilde over (A)}CCACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 78) GG{circumflex over (C)}ACCACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 79) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 80) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGCCG{tilde over (A)}{circumflex over (C)}{circumflex over (C)} (SEQ ID NO: 81) GGCACCACCACUGACCUGGGACAGUGAAUCGACAG{circumflex over (C)}{circumflex over (C)}{circumflex over (G)}ACC (SEQ ID NO: 82) GGCACCACCACUGACCUGGGACAGUGAAUCGA{circumflex over (C)}{tilde over (A)}{circumflex over (G)}CCGACC (SEQ ID NO: 83) GGCACCACCACUGACCUGGGACAGUGAAUCGACAGC{circumflex over (C)}{circumflex over (G)}{tilde over (A)}CC (SEQ ID NO: 84) GGCACCACCACUGACCUGGGACAGUG{tilde over (A)}{tilde over (A)}{tilde over (U)}CGACAGCCGACC (SEQ ID NO: 85) GGCACCACCACUGACCUGGGACA{circumflex over (G)}{tilde over (U)}{circumflex over (G)}AAUCGACAGCCGACC (SEQ ID NO: 86) GGCACCACCACUGACCUGGG{tilde over (U)}{circumflex over (C)}{tilde over (A)}GUGAAUCGACAGCCGACC (SEQ ID NO: 87) GGCACCACCACUGACCU{circumflex over (G)}{circumflex over (G)}{circumflex over (G)}ACAGUGAAUCGACAGCCGACC (SEQ ID NO: 88) GGCACCACCACUGA{circumflex over (C)}{circumflex over (C)}{tilde over (U)}GGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 89) GGCACCACCAC{tilde over (U)}{circumflex over (G)}{tilde over (A)}CCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 90) GGCACCAC{circumflex over (C)}{tilde over (A)}{circumflex over (C)}UGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 91) GGCAC{circumflex over (C)}{tilde over (A)}{circumflex over (C)}CACUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 92) GG{circumflex over (C)}{tilde over (A)}{circumflex over (C)}CACCACUGACCUGGGACAGUGAAUCGACAGCCGACC (SEQ ID NO: 93) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGACAGCCG{tilde over (A)}C{circumflex over (C)} (SEQ ID NO: 94) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGACAGCC{circumflex over (G)}AC{circumflex over (C)} (SEQ ID NO: 95) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGACAGC{circumflex over (C)}GAC{circumflex over (C)} (SEQ ID NO: 96) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGACAG{circumflex over (C)}CGAC{circumflex over (C)} (SEQ ID NO: 97) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGACA{circumflex over (G)}CCGAC{circumflex over (C)} (SEQ ID NO: 98) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCG{tilde over (A)}CAGCCGAC{circumflex over (C)} (SEQ ID NO: 99) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGA{circumflex over (C)}AGCCGAC{circumflex over (C)} (SEQ ID NO: 100) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCG{tilde over (A)}CAGCCGAC{circumflex over (C)} (SEQ ID NO: 101) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUC{circumflex over (G)}ACAGCCGAC{circumflex over (C)} (SEQ ID NO: 102) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAU{circumflex over (C)}GACAGCCGAC{circumflex over (C)} (SEQ ID NO: 103) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAA{tilde over (U)}CGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 104) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUGA{tilde over (A)}UCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 105) G{circumflex over (G)}CACCACCACUGACCUGGGACAGUG{tilde over (A)}AUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 106) G{circumflex over (G)}CACCACCACUGACCUGGGACAGU{circumflex over (G)}AAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 107) G{circumflex over (G)}CACCACCACUGACCUGGGACAG{tilde over (U)}GAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 108) G{circumflex over (G)}CACCACCACUGACCUGGGACA{circumflex over (G)}UGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 109) G{circumflex over (G)}CACCACCACUGACCUGGGAC{tilde over (A)}GUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 110) G{circumflex over (G)}CACCACCACUGACCUGGGA{circumflex over (C)}AGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 111) G{circumflex over (G)}CACCACCACUGACCUGGG{tilde over (A)}CAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 112) G{circumflex over (G)}CACCACCACUGACCUGG{circumflex over (G)}ACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 113) G{circumflex over (G)}CACCACCACUGACCUG{circumflex over (G)}GACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 114) G{circumflex over (G)}CACCACCACUGACCU{circumflex over (G)}GGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 115) G{circumflex over (G)}CACCACCACUGACC{tilde over (U)}GGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 116) G{circumflex over (G)}CACCACCACUGAC{circumflex over (C)}UGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 117) G{circumflex over (G)}CACCACCACUGA{circumflex over (C)}CUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 118) G{circumflex over (G)}CACCACCACUG{tilde over (A)}CCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 119) G{circumflex over (G)}CACCACCACU{circumflex over (G)}ACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 120) G{circumflex over (G)}CACCACCAC{tilde over (U)}GACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 121) G{circumflex over (G)}CACCACCA{circumflex over (C)}UGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 122) G{circumflex over (G)}CACC{tilde over (A)}CCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 123) G{circumflex over (G)}CACCAC{circumflex over (C)}ACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 124) G{circumflex over (G)}CACCA{circumflex over (C)}CACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 125) G{circumflex over (G)}CACC{tilde over (A)}CCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 126) G{circumflex over (G)}CAC{circumflex over (C)}ACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 127) G{circumflex over (G)}CA{circumflex over (C)}CACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 128) G{circumflex over (G)}C{tilde over (A)}CCACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 129) G{circumflex over (G)}{circumflex over (C)}ACCACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} (SEQ ID NO: 130) {circumflex over (G)}{circumflex over (G)}CACCACCACUGACCUGGGACAGUGAAUCGACAGCCGAC{circumflex over (C)} - In this example, the structures of mUNA molecules for use in expressing human Erythropoietin (EPO) are shown.
- Erythropoietin is available as a commercial drug and is indicated for anemia resulting from chronic kidney disease, inflammatory bowel disease including Crohn's disease and ulcer colitis, and myelodysplasia from the treatment of cancer with chemotherapy or radiation.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Erythropoietin. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Erythropoietin.
-
Human Erythropoietin is accession NM_000799.2. (SEQ ID NO: 131) A{tilde over (U)}{circumflex over (G)}G{circumflex over (G)}GGUGCACGAAUGUCCUGCCUGGCUGUGGCUUCUCCUGUCCCUGC UGUCGCUCCCUCUGGGCCUCCCAGUCCUGGGCGCCCCACCACGCCUCAU CUGUGACAGCCGAGUCCUGGAGAGGUACCUCUUGGAGGCCAAGGAGGCC GAGAAUAUCACGACGGGCUGUGCUGAACACUGCAGCUUGAAUGAGAAUA UCACUGUCCCAGACACCAAAGUUAAUUUCUAUGCCUGGAAGAGGAUGGA GGUCGGGCAGCAGGCCGUAGAAGUCUGGCAGGGCCUGGCCCUGCUGUCG GAAGCUGUCCUGCGGGGCCAGGCCCUGUUGGUCAACUCUUCCCAGCCGU GGGAGCCCCUGCAGCUGCAUGUGGAUAAAGCCGUCAGUGGCCUUCGCAG CCUCACCACUCUGCUUCGGGCUCUGGGAGCCCAGAAGGAAGCCAUCUCC CCUCCAGAUGCGGCCUCAGCUGCUCCACUCCGAACAAUCACUGCUGACA CUUUCCGCAAACUCUUCCGAGUCUACUCCAAUUUCCUCCGGGGAAAGCU GAAGCUGUACACAGGGGAGGCCUGCAGGACAGGGGACAG{tilde over (A)}{tilde over (U)}{circumflex over (G)}A (SEQ ID NO: 132) AU{circumflex over (G)}GGGGUGCACGA{tilde over (A)}UGUCCUGCCUG{circumflex over (G)}CUGUGGCUUCU{circumflex over (C)}CUGUCCCUGC U{circumflex over (G)}UCGCUCCCUCU{circumflex over (G)}GGCCUCCCAGU{circumflex over (C)}CUGGGCGCCCC{tilde over (A)}CCACGCCUCAU {circumflex over (C)}UGUGACAGCCG{tilde over (A)}GUCCUGGAGAG{circumflex over (G)}UACCUCUUGGA{circumflex over (G)}GCCAAGGAGGC {circumflex over (C)}GAGAAUAUCAC{circumflex over (G)}ACGGGCUGUGC{tilde over (U)}GAACACUGCAG{circumflex over (C)}UUGAAUGAGAA {tilde over (U)}AUCACUGUCCC{tilde over (A)}GACACCAAAGU{tilde over (U)}AAUUUCUAUGC{circumflex over (C)}UGGAAGAGGAU {circumflex over (G)}GAGGUCGGGCA{circumflex over (G)}CAGGCCGUAGA{tilde over (A)}GUCUGGCAGGG{circumflex over (C)}UUGGCCCUGCU {circumflex over (G)}UCGGAAGCUGU{circumflex over (C)}CUGCGGGGCCA{circumflex over (G)}GCCCUGUUGGU{circumflex over (C)}AACUCUUCCC A{circumflex over (G)}CCGUGGGAGCC{circumflex over (G)}CUGCAGCUGCA{tilde over (U)}GUGGAUAAAGC{circumflex over (C)}GUCAGUGGCC U{tilde over (U)}CGCAGCCUCAC{circumflex over (C)}ACUCUGCUUCGGGCUCUGGGAGC{circumflex over (C)}CAGAAGGAAG CCAUCUCCCCUCC{tilde over (A)}GAUGCGGCCUC{tilde over (A)}GCUGCUCCACU{circumflex over (C)}CGAACAAUCA C{tilde over (U)}GCUGACACUUU{circumflex over (C)}CGCAAACUCUU{circumflex over (C)}CGAGUCUACUC{circumflex over (C)}AAUUUCCUCC G{circumflex over (G)}GGAAAGCUGAA{circumflex over (G)}CUGUACACAGG{circumflex over (G)}GAGGCCUGCAG{circumflex over (G)}ACAGGGGAC AG{tilde over (A)}UGA (SEQ ID NO: 133) A{tilde over (U)}GGGGG{tilde over (U)}GCACGAA{tilde over (U)}G{tilde over (U)}CC{tilde over (U)}GCC{tilde over (U)}GGC{tilde over (U)}G{tilde over (U)}GGC{tilde over (U)}{tilde over (U)}C{tilde over (U)}CC{tilde over (U)}G{tilde over (U)}CCC{tilde over (U)}GC {tilde over (U)}G{tilde over (U)}CGC{tilde over (U)}CCC{tilde over (U)}C{tilde over (U)}GGGCC{tilde over (U)}CCCAG{tilde over (U)}CC{tilde over (U)}GGGCGCCCCACCACGCC{tilde over (U)}CA{tilde over (U)} C{tilde over (U)}G{tilde over (U)}GACAGCCGAG{tilde over (U)}CC{tilde over (U)}GGAGAGG{tilde over (U)}ACC{tilde over (U)}C{tilde over (U)}{tilde over (U)}GGAGGCCAAGGAGGCC GAGAA{tilde over (U)}A{tilde over (U)}CACGACGGGC{tilde over (U)}G{tilde over (U)}GC{tilde over (U)}GAACAC{tilde over (U)}GCAGC{tilde over (U)}{tilde over (U)}GAA{tilde over (U)}GAGAA{tilde over (U)}A {tilde over (U)}CAC{tilde over (U)}G{tilde over (U)}CCCAGACACCAAAG{tilde over (U)}{tilde over (U)}AA{tilde over (U)}{tilde over (U)}{tilde over (U)}C{tilde over (U)}A{tilde over (U)}GCC{tilde over (U)}GGAAGAGGA{tilde over (U)}GGA GG{tilde over (U)}CGGGCAGCAGGCCG{tilde over (U)}AGAAG{tilde over (U)}C{tilde over (U)}GGCAGGGCC{tilde over (U)}GGCCC{tilde over (U)}GC{tilde over (U)}G{tilde over (U)}CG GAAGC{tilde over (U)}G{tilde over (U)}CC{tilde over (U)}GCGGGGCCAGGCCC{tilde over (U)}G{tilde over (U)}{tilde over (U)}GG{tilde over (U)}CAAC{tilde over (U)}C{tilde over (U)}{tilde over (U)}CCCAGCCG{tilde over (U)} GGGAGCCCC{tilde over (U)}GCAGC{tilde over (U)}GCA{tilde over (U)}G{tilde over (U)}GGA{tilde over (U)}AAAGCCG{tilde over (U)}CAG{tilde over (U)}GGCC{tilde over (U)}{tilde over (U)}CGCAG CC{tilde over (U)}CACCAC{tilde over (U)}C{tilde over (U)}GC{tilde over (U)}{tilde over (U)}CGGGC{tilde over (U)}C{tilde over (U)}GGGAGCCCAGAAGGAAGCCA{tilde over (U)}C{tilde over (U)}CC CC{tilde over (U)}CCAGA{tilde over (U)}GCGGCC{tilde over (U)}CAGC{tilde over (U)}GC{tilde over (U)}CCAC{tilde over (U)}CCGAACAA{tilde over (U)}CAC{tilde over (U)}GC{tilde over (U)}GACA C{tilde over (U)}{tilde over (U)}{tilde over (U)}CCGCAAAC{tilde over (U)}C{tilde over (U)}{tilde over (U)}CCGAG{tilde over (U)}C{tilde over (U)}AC{tilde over (U)}CCAA{tilde over (U)}{tilde over (U)}{tilde over (U)}CC{tilde over (U)}CCGGGGAAAGC{tilde over (U)} GAAGC{tilde over (U)}G{tilde over (U)}ACACAGGGGAGGCC{tilde over (U)}GCAGGACAGGGGACAGA{tilde over (U)}GA - In this example, the structures of mUNA molecules for use in expressing human Ornithine transcarbamylase are shown.
- Ornithine transcarbamylase is associated with Ornithine transcarbamylase deficiency.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Ornithine transcarbamylase. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Ornithine transcarbamylase.
-
Human Ornithine transcarbamylase is accession NM_000531.5. (SEQ ID NO: 134) AU{circumflex over (G)}CUGUUUAAUCU{circumflex over (G)}AGGAUCCUGUU{tilde over (U)}AAACAAUGCAG{circumflex over (C)}UUUUAGAAAUG{circumflex over (G)}UCACAACU UCA{tilde over (U)}GGUUCGAAAUU{tilde over (U)}UCGGUGUGGAC{tilde over (A)}ACCACUACAAA{tilde over (A)}UAAAGUGCAGC{tilde over (U)}GAAGGGC CGUG{tilde over (A)}CCUUCUCACUC{tilde over (U)}AAAAAACUUUA{circumflex over (C)}CGGAGAAGAAA{tilde over (U)}UAAAUAUAUGC{tilde over (U)}AUGGCU AUCAG{circumflex over (C)}AGAUCUGAAAU{tilde over (U)}UAGGAUAAAAC{tilde over (A)}GAAAGGAGAGU{tilde over (A)}UUUGCCUUUAU{tilde over (U)}GCAAG GGAAGU{circumflex over (C)}CUUAGGCAUGA{tilde over (U)}UUUUGAGAAAA{circumflex over (G)}AAGUACUCGAA{circumflex over (C)}AAGAUUGUCUA{circumflex over (C)}AGAA ACAGGCU{tilde over (U)}UGCACUUCUGG{circumflex over (G)}AGGACAUCCUU{circumflex over (G)}UUUUCUUACCA{circumflex over (C)}ACAAGAUAUUC{tilde over (A)}UUU GGGUGUGA{tilde over (A)}UGAAAGUCUCA{circumflex over (C)}GGACACGGCCC{circumflex over (G)}UGUAUUGUCUAGCAU{circumflex over (G)}GCAGAUG{circumflex over (C)}AG UAUUGGCUC{circumflex over (G)}AGUGUAUAAAC{tilde over (A)}AUCAGAUUUGG{tilde over (A)}CACCCUGGCUA{tilde over (A)}AGAAGCAUCCA{tilde over (U)}C CCAAUUAUCA{tilde over (A)}UGGGCUGUCAG{tilde over (A)}UUUGUACCAUC{circumflex over (C)}UAUCCAGAUCC{tilde over (U)}GGCUGAUUACC{tilde over (U)} CACGCUCCAGG{tilde over (A)}ACACUAUAGCU{circumflex over (C)}UCUGAAAGGUC{tilde over (U)}UACCCUCAGCU{circumflex over (G)}GAUCGGGGAUG {circumflex over (G)}GAACAAUAUCC{tilde over (U)}GCACUCCAUCA{tilde over (U)}GAUGAGCGCAG{circumflex over (C)}GAAAUUCGGAA{tilde over (U)}GCACCUUCAG G{circumflex over (C)}AGCUACUCCAA{tilde over (A)}GGGUUAUGAGC{circumflex over (C)}GGAUGCUAGUG{tilde over (U)}AACCAAGUUGG{circumflex over (C)}AGAGCAGUA UG{circumflex over (C)}CAAAGAGAAUG{circumflex over (G)}UACCAAGCUGU{tilde over (U)}GCUGACAAAUG{tilde over (A)}UCCAUUGGAAG{circumflex over (C)}AGCGCAUG GAG{circumflex over (G)}CAAUGUAUUAA{tilde over (U)}UACAGACACUU{circumflex over (G)}GAUAAGCAUGG{circumflex over (G)}ACAAGAAGAGG{tilde over (A)}GAAGAAA AAGC{circumflex over (G)}GCUCCAGGCUU{tilde over (U)}CCAAGGUUACC{tilde over (A)}GGUUACAAUGA{tilde over (A)}GACUGCUAAAG{tilde over (U)}UGCUGC CUCUG{tilde over (A)}CUGGACAUUUU{tilde over (U)}ACACUGCUUGC{circumflex over (C)}CAGAAAGCCAG{tilde over (A)}AGAAGUGGAUG{tilde over (A)}UGAAG UCUUUU{tilde over (A)}UUCUCCUCGAU{circumflex over (C)}ACUAGUGUUCC{circumflex over (C)}AGAGGCAGAAA{tilde over (A)}CAGAAAGUGGA{circumflex over (C)}AAUC AUGGCUG{tilde over (U)}CAUGGUGUCCC{tilde over (U)}GCUGACAGAUU{tilde over (A)}CUCACCUCAGC{tilde over (U)}CCAGAAGCCUA{tilde over (A)}AUU UU{circumflex over (G)}A (SEQ ID NO: 135) A{tilde over (U)}{circumflex over (G)}{circumflex over (C)}UGUUUAAUCUGAGGAUCCUGUUAAACAAUGCAGCUUUUAGAAAUGGUCACAACUU CAUGGUUCGAAAUUUUCGGUGUGGACAACCACUACAAAAUAAAGUGCAGCUGAAGGGCC GUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAUUAAAUAUAUGCUAUGGCUA UCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAGUAUUUGCCUUUAUUGCAAGG GAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAACAAGAUUGUCUACAGAAA CAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCACACAAGAUAUUCAUUUG GGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCUAGCAUGGCAGAUGCAGU AUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCUGGCUAAAGAAGCAUCCAUCC CAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAGAUCCUGGCUGAUUACCUC ACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCAGCUGGAUCGGGGAUGG GAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUCGGAAUGCACCUUCAGG CAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAAGUUGGCAGAGCAGUAU GCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAUUGGAAGCAGCGCAUGG AGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAAGAAGAGGAGAAGAAAA AGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGACUGCUAAAGUUGCUGCC UCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAAGAAGUGGAUGAUGAAGU CUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAACAGAAAGUGGACAAUCA UGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCUCCAGAAGCCUAAAUU{tilde over (U)} {tilde over (U)}{circumflex over (G)}A (SEQ ID NO: 136) A{tilde over (U)}GC{tilde over (U)}G{tilde over (U)}{tilde over (U)}{tilde over (U)}AA{tilde over (U)}C{tilde over (U)}GAGGA{tilde over (U)}CC{tilde over (U)}G{tilde over (U)}{tilde over (U)}AAACAA{tilde over (U)}GCAGC{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}AGAAA{tilde over (U)}GG{tilde over (U)}CACAAC{tilde over (U)}{tilde over (U)} CA{tilde over (U)}GG{tilde over (U)}{tilde over (U)}CGAAA{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}CGG{tilde over (U)}G{tilde over (U)}GGACAACCAC{tilde over (U)}ACAAAA{tilde over (U)}AAAG{tilde over (U)}GCAGC{tilde over (U)}GAAGGGCC G{tilde over (U)}GACC{tilde over (U)}{tilde over (U)}C{tilde over (U)}CAC{tilde over (U)}C{tilde over (U)}AAAAAAC{tilde over (U)}{tilde over (U)}{tilde over (U)}ACCGGAGAAGAAA{tilde over (U)}{tilde over (U)}AAA{tilde over (U)}A{tilde over (U)}A{tilde over (U)}GC{tilde over (U)}A{tilde over (U)}GGC{tilde over (U)}A {tilde over (U)}CAGCAGA{tilde over (U)}C{tilde over (U)}GAAA{tilde over (U)}{tilde over (U)}{tilde over (U)}AGGA{tilde over (U)}AAAACAGAAAGGAGAG{tilde over (U)}A{tilde over (U)}{tilde over (U)}{tilde over (U)}GCC{tilde over (U)}{tilde over (U)}{tilde over (U)}A{tilde over (U)}{tilde over (U)}GCAAGG GAAG{tilde over (U)}CC{tilde over (U)}{tilde over (U)}AGGCA{tilde over (U)}GA{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}GAGAAAAGAAG{tilde over (U)}AC{tilde over (U)}CGAACAAGA{tilde over (U)}{tilde over (U)}G{tilde over (U)}C{tilde over (U)}ACAGAAA CAGGC{tilde over (U)}{tilde over (U)}{tilde over (U)}GCAC{tilde over (U)}{tilde over (U)}C{tilde over (U)}GGGAGGACA{tilde over (U)}CC{tilde over (U)}{tilde over (U)}G{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}ACCACACAAGA{tilde over (U)}A{tilde over (U)}{tilde over (U)}CA{tilde over (U)}{tilde over (U)}{tilde over (U)}G GG{tilde over (U)}G{tilde over (U)}GAA{tilde over (U)}GAAAG{tilde over (U)}C{tilde over (U)}CACGGACACGGCCCG{tilde over (U)}G{tilde over (U)}A{tilde over (U)}{tilde over (U)}G{tilde over (U)}C{tilde over (U)}AGCA{tilde over (U)}GGCAGA{tilde over (U)}GCAG{tilde over (U)} A{tilde over (U)}{tilde over (U)}GGC{tilde over (U)}CGAG{tilde over (U)}G{tilde over (U)}A{tilde over (U)}AAACAA{tilde over (U)}CAGA{tilde over (U)}{tilde over (U)}{tilde over (U)}GGACACCC{tilde over (U)}GGC{tilde over (U)}AAAGAAGCA{tilde over (U)}CCA{tilde over (U)}CC CAA{tilde over (U)}{tilde over (U)}A{tilde over (U)}CAA{tilde over (U)}GGGC{tilde over (U)}G{tilde over (U)}CAGA{tilde over (U)}{tilde over (U)}{tilde over (U)}G{tilde over (U)}ACCA{tilde over (U)}CC{tilde over (U)}A{tilde over (U)}CCAGA{tilde over (U)}CC{tilde over (U)}GGC{tilde over (U)}GA{tilde over (U)}{tilde over (U)}ACC{tilde over (U)}C ACGC{tilde over (U)}CCAGGAACAC{tilde over (U)}A{tilde over (U)}AGC{tilde over (U)}C{tilde over (U)}C{tilde over (U)}GAAAGG{tilde over (U)}C{tilde over (U)}{tilde over (U)}ACCC{tilde over (U)}CAGC{tilde over (U)}GGA{tilde over (U)}CGGGGA{tilde over (U)}GG GAACAA{tilde over (U)}A{tilde over (U)}CC{tilde over (U)}GCAC{tilde over (U)}CCA{tilde over (U)}CA{tilde over (U)}GA{tilde over (U)}GAGCGCAGCGAAA{tilde over (U)}{tilde over (U)}CGGAA{tilde over (U)}GCACC{tilde over (U)}{tilde over (U)}CAGG CAGC{tilde over (U)}AC{tilde over (U)}CCAAAGGG{tilde over (U)}{tilde over (U)}A{tilde over (U)}GAGCCGGA{tilde over (U)}GC{tilde over (U)}AG{tilde over (U)}G{tilde over (U)}AACCAAG{tilde over (U)}{tilde over (U)}GGCAGAGCAG{tilde over (U)}A{tilde over (U)} GCCAAAGAGAA{tilde over (U)}GG{tilde over (U)}ACCAAGC{tilde over (U)}G{tilde over (U)}{tilde over (U)}GC{tilde over (U)}GACAAA{tilde over (U)}GA{tilde over (U)}CCA{tilde over (U)}{tilde over (U)}GGAAGCAGCGCA{tilde over (U)}GG AGGCAA{tilde over (U)}G{tilde over (U)}A{tilde over (U)}{tilde over (U)}AA{tilde over (U)}{tilde over (U)}ACAGACAC{tilde over (U)}{tilde over (U)}GGA{tilde over (U)}AAGCA{tilde over (U)}GGGACAAGAAGAGGAGAAGAAAA AGCGGC{tilde over (U)}CCAGGC{tilde over (U)}{tilde over (U)}{tilde over (U)}CCAAGG{tilde over (U)}{tilde over (U)}ACCAGG{tilde over (U)}{tilde over (U)}ACAA{tilde over (U)}GAAGAC{tilde over (U)}GC{tilde over (U)}AAAG{tilde over (U)}{tilde over (U)}GC{tilde over (U)}GCC {tilde over (U)}C{tilde over (U)}GAC{tilde over (U)}GGACA{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}ACAC{tilde over (U)}GC{tilde over (U)}{tilde over (U)}GCCCAGAAAGCCAGAAGAAG{tilde over (U)}GGA{tilde over (U)}GA{tilde over (U)}GAAG{tilde over (U)} C{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}A{tilde over (U)}{tilde over (U)}C{tilde over (U)}CC{tilde over (U)}CGA{tilde over (U)}CAC{tilde over (U)}AG{tilde over (U)}G{tilde over (U)}{tilde over (U)}CCCAGAGGCAGAAAACAGAAAG{tilde over (U)}GGACAA{tilde over (U)}CA {tilde over (U)}GGC{tilde over (U)}G{tilde over (U)}CA{tilde over (U)}GG{tilde over (U)}G{tilde over (U)}CCC{tilde over (U)}GC{tilde over (U)}GACAGA{tilde over (U)}{tilde over (U)}AC{tilde over (U)}CACC{tilde over (U)}CAGC{tilde over (U)}CCAGAAGCC{tilde over (U)}AAA{tilde over (U)}{tilde over (U)}{tilde over (U)} {tilde over (U)}GA - In this example, the structures of mUNA molecules for use in expressing human beta-globin are shown.
- Beta-globin may be associated with sickle-cell disease, beta thalassemia, and genetic resistance to malaria.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 3′-UTR of the native mRNA of human beta-globin. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), 5′-UTR, and coding region (CDS) for human beta-globin upstream of the sequence below, and a polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human beta-globin.
-
Human beta-globin is accession NM_000518.4. (SEQ ID NO: 137) G{circumflex over (C)}UCGCUUUCUUGCUGUCCAAUUUCUAUUAAAGGUUCCUUUGUUCCCUA AGUCCAACUACUAAACUGGGGGAUAUUAUGAAGGGCCUUGAGCAUCUGG AUUCUGCCUAAUAAAAAACAUUUAUUUUCAUUGC{tilde over (A)}A (SEQ ID NO: 138) G{circumflex over (C)}{tilde over (U)}{circumflex over (C)}GCUUUCUUGCUGUCCAAUUUCUAUUAAAGGUUCCUUUGUUCCCUA AGUCCAACUACUAAACUGGGGGAUAUUAUGAAGGGCCUUGAGCAUCUGG AUUCUGCCUAAUAAAAAACAUUUAUUUUCAUU{circumflex over (G)}{circumflex over (C)}{tilde over (A)}A (SEQ ID NO: 139) G{circumflex over (C)}UCGCU{tilde over (U)}UCUUG{circumflex over (C)}UGUCC{tilde over (A)}AUUUC{tilde over (U)}AUUAA{tilde over (A)}GGUUC{circumflex over (C)}UUUGU{tilde over (U)}CCCUA {tilde over (A)}GUCCA{tilde over (A)}CUACU{tilde over (A)}AACUG{circumflex over (G)}GGGAU{tilde over (A)}UUAUG{tilde over (A)}AGGGC{circumflex over (C)}UUGAG{circumflex over (C)}AUCUG{circumflex over (G)} AUUCU{circumflex over (G)}CCUAA{tilde over (U)}AAAAA{tilde over (A)}CAUUU{tilde over (A)}UUUUC{tilde over (A)}UUGC{tilde over (A)}A (SEQ ID NO: 140) G{circumflex over (C)}{tilde over (U)}CGCU{tilde over (U)}{tilde over (U)}CUUG{circumflex over (C)}{tilde over (U)}GUCC{tilde over (A)}{tilde over (A)}UUUC{tilde over (U)}{tilde over (A)}UUAA{tilde over (A)}{circumflex over (G)}GUUC{circumflex over (C)}{tilde over (U)}UUGU{tilde over (U)}{circumflex over (C)}CCU A{tilde over (A)}{circumflex over (G)}UCCA{tilde over (A)}{circumflex over (C)}UACU{tilde over (A)}{tilde over (A)}ACUG{circumflex over (G)}{circumflex over (G)}GGAU{tilde over (A)}{tilde over (U)}UAUG{tilde over (A)}{tilde over (A)}GGGC{circumflex over (C)}{tilde over (U)}UGAG{circumflex over (C)}{tilde over (A)}UCU G{circumflex over (G)}{tilde over (A)}UUCU{circumflex over (G)}{circumflex over (C)}CUAA{tilde over (U)}{tilde over (A)}AAAA{tilde over (A)}{circumflex over (C)}AUUU{tilde over (A)}{tilde over (U)}UUUC{tilde over (A)}{tilde over (U)}UGC{tilde over (A)}A (SEQ ID NO: 141) {circumflex over (G)}{circumflex over (C)}{tilde over (U)}{circumflex over (C)}{circumflex over (G)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{circumflex over (G)}{circumflex over (C)}{tilde over (U)}{circumflex over (G)}{tilde over (U)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{circumflex over (G)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{circumflex over (G)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{circumflex over (C)}{circumflex over (C)}{tilde over (U)} {tilde over (A)}{tilde over (A)}{circumflex over (G)}{tilde over (U)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{tilde over (U)}{circumflex over (G)}{circumflex over (G)}{circumflex over (G)}{circumflex over (G)}{circumflex over (G)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{tilde over (U)}{circumflex over (G)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{circumflex over (G)}{circumflex over (G)}{circumflex over (C)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{circumflex over (G)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{circumflex over (C)}{tilde over (U)} {circumflex over (G)}{circumflex over (G)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{circumflex over (G)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{tilde over (A)} - In this example, the structures of mUNA molecules for use in enhancing translational efficiency are shown.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 3′-UTR of Xenopus beta-globin. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), 5′-UTR, and coding region (CDS) upstream of the sequence below, and a polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of a native human mRNA. Thus, a UNA oligomer incorprating the oligomer fragment below can have enhanced translational efficiency.
-
Xenopus beta-globin is accession NM_001096347.1. (SEQ ID NO: 142) C{tilde over (U)}AGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACC CGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUU GUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUU CUUCAC{tilde over (A)}U (SEQ ID NO: 143) C{tilde over (U)}{tilde over (A)}{circumflex over (G)}UGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACC CGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUU GUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUU CUUC{tilde over (A)}{circumflex over (C)}{tilde over (A)}U (SEQ ID NO: 144) C{tilde over (U)}AGUGA{circumflex over (C)}UGACU{tilde over (A)}GGAUC{tilde over (U)}GGUUA{circumflex over (C)}CACUA{tilde over (A)}ACCAG{circumflex over (C)}CUCAA{circumflex over (G)}AAAC {circumflex over (C)}CAAAU{circumflex over (G)}GAGUC{tilde over (U)}CUAAG{circumflex over (C)}UACAU{tilde over (A)}AUACC{tilde over (A)}ACUUA{circumflex over (C)}ACUUA{circumflex over (C)}AAAAU{circumflex over (G)}UU GUC{circumflex over (C)}CCCAA{tilde over (A)}AUGUA{circumflex over (G)}CCAUU{circumflex over (C)}GUAUC{tilde over (U)}GCUCC{tilde over (U)}AAUAA{tilde over (A)}AAGAA{tilde over (A)}GUUU C{tilde over (U)}UCAC{tilde over (A)}U (SEQ ID NO: 145) C{tilde over (U)}{tilde over (A)}GUGA{circumflex over (C)}{tilde over (U)}GACU{tilde over (A)}{circumflex over (G)}GAUC{tilde over (U)}{circumflex over (G)}GUUA{circumflex over (C)}{circumflex over (C)}ACUA{tilde over (A)}{tilde over (A)}CCAG{circumflex over (C)}{circumflex over (C)}UCAA{circumflex over (G)}{tilde over (A)}ACAC {circumflex over (C)}{circumflex over (C)}GAAU{circumflex over (G)}{circumflex over (G)}AGUC{tilde over (U)}{circumflex over (C)}UAAG{circumflex over (C)}{tilde over (U)}ACAU{tilde over (A)}{tilde over (A)}UACC{tilde over (A)}{tilde over (A)}CUUA{circumflex over (C)}{tilde over (A)}CUUA{circumflex over (C)}{tilde over (A)}AAAU{circumflex over (G)}{tilde over (U)}U GUC{circumflex over (C)}{circumflex over (C)}CCAA{tilde over (A)}{tilde over (A)}UGUA{circumflex over (G)}{circumflex over (C)}CAUU{circumflex over (C)}{circumflex over (G)}UAUC{tilde over (U)}{circumflex over (G)}CUCC{tilde over (U)}{tilde over (A)}AUAA{tilde over (A)}{tilde over (A)}AGAA{tilde over (A)}{circumflex over (G)}UUU C{tilde over (U)}{tilde over (U)}CAC{tilde over (A)}U (SEQ ID NO: 146) {circumflex over (C)}{tilde over (U)}{tilde over (A)}{circumflex over (G)}{tilde over (U)}{circumflex over (G)}{tilde over (A)}{circumflex over (C)}{tilde over (U)}{circumflex over (G)}{tilde over (A)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{circumflex over (G)}{circumflex over (G)}{tilde over (A)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{circumflex over (G)}{circumflex over (G)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{circumflex over (C)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{circumflex over (C)} {circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{circumflex over (G)}{circumflex over (G)}{tilde over (A)}{circumflex over (G)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{circumflex over (G)}{tilde over (U)}{tilde over (U)} {circumflex over (G)}{tilde over (U)}{circumflex over (C)}{circumflex over (C)}{circumflex over (C)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{circumflex over (G)}{tilde over (U)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{circumflex over (G)}{tilde over (U)}{tilde over (A)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{circumflex over (G)}{circumflex over (C)}{tilde over (U)}{circumflex over (C)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{tilde over (U)}{tilde over (U)}{tilde over (U)} {circumflex over (C)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (U)} - In this example, the structures of mUNA molecules for use in expressing human Thrombopoietin are shown.
- Thrombopoietin is associated with liver and kidney disease.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human Thrombopoietin. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human Thrombopoietin.
-
Human Thrombopoietin is accession NM_000460.3. (SEQ ID NO: 147) AU{circumflex over (G)}GAGCUGACUGAAUUGCU{circumflex over (C)}CUCGUGGUCAUGCUUCU{circumflex over (C)}CUAACUGCAA GGCUAAC{circumflex over (G)}CUGUCCAGCCCGGCUCC{tilde over (U)}CCUGCUUGUGACCUCCG{tilde over (A)}GUCCU CAGUAAACUGCU{tilde over (U)}CGUGACUCCCAUGUCCU{tilde over (U)}CACAGCAGACUGAGCCA{circumflex over (G)} UGCCCAG AGGUUCACCC{tilde over (U)}UUGCCUACACCUGUCCU{circumflex over (G)}CUGCCUGCUGUGG ACUU{tilde over (U)}AGCUUGGGAGAAUGGA{tilde over (A)}AACCCAGAUGGAGGAGA{circumflex over (C)}CAAGGCACA GGACAUUC{tilde over (U)}GGGAGCAGUGACCCUUC{tilde over (U)}GCUGGAGGGAGUGAUGG{circumflex over (C)}AGCA CGGGGACAACUGG{circumflex over (G)}ACCCACUUGCCUCUCAUC{circumflex over (C)}CUCCUGGGGCAGCUUU C{tilde over (U)}GGACAGGUCCGUCUCCU{circumflex over (C)}CUUGGGGCCCUGCAGAG{circumflex over (C)}CUCCUUGGAAC CCAGCU{tilde over (U)}CCUCCACAGGGCAGGAC{circumflex over (C)}ACAGCUCACAAGGAUCCCAAUGCC AUCUUCCUGAG{circumflex over (C)}UUCCAACACCUGCUCCG{tilde over (A)}GGAAAGGUGCGUUUCCUG{tilde over (A)} UGCUUGUAGGAGGGUCC{tilde over (A)}CCCUCUGCGUCAGGCGGG{circumflex over (G)}CCCCACCCACCA CAGCU{circumflex over (G)}UCCCCAGCAGAACCUCU{circumflex over (C)}UAGUCCUCACACUGAAC{circumflex over (G)}AGCUCCC AAACAGGACU{tilde over (U)}CUGGAUUGUUGGAGACA{tilde over (A)}ACUUCACUGCCUCAGCC{tilde over (A)}GA ACUACUGGCUCUGGG{circumflex over (C)}UUCUGAAGUGGCAGCAG{circumflex over (G)}GAUUCAGAGCCAAGA UU{circumflex over (C)}CUGGUCUGCUGAACCAA{tilde over (A)}CCUCCAGGUCCCUGGAC{circumflex over (C)}AAAUCCCCGG AUACCUG{tilde over (A)}ACAGGAUACACGAACUC{tilde over (U)}UGAAUGGAACUCGUGGA{circumflex over (C)}UCUUU CCUGGACCCUCA{circumflex over (C)}GCAGGACCCUAGGAGCC{circumflex over (C)}CGGACAUUUCCUCAGGA{tilde over (A)} CAUCAGACACAGGCUCC{circumflex over (C)}UGCCACCCAACCUCCAG{circumflex over (C)}CUGGAUAUUCUCC UUCC{circumflex over (C)}CAACCCAUCCUCCUACU{circumflex over (G)}GACAGUAUACGCUCUUC{circumflex over (C)}CUCUUCCA CCCACCUUG{circumflex over (C)}CCACCCCUGUGGUCCAG{circumflex over (C)}UCCACCCCCUGCUUCCU{circumflex over (G)}ACC CUUCUGCUCCAACG{circumflex over (C)}CCACCCCUACCAGCCCU{circumflex over (C)}UUCUAAACACAUCCUA C{tilde over (A)}CCCACUCCCAGAAUCUG{tilde over (U)}CUCAGGAAGGGU{tilde over (A)}A (SEQ ID NO: 148) A{tilde over (U)}{circumflex over (G)}{circumflex over (G)}AGCUGACUGAAUUGCUCCUCGUGGUCAUGCUUCUCCUAACUGCAA GGCUAACGCUGUCCAGCCCGGCUCCUCCUGCUUGUGACCUCCGAGUCCU CAGUAAACUGCUUCGUGACUCCCAUGUCCUUCACAGCAGACUGAGCCAG UGCCCAGAGGUUCACCCUUUGCCUACACCUGUCCUGCUGCCUGCUGUGG ACUUUAGCUUGGGAGAAUGGAAAACCCAGAUGGAGGAGACCAAGGCACA GGACAUUCUGGGAGCAGUGACCCUUCUGCUGGAGGGAGUGAUGGCAGCA CGGGGACAACUGGGACCCACUUGCCUCUCAUCCCUCCUGGGGCAGCUUU CUGGACAGGUCCGUCUCCUCCUUGGGGCCCUGCAGAGCCUCCUUGGAAC CCAGCUUCCUCCACAGGGCAGGACCACAGCUCACAAGGAUCCCAAUGCC AUCUUCCUGAGCUUCCAACACCUGCUCCGAGGAAAGGUGCGUUUCCUGA UGCUUGUAGGAGGGUCCACCCUCUGCGUCAGGCGGGCCCCACCCACCAC AGCUGUCCCCAGCAGAACCUCUCUAGUCCUCACACUGAACGAGCUCCCA AACAGGACUUCUGGAUUGUUGGAGACAAACUUCACUGCCUCAGCCAGAA CUACUGGCUCUGGGCUUCUGAAGUGGCAGCAGGGAUUCAGAGCCAAGAU UCCUGGUCUGCUGAACCAAACCUCCAGGUCCCUGGACCAAAUCCCCGGA UACCUGAACAGGAUACACGAACUCUUGAAUGGAACUCGUGGACUCUUUC CUGGACCCUCACGCAGGACCCUAGGAGCCCCGGACAUUUCCUCAGGAAC AUCAGACACAGGCUCCCUGCCACCCAACCUCCAGCCUGGAUAUUCUCCU UCCCCAACCCAUCCUCCUACUGGACAGUAUACGCUCUUCCCUCUUCCAC CCACCUUGCCCACCCCUGUGGUCCAGCUCCACCCCCUGCUUCCUGACCC UUCUGCUCCAACGCCCACCCCUACCAGCCCUCUUCUAAACACAUCCUAC ACCCACUCCCAGAAUCUGUCUCAGGAAGG{circumflex over (G)}{tilde over (U)}{tilde over (A)}A (SEQ ID NO: 149) A{tilde over (U)}GGAGC{tilde over (U)}GAC{tilde over (U)}GAA{tilde over (U)}{tilde over (U)}GC{tilde over (U)}CC{tilde over (U)}CG{tilde over (U)}GG{tilde over (U)}CA{tilde over (U)}GC{tilde over (U)}{tilde over (U)}C{tilde over (U)}CC{tilde over (U)}AAC{tilde over (U)}GC AAGGC{tilde over (U)}AACGC{tilde over (U)}G{tilde over (U)}CCAGCCCGGC{tilde over (U)}CC{tilde over (U)}CC{tilde over (U)}GC{tilde over (U)}G{tilde over (U)}GACC{tilde over (U)}CCGA G{tilde over (U)}CC{tilde over (U)}CAG{tilde over (U)}AAAC{tilde over (U)}GC{tilde over (U)}{tilde over (U)}CG{tilde over (U)}GAC{tilde over (U)}CCCA{tilde over (U)}GCC{tilde over (U)}{tilde over (U)}CACAGCAGA C{tilde over (U)}GAGCCAG{tilde over (U)}GCCCAGAGG{tilde over (U)}{tilde over (U)}CACCC{tilde over (U)}{tilde over (U)}{tilde over (U)}GCC{tilde over (U)}ACACC{tilde over (U)}G{tilde over (U)}CC{tilde over (U)}G C{tilde over (U)}GCC{tilde over (U)}GC{tilde over (U)}G{tilde over (U)}GGAC{tilde over (U)}{tilde over (U)}{tilde over (U)}AGC{tilde over (U)}{tilde over (U)}GGGAGAA{tilde over (U)}GGAAAACCCAGA{tilde over (U)}G GAGGAGACCAAGGCACAGGACA{tilde over (U)}{tilde over (U)}C{tilde over (U)}GGGAGCAG{tilde over (U)}GACCC{tilde over (U)}C{tilde over (U)}GC{tilde over (U)} GGAGGGAG{tilde over (U)}GA{tilde over (U)}GGCAGCACGGGGACAAC{tilde over (U)}GGGACCCAC{tilde over (U)}{tilde over (U)}GCC{tilde over (U)}C{tilde over (U)} CA{tilde over (U)}CCC{tilde over (U)}CC{tilde over (U)}GGGGCAGC{tilde over (U)}{tilde over (U)}{tilde over (U)}C{tilde over (U)}GGACAGG{tilde over (U)}CCG{tilde over (U)}C{tilde over (U)}CC{tilde over (U)}CC{tilde over (U)}{tilde over (U)}GG GGCCC{tilde over (U)}GCAGAGCC{tilde over (U)}CC{tilde over (U)}{tilde over (U)}GGAACCCAGC{tilde over (U)}{tilde over (U)}CC{tilde over (U)}CCACAGGGCAGGA CCACAGC{tilde over (U)}CACAAGGA{tilde over (U)}CCCAA{tilde over (U)}GCCA{tilde over (U)}C{tilde over (U)}{tilde over (U)}CC{tilde over (U)}GAGC{tilde over (U)}{tilde over (U)}CCAACAC C{tilde over (U)}GC{tilde over (U)}CCGAGGAAAGG{tilde over (U)}GCG{tilde over (U)}{tilde over (U)}{tilde over (U)}CC{tilde over (U)}GA{tilde over (U)}GC{tilde over (U)}{tilde over (U)}G{tilde over (U)}AGGAGGG{tilde over (U)}CCAC CC{tilde over (U)}C{tilde over (U)}GCG{tilde over (U)}CAGGCGGGCCCCACCCACCACAGC{tilde over (U)}G{tilde over (U)}CCCCAGCAGAAC C{tilde over (U)}C{tilde over (U)}C{tilde over (U)}AG{tilde over (U)}CC{tilde over (U)}CACAC{tilde over (U)}GAACGAGC{tilde over (U)}CCCAAACAGGAC{tilde over (U)}{tilde over (U)}C{tilde over (U)}GG A{tilde over (U)}{tilde over (U)}G{tilde over (U)}{tilde over (U)}GGAGACAAAC{tilde over (U)}{tilde over (U)}CAC{tilde over (U)}GCC{tilde over (U)}CAGCCAGAAC{tilde over (U)}AC{tilde over (U)}GGC{tilde over (U)}C{tilde over (U)}G GGC{tilde over (U)}C{tilde over (U)}GAAG{tilde over (U)}GGCAGCAGGGA{tilde over (U)}{tilde over (U)}CAGAGCCAAGA{tilde over (U)}{tilde over (U)}CC{tilde over (U)}GG{tilde over (U)}C{tilde over (U)}G C{tilde over (U)}GAACCAAACC{tilde over (U)}CCAGG{tilde over (U)}CCC{tilde over (U)}GGACCAAA{tilde over (U)}CCCCGGA{tilde over (U)}ACC{tilde over (U)}GAACA GGA{tilde over (U)}ACACGAAC{tilde over (U)}C{tilde over (U)}{tilde over (U)}GAA{tilde over (U)}GGAAC{tilde over (U)}CG{tilde over (U)}GGAC{tilde over (U)}C{tilde over (U)}{tilde over (U)}{tilde over (U)}CC{tilde over (U)}GGACC C{tilde over (U)}CACGCAGGACCC{tilde over (U)}AGGAGCCCCGGACA{tilde over (U)}{tilde over (U)}{tilde over (U)}CC{tilde over (U)}CAGGAACA{tilde over (U)}CAG ACACAGGC{tilde over (U)}CCC{tilde over (U)}GCCACCCAACC{tilde over (U)}CCAGCC{tilde over (U)}GGA{tilde over (U)}A{tilde over (U)}{tilde over (U)}C{tilde over (U)}CC{tilde over (U)}{tilde over (U)}CC CCAACCCA{tilde over (U)}CC{tilde over (U)}CC{tilde over (U)}AC{tilde over (U)}GGACAG{tilde over (U)}A{tilde over (U)}ACGC{tilde over (U)}C{tilde over (U)}{tilde over (U)}CCC{tilde over (U)}C{tilde over (U)}{tilde over (U)}CCACCC ACC{tilde over (U)}{tilde over (U)}GCCCACCCC{tilde over (U)}G{tilde over (U)}GG{tilde over (U)}CCAGC{tilde over (U)}CCACCCCC{tilde over (U)}GC{tilde over (U)}{tilde over (U)}CC{tilde over (U)}GACCC {tilde over (U)}{tilde over (U)}C{tilde over (U)}GC{tilde over (U)}CCAACGCCCACCCC{tilde over (U)}ACCAGCCC{tilde over (U)}C{tilde over (U)}{tilde over (U)}C{tilde over (U)}AAACACA{tilde over (U)}CC{tilde over (U)} ACACCCAC{tilde over (U)}CCCAGAA{tilde over (U)}C{tilde over (U)}G{tilde over (U)}C{tilde over (U)}CAGGAAGGG{tilde over (U)}AA - In this example, the structures of mUNA molecules for use in expressing human amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) are shown.
- AGL is associated with glycogen storage disease.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human AGL. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human AGL.
-
Human AGL is accession NM_000642.2. (SEQ ID NO: 150) A{tilde over (U)}{circumflex over (G)}{circumflex over (G)}GACACAGUAAACAGAUUCGAAUUUUACUUCUGAACGAAAUGGAGA AACUGGAAAAGACCCUCUUCAGACUUGAACAAGGGUAUGAGCUACAGUU CCGAUUAGGCCCAACUUUACAGGGAAAAGCAGUUACCGUGUAUACAAAU UACCCAUUUCCUGGAGAAACAUUUAAUAGAGAAAAAUUCCGUUCUCUGG AUUGGGAAAAUCCAACAGAAAGAGAAGAUGAUUCUGAUAAAUACUGUAA ACUUAAUCUGCAACAAUCUGGUUCAUUUCAGUAUUAUUUCCUUCAAGGA AAUGAGAAAAGUGGUGGAGGUUACAUAGUUGUGGACCCCAUUUUACGUG UUGGUGCUGAUAAUCAUGUGCUACCCUUGGACUGUGUUACUCUUCAGAC AUUUUUAGCUAAGUGUUUGGGACCUUUUGAUGAAUGGGAAAGCAGACUU AGGGUUGCAAAAGAAUCAGGCUACAACAUGAUUCAUUUUACCCCAUUGC AGACUCUUGGACUAUCUAGGUCAUGCUACUCCCUUGCCAAUCAGUUAGA AUUAAAUCCUGACUUUUCAAGACCUAAUAGAAAGUAUACCUGGAAUGAU GUUGGACAGCUAGUGGAAAAAUUAAAAAAGGAAUGGAAUGUUAUUUGUA UUACUGAUGUUGUCUACAAUCAUACUGCUGCUAAUAGUAAAUGGAUCCA GGAACAUCCAGAAUGUGCCUAUAAUCUUGUGAAUUCUCCACACUUAAAA CCUGCCUGGGUCUUAGACAGAGCACUUUGGCGUUUCUCCUGUGAUGUUG CAGAAGGGAAAUACAAAGAAAAGGGAAUACCUGCUUUGAUUGAAAAUGA UCACCAUAUGAAUUCCAUCCGAAAAAUAAUUUGGGAGGAUAUUUUUCCA AAGCUUAAACUCUGGGAAUUUUUCCAAGUAGAUGUCAACAAAGCGGUUG AGCAAUUUAGAAGACUUCUUACACAAGAAAAUAGGCGAGUAACCAAGUC UGAUCCAAACCAACACCUUACGAUUAUUCAAGAUCCUGAAUACAGACGG UUUGGCUGUACUGUAGAUAUGAACAUUGCACUAACGACUUUCAUACCAC AUGACAAGGGGCCAGCAGCAAUUGAAGAAUGCUGUAAUUGGUUUCAUAA AAGAAUGGAGGAAUUAAAUUCAGAGAAGCAUCGACUCAUUAACUAUCAU CAGGAACAGGCAGUUAAUUGCCUUUUGGGAAAUGUGUUUUAUGAACGAC UGGCUGGCCAUGGUCCAAAACUAGGACCUGUCACUAGAAAGCAUCCUUU AGUUACCAGGUAUUUUACUUUCCCAUUUGAAGAGAUAGACUUCUCCAUG GAAGAAUCUAUGAUUCAUCUGCCAAAUAAAGCUUGUUUUCUGAUGGCAC ACAAUGGAUGGGUAAUGGGAGAUGAUCCUCUUCGAAACUUUGCUGAACC GGGUUCAGAAGUUUACCUAAGGAGAGAACUUAUUUGCUGGGGAGACAGU GUUAAAUUACGCUAUGGGAAUAAACCAGAGGACUGUCCUUAUCUCUGGG CACACAUGAAAAAAUACACUGAAAUAACUGCAACUUAUUUCCAGGGAGU ACGUCUUGAUAACUGCCACUCAACACCUCUUCACGUAGCUGAGUACAUG UUGGAUGCUGCUAGGAAUUUGCAACCCAAUUUAUAUGUAGUAGCUGAAC UGUUCACAGGAAGUGAAGAUCUGGACAAUGUCUUUGUUACUAGACUGGG CAUUAGUUCCUUAAUAAGAGAGGCAAUGAGUGCAUAUAAUAGUCAUGAA GAGGGCAGAUUAGUUUACCGAUAUGGAGGAGAACCUGUUGGAUCCUUUG UUCAGCCCUGUUUGAGGCCUUUAAUGCCAGCUAUUGCACAUGCCCUGUU UAUGGAUAUUACGCAUGAUAAUGAGUGUCCUAUUGUGCAUAGAUCAGCG UAUGAUGCUCUUCCAAGUACUACAAUUGUUUCUAUGGCAUGUUGUGCUA GUGGAAGUACAAGAGGCUAUGAUGAAUUAGUGCCUCAUCAGAUUUCAGU GGUUUCUGAAGAACGGUUUUACACUAAGUGGAAUCCUGAAGCAUUGCCU UCAAACACAGGUGAAGUUAAUUUCCAAAGCGGCAUUAUUGCAGCCAGGU GUGCUAUCAGUAAACUUCAUCAGGAGCUUGGAGCCAAGGGUUUUAUUCA GGUGUAUGUGGAUCAAGUUGAUGAAGACAUAGUGGCAGUAACAAGACAC UCACCUAGCAUCCAUCAGUCUGUUGUGGCUGUAUCUAGAACUGCUUUCA GGAAUCCCAAGACUUCAUUUUACAGCAAGGAAGUGCCUCAAAUGUGCAU CCCUGGCAAAAUUGAAGAAGUAGUUCUUGAAGCUAGAACUAUUGAGAGA AACACGAAACCUUAUAGGAAGGAUGAGAAUUCAAUCAAUGGAACACCAG AUAUCACAGUAGAAAUUAGAGAACAUAUUCAGCUUAAUGAAAGUAAAAU UGUUAAACAAGCUGGAGUUGCCACAAAAGGGCCCAAUGAAUAUAUUCAA GAAAUAGAAUUUGAAAACUUGUCUCCAGGAAGUGUUAUUAUAUUCAGAG UUAGUCUUGAUCCACAUGCACAAGUCGCUGUUGGAAUUCUUCGAAAUCA UCUGACACAAUUCAGUCCUCACUUUAAAUCUGGCAGCCUAGCUGUUGAC AAUGCAGAUCCUAUAUUAAAAAUUCCUUUUGCUUCUCUUGCCUCCAGAU UAACUUUGGCUGAGCUAAAUCAGAUCCUUUACCGAUGUGAAUCAGAAGA AAAGGAAGAUGGUGGAGGGUGCUAUGACAUACCAAACUGGUCAGCCCUU AAAUAUGCAGGUCUUCAAGGUUUAAUGUCUGUAUUGGCAGAAAUAAGAC CAAAGAAUGACUUGGGGCAUCCUUUUUGUAAUAAUUUGAGAUCUGGAGA UUGGAUGAUUGACUAUGUCAGUAACCGGCUUAUUUCACGAUCAGGAACU AUUGCUGAAGUUGGUAAAUGGUUGCAGGCUAUGUUCUUCUACCUGAAGC AGAUCCCACGUUACCUUAUCCCAUGUUACUUUGAUGCUAUAUUAAUUGG UGCAUAUACCACUCUUCUGGAUACAGCAUGGAAGCAGAUGUCAAGCUUU GUUCAGAAUGGUUCAACCUUUGUGAAACACCUUUCAUUGGGUUCAGUUC AACUGUGUGGAGUAGGAAAAUUCCCUUCCCUGCCAAUUCUUUCACCUGC CCUAAUGGAUGUACCUUAUAGGUUAAAUGAGAUCACAAAAGAAAAGGAG CAAUGUUGUGUUUCUCUAGCUGCAGGCUUACCUCAUUUUUCUUCUGGUA UUUUCCGCUGCUGGGGAAGGGAUACUUUUAUUGCACUUAGAGGUAUACU GCUGAUUACUGGACGCUAUGUAGAAGCCAGGAAUAUUAUUUUAGCAUUU GCGGGUACCCUGAGGCAUGGUCUCAUUCCUAAUCUACUGGGUGAAGGAA UUUAUGCCAGAUACAAUUGUCGGGAUGCUGUGUGGUGGUGGCUGCAGUG UAUCCAGGAUUACUGUAAAAUGGUUCCAAAUGGUCUAGACAUUCUCAAG UGCCCAGUUUCCAGAAUGUAUCCUACAGAUGAUUCUGCUCCUUUGCCUG CUGGCACACUGGAUCAGCCAUUGUUUGAAGUCAUACAGGAAGCAAUGCA AAAACACAUGCAGGGCAUACAGUUCCGAGAAAGGAAUGCUGGUCCCCAG AUAGAUCGAAACAUGAAGGACGAAGGUUUUAAUAUAACUGCAGGAGUUG AUGAAGAAACAGGAUUUGUUUAUGGAGGAAAUCGUUUCAAUUGUGGCAC AUGGAUGGAUAAAAUGGGAGAAAGUGACAGAGCUAGAAACAGAGGAAUC CCAGCCACACCAAGAGAUGGGUCUGCUGUGGAAAUUGUGGGCCUGAGUA AAUCUGCUGUUCGCUGGUUGCUGGAAUUAUCCAAAAAAAAUAUUUUCCC UUAUCAUGAAGUCACAGUAAAAAGACAUGGAAAGGCUAUAAAGGUCUCA UAUGAUGAGUGGAACAGAAAAAUACAAGACAACUUUGAAAAGCUAUUUC AUGUUUCCGAAGACCCUUCAGAUUUAAAUGAAAAGCAUCCAAAUCUGGU UCACAAACGUGGCAUAUACAAAGAUAGUUAUGGAGCUUCAAGUCCUUGG UGUGACUAUCAGCUCAGGCCUAAUUUUACCAUAGCAAUGGUUGUGGCCC CUGAGCUCUUUACUACAGAAAAAGCAUGGAAAGCUUUGGAGAUUGCAGA AAAAAAAUUGCUUGGUCCCCUUGGCAUGAAAACUUUAGAUCCAGAUGAU AUGGUUUACUGUGGAAUUUAUGACAAUGCAUUAGACAAUGACAACUACA AUCUUGCUAAAGGUUUCAAUUAUCACCAAGGACCUGAGUGGCUGUGGCC UAUUGGGUAUUUUCUUCGUGCAAAAUUAUAUUUUUCCAGAUUGAUGGGC CCGGAGACUACUGCAAAGACUAUAGUUUUGGUUAAAAAUGUUCUUUCCC GACAUUAUGUUCAUCUUGAGAGAUCCCCUUGGAAAGGACUUCCAGAACU GACCAAUGAGAAUGCCCAGUACUGUCCUUUCAGCUGUGAAACACAAGCC UGGUCAAUUGCUACUAUUCUUGAGACACUUUAUGAUUU{tilde over (A)}{tilde over (U)}{tilde over (A)}G (SEQ ID NO: 151) AŨGGGACACAGŨAAACAGAŨŨCGAAŨŨACŨŨCŨGAACGAAAŨGGAGAA ACŨGGAAAAGACCCŨCŨŨCAGACŨŨGAACAAGGGŨAŨGAGCŨACAGŨŨ CCGAŨŨAGGCCCAACŨŨŨACAGGGAAAAGCAGŨŨACCGŨGŨAŨACAA AŨŨACCCAŨŨŨCCŨGGAGAAACAŨŨŨAAŨAGAGAAAAAŨŨCCGŨŨCŨ CŨGGAŨŨGGGAAAAŨCCAACAGAAAGAGAAGAŨGAŨŨCŨGAŨAAAŨA CŨGŨAAACŨŨAAŨCŨGCAACAAŨCŨGGŨŨCAŨŨŨCAGŨAŨŨAŨŨŨC CŨŨCAAGGAAAŨGAGAAAAGŨGGŨGGAGGŨŨACAŨAGŨŨGŨGGACCCCA ŨŨŨŨACGŨGŨŨGGŨGCŨGAŨAAŨCAŨGŨGCŨACCCŨŨGGACŨGŨG ŨŨACŨCŨŨCAGACAŨŨŨŨŨAGCŨAAGŨGŨŨŨGGGACCŨŨŨŨGAŨGAA ŨGGGAAAGCAGACŨŨAGGGŨŨGCAAAAGAAŨCAGGCŨACAACAŨGA ŨŨCAŨŨŨŨACCCCAŨŨGCAGACŨCŨŨGGACŨAŨCŨAGGŨCAŨGCŨAC ŨCCCŨŨGCCAAŨCAGŨŨAGAAŨŨAAAŨCCŨGACŨŨŨŨCAAGACCŨAA ŨAGAAAGŨAŨACCŨGGAAŨGAŨGŨŨGGACAGCŨAGŨGGAAAAAŨŨAAA AAAGGAAŨGGAAŨGŨŨAŨŨGŨAŨŨACŨGAŨGŨŨGŨCŨACAAŨCAŨAC ŨGCŨGCŨAAŨAGŨAAAŨGGAŨCCAGGAACAŨCCAGAAŨGŨGCCŨAŨAA ŨCUŨGŨGAANCŨCCACACŨŨAAAACCŨGCCŨGGGŨCŨŨAGACAGAGCA CŨŨŨGGCGŨŨŨŨŨCCŨGŨGAŨGŨŨGCAGAAGGGAAAŨACAAAGAAAA GGGAAŨACCŨGCŨŨŨGAŨŨGAAAAŨGAŨCACCAŨAŨGAAŨŨCCAŨCC GAAAAAŨAAŨŨŨGGGAGGAŨAŨŨŨŨŨCCAAAGCŨŨAAACŨCŨGGGA AŨŨŨŨŨCCAAGŨAGAŨGŨCAACAAAGCGGŨŨGAGCAŨŨŨŨAGAAGAC ŨŨCŨŨACACAAGAAAAŨAGGCGAGŨAACCAAGŨCŨGAŨCCAAACCAA CACCŨŨACGAŨŨAŨŨCAAGAŨCCŨGAAŨACAGACGGŨŨŨGGCŨGŨAC ŨGŨAGAŨAŨGAACAŨŨGCACŨAACGACŨCAŨACCACAŨGACAAGGGG CCAGCAGCAAŨŨGAAGAAŨGCŨGŨAAŨŨGGŨŨŨCAŨAAAAGAAŨGGA GGAAŨŨAAAŨŨCAGAGAAGCAŨCGACŨCAŨŨAACŨAŨCAŨCAGGAACA GGCAGŨŨAAŨŨGCCŨŨŨŨGGGAAAŨGŨGŨŨŨŨAŨGAACGACŨGGCŨG GCCAŨGGŨCCAAAACŨAGGACCŨGŨCACŨAGAAAGCAŨCCŨŨŨAGŨŨA CCAGGŨAŨŨŨŨACŨŨŨCCCAŨŨŨGAAGAGAŨAGACŨŨCŨCCAŨGGAA GAAŨCŨAŨGAŨŨCAŨCŨGCCAAAŨAAAGCŨŨGŨŨŨCŨGAŨGGCACACA AŨGGAŨGGGŨAAŨGGGAGAŨGAŨCCŨCŨŨCGAAACŨŨŨGCŨGAACCGG GŨŨCAGAAGŨŨŨACCŨAAGGAGAGAACŨŨAŨŨŨGCŨGGGGAGACAGŨ GŨŨAAAŨŨACGCŨAŨGGGAAŨAAACCAGAGGACŨGŨCCŨŨAŨCŨCŨGG GCACACAŨGAAAAAAŨACACŨGAAAŨAACŨGCAACŨŨAŨŨŨCCAGGGA GŨACGŨCŨŨGAŨAACŨGCCACŨCAACACCŨCŨŨCACGŨAGCŨGAGŨAC AŨGŨŨGGAŨGCŨGCŨAGGAAŨŨŨGCAACCCAAŨŨŨAŨAŨGŨAGŨAGC ŨGAACŨGŨŨCACAGGAAGŨGAAGAŨCŨGGACAAŨGŨCŨŨŨGŨŨACŨA GACŨGGGCAŨŨAGŨŨCCŨŨAAŨAAGAGAGGCAAŨGAGŨGCAŨAŨAAŨ AGŨCAŨGAAGAGGGCAGAŨŨAGŨŨŨACCGAŨAŨGGAGGAGAACCŨGŨ ŨGGAŨCCŨŨŨGŨŨCAGCCCŨGŨŨŨGAGGCCŨŨŨAAŨGCCAGCŨAŨŨG CACAŨGCCCŨGŨŨŨAŨGGAŨAŨŨACGCAŨGAŨAAŨGAGŨGŨCCŨAŨŨ GŨGCAŨAGAŨCAGCGŨAŨGAŨGCŨCŨŨCCAAGŨACŨACAAŨŨGŨŨŨC ŨAŨGGCAŨGŨŨGŨGCŨAGŨGGAAGŨACAAGAGGCŨAŨGAŨGAAŨŨAG ŨGCCŨCAŨCAGAŨŨŨCAGŨGGŨŨŨCŨGAAGAACGGŨŨŨŨACACŨAAG ŨGGAAŨCCŨGAAGCAŨGCCŨŨCAAACACAGGŨGAAGŨŨAAŨŨŨCCAAA GCGGCAŨŨAŨŨGCAGCCAGGŨGŨGCŨAŨCAGŨAAACŨŨCAŨCAGGAGC ŨŨGGAGCCAAGGGŨŨŨŨAŨŨCAGGŨGŨAŨGŨGGAŨCAAGŨŨGAŨG AAGACAŨAGŨGGCAGŨAACAAGACACŨCACCŨAGCAŨCCAŨCAGŨC ŨGŨŨGŨGGCŨGŨAŨCŨAGAACŨGCŨŨŨCAGGAAŨCCCAAGACŨŨCA ŨŨŨŨACAGCAAGGAAGŨGCCŨCAAAŨGŨGCAŨCCCŨGGCAAAAŨŨ GAAGAAGŨAGŨŨCŨŨGAAGCŨAGAACŨAŨŨGAGAGAAACACGAAAC CŨŨAŨAGGAAGGAŨGAGAAŨŨCAAŨCAAŨGGAACACCAGAŨAŨCAC AGŨAGAAAŨŨAGAGAACAŨAŨŨCAGCŨŨAAŨGAAAGŨAAAAŨŨGŨŨA AACAAGCŨGGAGŨŨGCCACAAAAGGGCCCAAŨGAAŨAŨAŨŨCAAGAA AŨAGAAŨŨŨGAAAACŨŨGŨCŨCCAGGAAGŨGŨŨAŨŨAŨAŨŨCAGAGŨŨ AGŨCŨŨGAŨCCACAŨGCACAAGŨCGCŨGŨŨGGAAŨŨCŨŨCGAAAŨCAŨ CŨGACACAAŨŨCAGŨCCŨCACŨŨŨAAAŨCŨGGCAGCCŨAGCŨGŨŨ GACAAŨGCAGAŨCCŨAŨAŨŨAAAAAŨŨCCŨŨŨGCŨŨCŨCŨŨGCCŨCC AGAŨŨAACŨŨŨGGCŨGAGCŨAAAŨCAGAŨCCŨŨŨACCGAŨGŨGAAŨC AGAAGAAAAGGAAGAŨGGŨGGAGGGŨGCŨAŨGACAŨACCAAACŨGGŨ CAGCCCŨŨAAAŨAŨGCAGGŨCŨŨCAAGGŨŨŨAAŨGŨCŨGŨAŨŨGGC AGAAAŨAAGACCAAAGAAŨGACŨŨGGGGCAŨCCŨŨŨŨŨGŨAAŨAA ŨŨŨGAGAŨCŨGGAGAŨŨGGAŨGAŨŨGACŨAŨGŨCAGŨAACCGGC ŨŨAŨŨŨCACGAŨCAGGAACŨAŨŨGCŨGAAGŨŨGGŨAAAŨGGŨŨGCAG GCŨAŨGŨŨCŨŨCŨACCŨGAAGCAGAŨCCCACGŨŨACCŨŨAŨCCCAŨG ŨŨACŨŨŨGAŨGCŨAŨAŨŨAAŨŨGGŨGCAŨAŨACCACŨCŨŨCŨGGAŨA CAGCAŨGGAAGCAGAŨGŨCAAGCŨŨŨGŨŨCAGAAŨGGŨŨCAACCŨŨŨ GŨGAAACACCŨŨŨCAŨŨGGGŨŨCAGŨŨCAACŨGŨGŨGGAGŨAGGAAAA ŨŨCCCŨŨCCCŨGCCAAŨŨCŨŨŨCACCŨGCCCŨAAŨGGAŨGŨACCŨŨAŨ AGGŨŨAAAŨGAGAŨCACAAAAGAAAAGGAGCAAŨGŨŨGŨGŨŨŨŨCŨAG CŨGCAGGCŨŨACCŨCAŨŨŨŨŨCŨŨCŨGGŨAŨŨŨŨCCGCŨGCŨGGGGA AGGGAŨACŨŨŨAŨŨGCACŨŨAGAGGŨAŨACŨGCŨGAŨŨACŨGGACGC ŨAŨGŨAGAAGCCAGGAAŨAŨŨAŨŨŨŨAGCAŨŨŨGCGGGŨACCCŨGAGG CAŨGGŨCŨCAŨŨCCŨAAŨCŨACŨGGGŨGAAGGAŨŨŨŨAŨGCCAGAŨA CAAŨŨGŨCGGGAŨGCŨGŨGŨGGŨGGŨGGCŨGCAGŨGŨAŨCCAGGA ŨŨACŨGŨAAAAŨGGŨŨCCAAAŨGGŨCŨAGACAŨŨCŨCAAGŨGCCCA GŨŨŨCCAGAAŨGŨAŨCCŨACAGAŨGAŨŨCŨGCŨCCŨŨŨGCCŨGCŨG GCACACŨGGAŨCAGCCAŨŨGŨŨŨGAAGŨCAŨACAGGAAGCAAŨGCAA AAACACAŨGCAGGGCAŨACAGŨŨCCGAGAAAGGAAŨGCŨGGŨCCCCAG AŨAGAŨCGAAACAŨGAAGGACGAAGGŨŨŨAAŨAŨAACŨGCAGGAGŨŨ GAŨGAAGAAACAGGAŨŨŨGŨŨŨAŨGGAGGAAAŨCGŨŨŨCAAŨŨGŨGGC ACAŨGGAŨGGAŨAAAAŨGGGAGAAAGŨGACAGAGCŨAGAAACAGAGGAA ŨCCCAGCCACACCAAGAGAŨGGGŨCŨGCŨGŨGGAAAŨŨGŨGGGCCŨGA GŨAAAŨCŨGCŨGŨŨCGCŨGGŨŨGCŨGGAAŨŨAŨCCAAAAAAAAŨŨŨŨŨ ŨCCCŨŨAŨCAŨGAAGŨCACAGŨAAAAAGACAŨGGAAAGGCŨAŨAAA GGŨCŨCAŨAŨGAŨGAGŨGGAACAGAAAAAŨACAAGACAACŨŨŨGAAAA GCŨAŨŨŨCAŨGŨŨŨCCGAAGACCCŨŨCAGAŨŨŨAAAŨGAAAAGCAŨCC AAAŨCŨGGŨŨCACAAACGŨGGCAŨAŨACAAAGAŨAGŨŨAŨGGAGCŨŨ CAAGŨCCŨŨGGŨGŨGACŨAŨCAGCŨCAGGCCŨAAŨŨŨŨACCAŨAGCAA ŨGGŨGŨGGCCCCŨGAGCŨCŨŨŨACŨACAGAAAAAGCAŨGGAAAGC ŨŨŨGGAGAŨŨGCAGAAAAAAAAŨŨGCŨŨGGŨCCCCŨŨGGCAŨGAAA ACŨŨŨAGAŨCCAGAŨGAŨAŨGGŨŨŨACŨGŨGGAŨŨŨŨAŨGACAAŨG CAŨŨAGACAAŨGACAACŨACAAŨCŨŨGCŨAAAGGŨŨŨCAAŨŨAŨCACC AAGGACCŨGAGŨGGCŨGŨGGCCŨAŨŨGGGŨAŨŨŨŨŨŨCGŨGCAAAAŨŨ AŨAŨŨŨŨCCAGAŨŨGAŨGGGCCCGGAGACŨACŨGCAAAGACŨAŨAGŨŨ ŨŨGGŨŨAAAAAŨGŨŨCŨŨŨCCCGACAŨŨAŨGŨŨCAŨCŨŨGAGAGAŨC CCCŨŨGGAAAGGACŨŨCCAGAACŨGACCAAŨGAGAAŨGCCCAGŨACŨGŨ CCŨŨŨCAGCŨGŨGAAACACAAGCCŨGGŨCAAŨŨGCŨACŨAŨŨCŨŨGAG ACACŨŨŨAŨGAŨŨŨAŨAG - In this example, the structures of mUNA molecules for use in expressing human protein S (alpha) (PROS1) are shown.
- Human protein S (alpha) is associated with Protein S deficiency, thrombosis, and arterial occlusive disease.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human protein S (alpha). The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human protein S (alpha).
-
Human protein S (alpha) is accession NM_001314077.1. (SEQ ID NO: 152) A{tilde over (U)}{circumflex over (G)}{tilde over (A)}GGGUCCUGGGUGGGCGCUGCGGGGCGCUGCUGGCGUGUCUCCUC CUAGUGCUUCCCGUCUCAGAGGCAAACUUUUGUUUAUAUUUUAGAAAUG AUUUUAUAUACAACCGUGCAUGCAUUUCUGUAUUGGUCGGCUUAUCUGG AUGCAAUCUUUUUUCUAUUCUAUAUGCUUUUUGAAAGCAACAGGCUUCA CAAGUCCUGGUUAGGAAGCGUCGUGCAAAUUCUUUACUUGAAGAAACCA AACAGGGUAAUCUUGAAAGAGAAUGCAUCGAAGAACUGUGCAAUAAAGA AGAAGCCAGGGAGGUCUUUGAAAAUGACCCGGAAACGGAUUAUUUUUAU CCAAAAUACUUAGUUUGUCUUCGCUCUUUUCAAACUGGGUUAUUCACUG CUGCACGUCAGUCAACUAAUGCUUAUCCUGACCUAAGAAGCUGUGUCAA UGCCAUUCCAGACCAGUGUAGUCCUCUGCCAUGCAAUGAAGAUGGAUAU AUGAGCUGCAAAGAUGGAAAAGCUUCUUUUACUUGCACUUGUAAACCAG GUUGGCAAGGAGAAAAGUGUGAAUUUGACAUAAAUGAAUGCAAAGAUCC CUCAAAUAUAAAUGGAGGUUGCAGUCAAAUUUGUGAUAAUACACCUGGA AGUUACCACUGUUCCUGUAAAAAUGGUUUUGUUAUGCUUUCAAAUAAGA AAGAUUGUAAAGAUGUGGAUGAAUGCUCUUUGAAGCCAAGCAUUUGUGG CACAGCUGUGUGCAAGAACAUCCCAGGAGAUUUUGAAUGUGAAUGCCCC GAAGGCUACAGAUAUAAUCUCAAAUCAAAGUCUUGUGAAGAUAUAGAUG AAUGCUCUGAGAACAUGUGUGCUCAGCUUUGUGUCAAUUACCCUGGAGG UUACACUUGCUAUUGUGAUGGGAAGAAAGGAUUCAAACUUGCCCAAGAU CAGAAGAGUUGUGAGGUUGUUUCAGUGUGCCUUCCCUUGAACCUUGACA CAAAGUAUGAAUUACUUUACUUGGCGGAGCAGUUUGCAGGGGUUGUUUU AUAUUUAAAAUUUCGUUUGCCAGAAAUCAGCAGAUUUUCAGCAGAAUUU GAUUUCCGGACAUAUGAUUCAGAAGGCGUGAUACUGUACGCAGAAUCUA UCGAUCACUCAGCGUGGCUCCUGAUUGCACUUCGUGGUGGAAAGAUUGA AGUUCAGCUUAAGAAUGAACAUACAUCCAAAAUCACAACUGGAGGUGAU GUUAUUAAUAAUGGUCUAUGGAAUAUGGUGUCUGUGGAAGAAUUAGAAC AUAGUAUUAGCAUUAAAAUAGCUAAAGAAGCUGUGAUGGAUAUAAAUAA ACCUGGACCCCUUUUUAAGCCGGAAAAUGGAUUGCUGGAAACCAAAGUA UACUUUGCAGGAUUCCCUCGGAAAGUGGAAAGUGAACUCAUUAAACCGA UUAACCCUCGUCUAGAUGGAUGUAUACGAAGCUGGAAUUUGAUGAAGCA AGGAGCUUCUGGAAUAAAGGAAAUUAUUCAAGAAAAACAAAAUAAGCAU UGCCUGGUUACUGUGGAGAAGGGCUCCUACUAUCCUGGUUCUGGAAUUG CUCAAUUUCACAUAGAUUAUAAUAAUGUAUCCAGUGCUGAGGGUUGGCA UGUAAAUGUGACCUUGAAUAUUCGUCCAUCCACGGGCACUGGUGUUAUG CUUGCCUUGGUUUCUGGUAACAACACAGUGCCCUUUGCUGUGUCCUUGG UGGACUCCACCUCUGAAAAAUCACAGGAUAUUCUGUUAUCUGUUGAAAA UACUGUAAUAUAUCGGAUACAGGCCCUAAGUCUAUGUUCCGAUCAACAA UCUCAUCUGGAAUUUAGAGUCAACAGAAACAAUCUGGAGUUGUCGACAC CACUUAAAAUAGAAACCAUCUCCCAUGAAGACCUUCAAAGACAACUUGC CGUCUUGGACAAAGCAAUGAAAGCAAAAGUGGCCACAUACCUGGGUGGC CUUCCAGAUGUUCCAUUCAGUGCCACACCAGUGAAUGCCUUUUAUAAUG GCUGCAUGGAAGUGAAUAUUAAUGGUGUACAGUUGGAUCUGGAUGAAGC CAUUUCUAAACAUAAUGAUAUUAGAGCUCACUC AUGUCCAUCAGUUUGGAAAAAGACAAAGAAUUCU{tilde over (U)}{tilde over (U)}{tilde over (A)}A (SEQ ID NO: 153) AŨGAGGGŨCCŨGGGŨGGGCGCŨGCGGGGCGCŨGCŨGGCGŨGŨCŨCCŨ CCŨAGŨGCŨŨCCCGŨCŨCAGAGGCAAACŨŨŨGŨŨŨAŨAŨŨŨŨAGAAA ŨGAŨŨŨŨAŨAŨACAACCGŨGCAŨGCAŨŨŨCŨGŨAŨŨGGŨCGGCŨŨA ŨCŨGGAŨGCAAŨŨŨŨŨŨCŨAŨŨCŨAŨAŨGCŨŨŨŨŨGŨCAAAGCAACA GGCŨŨCACAAGŨCCŨGGŨŨAGGAAGCGŨCGŨGCAAAŨŨCŨŨŨACŨŨG AAGAAACCAAACAGGGŨAAŨCŨŨGAAAGAGAAŨGCAŨCGAAGAACŨGŨG CAAŨAAAGAAGAAGCCAGGGAGGŨCŨŨŨGAAAAŨGACCCGGAAACGGA ŨŨAŨŨŨŨŨAŨCCAAAAŨACŨŨAGŨŨŨGŨCŨŨCGCŨCŨŨŨŨCAAACŨ GGGŨŨAŨŨCACŨGCŨGCACGŨCAGŨCAACŨAAŨGCŨŨAŨCCŨGACCŨA AGAAGCŨGŨGŨCAAŨGCCAŨŨCCAGACCAGŨGŨAGŨCCŨCŨGCCAŨGC AAŨGAAGAŨGGAŨAŨAŨGAGCŨGCAAAGAŨGGAAAAGCŨŨCŨŨŨŨACŨŨ GCACŨŨGŨAAACCAGGŨŨGGCAAGGAGAAAAGŨGŨGAAŨŨŨGACAŨAAA ŨGAAŨGCAAAGAŨCCCŨCAAAŨAŨAAAŨGGAGGŨŨGCAGŨCAAAŨŨŨG ŨGAŨAAŨACACCŨGGAAGŨACCACŨGŨŨCCŨGŨAAAAAŨGGŨŨŨŨGŨ ŨAŨGCŨŨŨCAAAŨAAGAAAGAŨŨGŨAAAGAŨGŨGGAŨGAAŨGCŨCŨŨŨ GAAGCCAAGCAŨŨŨGŨGGCACAGCŨGŨGŨGCAAGAACAŨCCCAGGAGA ŨŨŨŨGAAŨGŨGAAŨGCCCCGAAGGCŨACAGAŨAŨAAŨCŨCAAAŨCAAAG ŨCŨŨGŨGAAGAŨAŨAGAŨGAAŨGCŨCŨGAGAACAŨGŨGŨGCŨCAGCŨ NGŨGŨCAAŨŨACCCŨGGAGGŨŨACACŨŨGCŨAŨŨGŨGAŨGGGAAGAAA GGAŨŨCAAACŨŨGCCCAAGAŨCAGAAGAGŨŨGŨGAGGŨŨGŨŨŨCAGŨG ŨGCCŨŨCCCŨŨGAACCŨŨGACACAAAGŨAŨGAAŨŨACŨŨŨACŨŨGGC GGAGCAGŨŨŨGCAGGGGŨŨGŨŨŨŨAŨŨŨŨŨAAAAŨŨŨCGŨŨŨGCCAGA AAŨCAGCAGAŨŨŨŨCAGCAGAAŨŨŨGAŨŨŨCCGGACAŨAŨGAŨŨCAGA AGGCGŨGAŨACŨGŨACGCAGAAŨCŨAŨCGAŨCACŨCAGCGŨŨGGCŨC CŨGAŨŨGCACŨŨCGŨGGŨGGAAAGAŨŨGAAGŨŨCAGCŨŨAAGAAŨGAA CAŨACAŨCCAAAAŨCACAACŨGGAGGŨGAŨGŨŨAŨŨAAŨAAŨGGŨ CŨAŨGGAAŨAŨGGŨGŨCŨGŨGGAAGAAŨŨAGAACAŨAGŨAŨŨAGCA ŨŨAAAAŨAGCŨAAAGAAGCŨGŨGAŨGGAŨAŨAAAŨAAACCŨGGACCCC ŨŨŨŨŨAAGCCGGAAAAŨGGAŨŨGCŨGGAAACCAAAGŨAŨACŨŨŨGCAGG AŨŨCCCŨCGGAAAGŨGGAAAGŨGAACŨCAŨŨAAACCGAŨŨAACCCŨC GŨCŨAGAŨGGAŨGŨAŨACGAAGCŨGGAAŨŨŨGAŨGAAGCAAGGAGCŨ ŨŨŨGGAAŨAAAGGAAAŨŨAŨŨCAAGAAAAACAAAAŨAAGCAŨŨGCCŨG GŨŨACŨGŨGGAGAAGGGCŨCCŨACŨAŨCCŨGGŨŨCŨGGAAŨŨGCŨCAA ŨŨŨCACAŨAGAŨŨAŨAAŨAAŨGŨAŨCCAGŨGCŨGAGGGŨŨGGCAŨG ŨAAAŨGŨGACCŨŨGAAŨAŨŨCGŨCCAŨCCACGGGCACŨGGŨGŨŨAŨG CŨŨGCCŨŨGGŨŨŨCŨGGŨAACAACACAGŨGCCCŨŨŨGCŨGŨGŨCCŨŨ GGŨGGACŨCCACCŨCŨGAAAAAŨCACAGGAŨAŨŨCŨGŨŨAŨCŨGŨŨGAA AAŨACŨGŨAAŨAŨAŨCGGAŨACAGGCCCŨAAGŨCŨAŨGŨŨCCGAŨCAAC AAŨCŨCAŨCŨGGAAŨŨŨAGAGŨCAACAGAAACAAŨCŨGGAGŨŨGŨCGA CACCACŨŨAAAAŨAGAAACCAŨCŨCCCAŨGAAGACCŨŨCAAAGACAAC ŨŨGCCGŨCŨŨGGACAAAGCAAŨGAAAGCAAAAGŨGGCCACAŨACCŨGGG ŨGGCCŨŨCCAGAŨGŨŨCCAŨŨCAGŨGCCACACCAGŨGAAŨGCCŨŨŨŨA ŨAAŨGGCŨGCAŨGGAAGŨGAAŨAŨŨAAŨGGŨGŨACAGŨŨGGAŨCŨGGAŨ GAAGCCAŨŨŨCŨAAACAŨAAŨGAŨAŨŨAGAGCŨCACŨCAŨGŨCCAŨCA GŨŨŨGGAAAAAGACAAAGAAŨŨCŨŨAA - In this example, the structures of mUNA molecules for use in expressing human pyruvate kinase, liver and RBC (PKLR) are shown.
- Human pyruvate kinase, liver and RBC (PKLR) is associated with chronic hereditary nonspherocytic hemolytic anemia.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human pyruvate kinase, liver and RBC (PKLR). The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human pyruvate kinase, liver and RBC (PKLR).
-
Human pyruvate kinase, liver and RBC (PKLR) is accession NM_000298.5. (SEQ ID NO: 154) A{tilde over (U)}{circumflex over (G)}{tilde over (U)}CGAUCCAGGAGAACAUAUCAUCCCUGCAGCUUCGGUCAUGGGUC UCUAAGUCCCAAAGAGACUUAGCAAAGUCCAUCCUGAUUGGGGCUCCA GGAGGGCCAGCGGGGUAUCUGCGGCGGGCCAGUGUGGCCCAACUGACC CAGGAGCUGGGCACUGCCUUCUUCCAGCAGCAGCAGCUGCCAGCUGCU AUGGCAGACACCUUCCUGGAACACCUCUGCCUACUGGACAUUGACUCC GAGCCCGUGGCUGCUCGCAGUACCAGCAUCAUUGCCACCAUCGGGCCA GCAUCUCGCUCCGUGGAGCGCCUCAAGGAGAUGAUCAAGGCCGGGAUG AACAUUGCGCGACUCAACUUCUCCCACGGCUCCCACGAGUACCAUGCU GAGUCCAUCGCCAACGUCCGGGAGGCGGUGGAGAGCUUUGCAGGUUCC CCACUCAGCUACCGGCCCGUGGCCAUCGCCCUGGACACCAAGGGACCG GAGAUCCGCACUGGGAUCCUGCAGGGGGGUCCAGAGUCGGAAGUGGAG CUGGUGAAGGGCUCCCAGGUGCUGGUGACUGUGGACCCCGCGUUCCGG ACGCGGGGGAACGCGAACACCGUGUGGGUGGACUACCCCAAUAUUGUC CGGGUCGUGCCGGUGGGGGGCCGCAUCUACAUUGACGACGGGCUCAUC UCCCUAGUGGUCCAGAAAAUCGGCCCAGAGGGACUGGUGACCCAAGUG GAGAACGGCGGCGUCCUGGGCAGCCGGAAGGGCGUGAACUUGCCAGGG GCCCAGGUGGACUUGCCCGGGCUGUCCGAGCAGGACGUCCGAGACCUG CGCUUCGGGGUGGAGCAUGGGGUGGACAUCGUCUUUGCCUCCUUUGUG CGGAAAGCCAGCGACGUGGCUGCCGUCAGGGCUGCUCUGGGUCCGGAA GGACACGGCAUCAAGAUCAUCAGCAAAAUUGAGAACCACGAAGGCGUG AAGAGGUUUGAUGAAAUCCUGGAGGUGAGCGACGGCAUCAUGGUGGCA CGGGGGGACCUAGGCAUCGAGAUCCCAGCAGAGAAGGUUUUCCUGGCU CAGAAGAUGAUGAUUGGGCGCUGCAACUUGGCGGGCAAGCCUGUUGUC UGUGCCACACAGAUGCUGGAGAGCAUGAUUACCAAGCCCCGGCCAACG AGGGCAGAGACAAGCGAUGUCGCCAAUGCUGUGCUGGAUGGGGCUGAC UGCAUCAUGCUGUCAGGGGAGACUGCCAAGGGCAACUUCCCUGUGGAA GCGGUGAAGAUGCAGCAUGCGAUUGCCCGGGAGGCAGAGGCCGCAGUG UACCACCGGCAGCUGUUUGAGGAGCUACGUCGGGCAGCGCCACUAAGC CGUGAUCCCACUGAGGUCACCGCCAUUGGUGCUGUGGAGGCUGCCUUC AAGUGCUGUGCUGCUGCCAUCAUUGUGCUGACCACAACUGGCCGCUCA GCCCAGCUUCUGUCUCGGUACCGACCUCGGGCAGCAGUCAUUGCUGUC ACCCGCUCUGCCCAGGCUGCCCGCCAGGUCCACUUAUGCCGAGGAGUC UUCCCCUUGCUUUACCGUGAACCUCCAGAAGCCAUCUGGGCAGAUGAU GUAGAUCGCCGGGUGCAAUUUGGCAUUGAAAGUGGAAAGCUCCGUGGC UUCCUCCGUGUUGGAGACCUGGUGAUUGUGGUGACAGGCUGGCGACCU GGCUCCGGCUACACCAACAUCAUGCGGGUGCUAAGCAUAUC{circumflex over (C)}{tilde over (U)}{circumflex over (G)}A (SEQ ID NO: 155) AŨGŨCGAŨCCAGGAGAACAŨAŨCAŨCCCŨGCAGCŨŨCGGŨCAŨGGGŨCŨCŨAAGŨCCCA AAGAGACŨŨAGCAAAGŨCCAŨCCŨGAŨŨGGGGCŨCCAGGAGGGCCAGCGGGGŨAŨCŨGC GGCGGGCCAGŨGŨGGCCCAACŨGACCCAGGAGCŨGGGCACŨGCCŨŨCŨŨCCAGCAGCAG CAGCŨGCCAGCŨGCŨAŨGGCAGACACCŨŨCCŨGGAACACCŨCŨGCCŨACŨGGACAŨŨGA CŨCCGAGCCCGŨGGCŨGCŨCGCAGŨACCAGCAŨCAŨŨGCCACCAŨCGGGCCAGCAŨCŨC GCŨCCGŨGGAGCGCCŨCAAGGAGAŨGAŨCAAGGCCGGGAŨGAACAŨŨGCGCGACŨCAAC ŨŨCŨCCCACGGCŨCCCACGAGŨACCAŨGCŨGAGŨCCAŨCGCCAACGŨCCGGGAGGCGGŨ GGAGAGCŨŨŨGCAGGŨŨCCCCACŨCAGCŨACCGGCCCGŨGGCCAŨCGCCCŨGGACACCA AGGGACCGGAGAŨCCGCACŨGGGAŨCCŨGCAGGGGGGŨCCAGAGŨCGGAAGŨGGAGCŨG GŨGAAGGGCŨCCCAGGŨGCŨGGŨGACŨGŨGGACCCCGCGŨŨCCGGACGCGGGGGAACGC GAACACCGŨGŨGGGŨGGACŨACCCCAAŨAŨŨGŨCCGGGŨCGŨGCCGGŨGGGGGGCCGCA ŨCŨACAŨŨGACGACGGGCŨCAŨCŨCCCŨAGŨGGŨCCAGAAAAŨCGGCCCAGAGGGACŨG GŨGACCCAAGŨGGAGAACGGCGGCGŨCCŨGGGCAGCCGGAAGGGCGŨGAACŨŨGCCAGG GGCCCAGGŨGGACŨŨGCCCGGGCŨGŨCCGAGCAGGACGŨCCGAGACCŨGCGCŨŨCGGGG ŨGGAGCAŨGGGGŨGGACAŨCGŨCŨŨŨGCCŨCCŨŨŨGŨGCGGAAAGCCAGCGACGŨGGCŨ GCCGŨCAGGGCŨGCŨCŨGGGŨCCGGAAGGACACGGCAŨCAAGAŨCAŨCAGCAAAAŨŨGA GAACCACGAAGGCGŨGAAGAGGŨŨŨGAŨGAAAŨCCŨGGAGGŨGAGCGACGGCAŨCAŨGG ŨGGCACGGGGGGACCŨAGGCAŨCGAGAŨCCCAGCAGAGAAGGŨŨŨŨCCŨGGCŨCAGAAG AŨGAŨGAŨŨGGGCGCŨGCAACŨŨGGCGGGCAAGCCŨGŨŨGŨCŨGŨGCCACACAGAŨGCŨ GGAGAGCAŨGAŨŨACCAAGCCCCGGCCAACGAGGGCAGAGACAAGCGAŨGŨCGCCAAŨG CŨGŨGCŨGGAŨGGGGCŨGACŨGCAŨCAŨGCŨGŨCAGGGGAGACŨGCCAAGGGCAACŨŨC CCŨGŨGGAAGCGGŨGAAGAŨGCAGCAŨGCGAŨŨGCCCGGGAGGCAGAGGCCGCAGŨGŨA CCACCGGCAGCŨGŨŨŨGAGGAGCŨACGŨCGGGCAGCGCCACŨAAGCCGŨGAŨCCCACŨG AGGŨCACCGCCAŨŨGGŨGCŨGŨGGAGGCŨGCCŨŨCAAGŨGCŨGŨGCŨGCŨGCCAŨCAŨŨ GŨGCŨGACCACAACŨGGCCGCŨCAGCCCAGCŨŨCŨGŨCŨCGGŨACCGACCŨCGGGCAGC AGŨCAŨŨGCŨGŨCACCCGCŨCŨGCCCAGGCŨGCCCGCCAGGŨCCACŨŨAŨGCCGAGGAG ŨCŨŨCCCCŨŨGCŨŨŨACCGŨGAACCŨCCAGAAGCCAŨCŨGGGCAGAŨGAŨGŨAGAŨCGC CGGGŨGCAAŨŨŨGGCAŨŨGAAAGŨGGAAAGCŨCCGŨGGCŨŨCCŨCCGŨGŨŨGGAGACCŨ GGŨGAŨŨGŨGGŨGACAGGCŨGGCGACCŨGGCŨCCGGCŨACACCAACAŨCAŨGCGGGŨGC ŨAAGCAŨAŨCCŨGA - In this example, the structures of mUNA molecules for use in expressing human phenylalanine hydroxylase are shown.
- Human phenylalanine hydroxylase is associated with phenylketonuria.
- The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the open reading frame of the native mRNA of human phenylalanine hydroxylase. The complete mUNA molecule comprises a 5′ cap (m7GpppGm), and a 5′-UTR upstream of the sequence below, and a 3′ UTR and polyA tail (SEQ ID NOs: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of the native mRNA of human phenylalanine hydroxylase.
-
Human phenylalanine hydroxylase is accession NM_000277.1. (SEQ ID NO: 156) A{tilde over (U)}{circumflex over (G)}{tilde over (U)}CCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAGGAAACUCUCUGACUUUGGACA GGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGGUGCCAUAUCACUGAUCUUCU CACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGCGCUUAUUUGAGGAGAAUGAU GUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAAAGAAAGAUGAGUAUGAAUU UUUCACCCAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAAACAUCAUCAAGAUCUUGA GGCAUGACAUUGGUGCCACUGUCCAUGAGCUUUCACGAGAUAAGAAGAAAGACACAGUG CCCUGGUUCCCAAGAACCAUUCAAGAGCUGGACAGAUUUGCCAAUCAGAUUCUCAGCUA UGGAGCGGAACUGGAUGCUGACCACCCUGGUUUUAAAGAUCCUGUGUACCGUGCAAGAC GGAAGCAGUUUGCUGACAUUGCCUACAACUACCGCCAUGGGCAGCCCAUCCCUCGAGUG GAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUCAAGACUCUGAAGUCCUU GUAUAAAACCCAUGCUUGCUAUGAGUACAAUCACAUUUUUCCACUUCUUGAAAAGUACU GUGGCUUCCAUGAAGAUAACAUUCCCCAGCUGGAAGACGUUUCUCAAUUCCUGCAGACU UGCACUGGUUUCCGCCUCCGACCUGUGGCUGGCCUGCUUUCCUCUCGGGAUUUCUUGGG UGGCCUGGCCUUCCGAGUCUUCCACUGCACACAGUACAUCAGACAUGGAUCCAAGCCCA UGUAUACCCCCGAACCUGACAUCUGCCAUGAGCUGUUGGGACAUGUGCCCUUGUUUUCA GAUCGCAGCUUUGCCCAGUUUUCCCAGGAAAUUGGCCUUGCCUCUCUGGGUGCACCUGA UGAAUACAUUGAAAAGCUCGCCACAAUUUACUGGUUUACUGUGGAGUUUGGGCUCUGCA AACAAGGAGACUCCAUAAAGGCAUAUGGUGCUGGGCUCCUGUCAUCCUUUGGUGAAUUA CAGUACUGCUUAUCAGAGAAGCCAAAGCUUCUCCCCCUGGAGCUGGAGAAGACAGCCAU CCAAAAUUACACUGUCACGGAGUUCCAGCCCCUGUAUUACGUGGCAGAGAGUUUUAAUG AUGCCAAGGAGAAAGUAAGGAACUUUGCUGCCACAAUACCUCGGCCCUUCUCAGUUCGC UACGACCCAUACACCCAAAGGAUUGAGGUCUUGGACAAUACCCAGCAGCUUAAGAUUUU GGCUGAUUCCAUUAACAGUGAAAUUGGAAUCCUUUGCAGUGCCCUCCAGAAAAUAAA{circumflex over (G)}{tilde over (U)} {tilde over (A)}A (SEQ ID NO: 157) AU{circumflex over (G)}UCCACUGCGGUCCUGGA{tilde over (A)}AACCCAGGCUUGGGCAG{circumflex over (G)}AAACUCUCUGACUUUGG{tilde over (A)}CA GGAAACAAGCUAUAUUGAAGACAACUGCAAUCA{tilde over (A)}AAUGGUGCCAUAUCACU{circumflex over (G)}AUCUUCU CACUCAAAGA{tilde over (A)}GAAGUUGGUGCAUUGGC{circumflex over (C)}AAAGUAUUGCGCUUAUU{tilde over (U)}GAGGAGAAUGAU GUAAA{circumflex over (C)}CUGACCCACAUUGAAUC{tilde over (U)}AGACCUUCUCGUUUAAA{circumflex over (G)}AAAGAUGAGUAUGAAUU {tilde over (U)}UUCACCCAUUUGGAUAA{tilde over (A)}CGUAGCCUGCCU{circumflex over (G)}CUCUGACAAACAUCAUCAAGAU{circumflex over (C)}UUGA GGCAUGACAUUGG{tilde over (U)}GCCACUGUCCAUGAGCU{tilde over (U)}UCACGAGAUAAGAAGAA{tilde over (A)}GACACAGUG CCCUGGUU{circumflex over (C)}CCAAGAACCAUUCAAGA{circumflex over (G)}CUGGACAGAUUUGCCAA{tilde over (U)}CAGAUUCUCAGCUA UGG{tilde over (A)}GCGGAACUGGAUGCUGA{circumflex over (C)}CACCCUGGUUUUAAAGA{tilde over (U)}CCUGUGUACCGUGCAAG{tilde over (A)}C GGAAGCAGUUUGCUGA{circumflex over (C)}AUUGCCUACAACUACCG{circumflex over (C)}CAUGGGCAGCCCAUCCC{tilde over (U)}CGAGUG GAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUCAAGAC{tilde over (U)}CUGAAGUCCUU GUAUAA{tilde over (A)}ACCCAUGCUUGCUAUGA{circumflex over (G)}UACAAUCACAUUUUUCC{tilde over (A)}CUUCUUGAAAAGUACU G{tilde over (U)}GGCUUCCAUGAAGAUAA{circumflex over (C)}AUUCCCCAGCUGGAAGA{circumflex over (C)}GUUUCUCAAUUCCUGCA{circumflex over (G)}ACU UGCACUGGUUUCCG{circumflex over (C)}CUCCGACCUGUGGCUGG{circumflex over (C)}CUGCUUUCCUCUCGGGA{tilde over (U)}UUCUUGGG UGGCCUGGC{circumflex over (C)}UUCCGAGUCUUCCACUG{circumflex over (C)}ACACAGUACAUCAGACA{tilde over (U)}GGAUCCAAGCCCA UGUA{tilde over (U)}ACCCCCGAACCUGACAU{circumflex over (C)}UGCCAUGAGCUGUUGGG{tilde over (A)}CAUGUGCCCUUGUUUUC{tilde over (A)} GAUCGCAGCUUUGCCCA{circumflex over (G)}UUUUCCCAGGAAAUUGG{circumflex over (C)}CUUGCCUCUCUGGGUGC{tilde over (A)}CCUGA UGAAUACAUUGA{tilde over (A)}AAGCUCGCCACAAUUUA{circumflex over (C)}UGGUUUACUGUGGAGUU{tilde over (U)}GGGCUCUGCA AACAAGG{tilde over (A)}GACUCCAUAAAGGCAUA{tilde over (U)}GGUGCUGGGCUCCUGUC{tilde over (A)}UCCUUUGGUGAAUUA CA{circumflex over (G)}UACUGCUUAUCAGAGAA{circumflex over (G)}CCAAAGCUUCUCCCCCU{circumflex over (G)}GAGCUGGAGAAGACAGC{circumflex over (C)}AU CCAAAAUUACACUGU{circumflex over (C)}ACGGAGUUCCAGCCCCU{circumflex over (G)}UAUUACGUGGCAGAGAG{tilde over (U)}UUUAAUG AUGCCAAGGA{circumflex over (G)}GAAAGUAAGGAACUUUG{circumflex over (C)}UGCCACAAUACCUCGGC{circumflex over (C)}CUUCUCAGUUCG CUACG{tilde over (A)}CCCAUACACCCAAAGGA{tilde over (U)}UGAGGUCUUGGACAAUA{circumflex over (C)}CCAGCAGCUUAAGAUUU {tilde over (U)}GGCUGAUUCCAUUAACA{circumflex over (G)}UGAAAUUGGAAUCCUUU{circumflex over (G)}CAGUGCCCUCCAGAAAA{tilde over (U)}AAAG UAA (SEQ ID NO: 158) AŨGŨCCACŨGCGGŨCCŨGGAAAACCCAGGCŨŨGGGCAGGAAACŨCŨCŨGACŨŨŨGGACA GGAAACAAGCŨAŨAŨŨGAAGACAACŨGCAAŨCAAAAŨGGŨGCCAŨAŨCACŨGAŨCŨŨCŨ CACŨCAAAGAAGAAGŨŨGGŨGCAŨŨGGCCAAAGŨAŨŨGCGCŨŨAŨŨŨGAGGAGAAŨGAŨ GŨAAACCŨGACCCACAŨŨGAAŨCŨAGACCŨŨCŨCGŨŨŨAAAGAAAGAŨGAGŨAŨGAAŨŨ ŨŨŨCACCCAŨŨŨGGAŨAAACGŨAGCCŨGCCŨGCŨCŨGACAAACAŨCAŨCAAGAŨCŨŨGA GGCAŨGACAŨŨGGŨGCCACŨGŨCCAŨGAGCŨŨŨCACGAGAŨAAGAAGAAAGACACAGŨG CCCŨGGŨŨCCCAAGAACCAŨŨCAAGAGCŨGGACAGAŨŨŨGCCAAŨCAGAŨŨCŨCAGCŨA ŨGGAGCGGAACŨGGAŨGCŨGACCACCCŨGGŨŨŨŨAAAGAŨCCŨGŨGŨACCGŨGCAAGAC GGAAGCAGŨŨŨGCŨGACAŨŨGCCŨACAACŨACCGCCAŨGGGCAGCCCAŨCCCŨCGAGŨG GAAŨACAŨGGAGGAAGAAAAGAAAACAŨGGGGCACAGŨGŨŨCAAGACŨCŨGAAGŨCCŨŨ GŨAŨAAAACCCAŨGCŨŨGCŨAŨGAGŨACAAŨCACAŨŨŨŨŨCCACŨŨCŨŨGAAAAGŨACŨ GŨGGCŨŨCCAŨGAAGAŨAACAŨŨCCCCAGCŨGGAAGACGŨŨŨCŨCAAŨŨCCŨGCAGACŨ ŨGCACŨGGŨŨŨCCGCCŨCCGACCŨGŨGGCŨGGCCŨGCŨŨŨCCŨCŨCGGGAŨŨŨCŨŨGGG ŨGGCCŨGGCCŨŨCCGAGŨCŨŨCCACŨGCACACAGŨACAŨCAGACAŨGGAŨCCAAGCCCA ŨGŨAŨACCCCCGAACCŨGACAŨCŨGCCAŨGAGCŨGŨŨGGGACAŨGŨGCCCŨŨGŨŨŨŨCA GAŨCGCAGCŨŨŨGCCCAGŨŨŨŨCCCAGGAAAŨŨGGCCŨŨGCCŨCŨCŨGGGŨGCACCŨGA ŨGAAŨACAŨŨGAAAAGCŨCGCCACAAŨŨŨACŨGGŨŨŨACŨGŨGGAGŨŨŨGGGCŨCŨGCA AACAAGGAGACŨCCAŨAAAGGCAŨAŨGGŨGCŨGGGCŨCCŨGŨCAŨCCŨŨŨGGŨGAAŨŨA CAGŨACŨGCŨŨAŨCAGAGAAGCCAAAGCŨŨCŨCCCCCŨGGAGCŨGGAGAAGACAGCCAŨ CCAAAAŨŨACACŨGŨCACGGAGŨŨCCAGCCCCŨGŨAŨŨACGŨGGCAGAGAGŨŨŨŨAAŨG AŨGCCAAGGAGAAAGŨAAGGAACŨŨŨGCŨGCCACAAŨACCŨCGGCCCŨŨCŨCAGŨŨCGC ŨACGACCCAŨACACCCAAAGGAŨŨGAGGŨCŨŨGGACAAŨACCCAGCAGCŨŨAAGAŨŨŨŨ GGCŨGAŨŨCCAŨŨAACAGŨGAAAŨŨGGAAŨCCŨŨŨGCAGŨGCCCŨCCAGAAAAŨAAAGŨ AA - In this example, the structures of mUNA molecules for enhancing translational efficiency are shown.
- The 5′-UTR of tobacco etch virus (TEV) is as follows:
-
(SEQ ID NO: 159) UCAACACAACAUAUACAAAAACAAACGAAUCUCAAGCAAUCAAGCAUU CUACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAA UUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCC - The base sequences shown below are the portion of the mUNA molecule that may correspond in functionality to the 5′-UTR of tobacco etch virus (TEV). The complete mUNA molecule comprises a 5′ cap upstream of the sequence below (m7GpppGm), and a coding region (CDS) of a protein of interest, a 3′-UTR, and a polyA tail (SEQ ID Nos: 4 to 12) downstream of the sequence below, each of which corresponds to the structure of any native human mRNA. Thus, a UNA oligomer incorprating the oligomer fragment below can have enhanced translational efficiency.
- The translation enhancer is placed upstream of the AUG translation start site, and the enhancer region is not translated into the therapeutic protein.
-
(SEQ ID NO: 160) U{circumflex over (C)}AAC{tilde over (A)}CAA{circumflex over (C)}AUA{tilde over (U)}ACAA{tilde over (A)}AACAAAC{circumflex over (G)}AAU{circumflex over (C)}UCA{tilde over (A)}GCA{tilde over (A)}UCA{tilde over (A)}GCA{tilde over (U)}UC U{tilde over (A)}CUU{circumflex over (C)}UAU{tilde over (U)}GCA{circumflex over (G)}CAA{tilde over (U)}UUA{tilde over (A)}AU{circumflex over (C)}AUUU{circumflex over (C)}UUUUAAA{circumflex over (G)}CAA{tilde over (A)}AGC{tilde over (A)}AUU {tilde over (U)}UCU{circumflex over (G)}AAA{tilde over (A)}UUU{tilde over (U)}CAC{circumflex over (C)}AUU{tilde over (U)}ACG{tilde over (A)}ACG{tilde over (A)}UAGCC (SEQ ID NO: 161) U{circumflex over (C)}AACACAACAUAUACAAAACAAACGAAUCU{circumflex over (C)}AAGCAAUCAAGCAUUCU ACUUCUAUUGCA{circumflex over (G)}CAAUUUAAAUCAUUUCUUUUAAAGCAAAA{circumflex over (G)}CAAUUU UCUGAAAAUUUUCACCAUUUACGAACGAUAGC{circumflex over (C)}C (SEQ ID NO: 162) U{circumflex over (C)}{tilde over (A)}{tilde over (A)}CACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCU ACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUU UCUGAAAAUUUUCACCAUUUACGAACGAU{tilde over (A)}{circumflex over (G)}{circumflex over (C)}CC (SEQ ID NO: 163) {tilde over (U)}CAACACAACA{tilde over (U)}A{tilde over (U)}ACAAAACAAACGAA{tilde over (U)}C{tilde over (U)}CAAGCAA{tilde over (U)}CAAGCA{tilde over (U)}{tilde over (U)}C{tilde over (U)} AC{tilde over (U)}{tilde over (U)}C{tilde over (U)}A{tilde over (U)}{tilde over (U)}GCAGCAA{tilde over (U)}{tilde over (U)}{tilde over (U)}AAA{tilde over (U)}CA{tilde over (U)}{tilde over (U)}{tilde over (U)}C{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}AAAGCAAAAGCAA{tilde over (U)}{tilde over (U)}{tilde over (U)} {tilde over (U)}C{tilde over (U)}GAAAA{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}CACCA{tilde over (U)}{tilde over (U)}{tilde over (U)}ACGAACGA{tilde over (U)}AGCCC (SEQ ID NO: 164) {tilde over (U)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{circumflex over (G)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (U)} {tilde over (A)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)} {tilde over (U)}{circumflex over (C)}{tilde over (U)}{circumflex over (G)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{circumflex over (C)}{tilde over (A)}{circumflex over (C)}{circumflex over (C)}{tilde over (A)}{tilde over (U)}{tilde over (U)}{tilde over (U)}{tilde over (A)}{circumflex over (C)}{circumflex over (G)}{tilde over (A)}{tilde over (A)}{circumflex over (C)}{circumflex over (G)}{tilde over (A)}{tilde over (U)}{tilde over (A)}{circumflex over (G)}{circumflex over (C)}{circumflex over (C)}{circumflex over (C)} - An nGFP transcript having a polyA tail of 30 monomers in length is ligated to a donor polyà tail of 30 UNA Monomers in length to give an UNA-nGFP mRNA product having a polyA 30Ã30 tail of 60 monomers in length. The UNA-nGFP has an increased lifetime and markedly increased translational activity in fibroblasts.
- An mRNA encoding HIV-1 gag antigen having a polyA tail of 30 monomers in length is ligated to a donor polyà tail of 20 UNA Monomers in length to give an UNA-HIV-1 gag antigen mRNA product having a polyA30Ã20 tail of 50 monomers in length. The UNA-HIV-1 gag antigen mRNA has an increased lifetime and markedly increased translational activity in fibroblasts.
- An mRNA encoding antigens overexpressed in lung cancers having a polyA tail of 30 monomers in length is ligated to a donor polyà tail of 10 UNA Monomers in length to give an UNA-mRNA product having a polyA30Ã10 tail of 40 monomers in length. The UNA-mRNA has an increased lifetime and markedly increased translational activity in fibroblasts.
- An mRNA encoding malarial P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) having a polyA tail of 30 monomers in length is ligated to a donor polyà tail of 10 UNA Monomers in length to give an UNA-mRNA product having a polyA30Ã10 tail of 40 monomers in length. The UNA-mRNA has an increased lifetime and markedly increased translational activity in fibroblasts. The UNA-mRNA is found to induce an antibody response in an animal model.
- An mRNA encoding malarial Plasmodium falciparum PfSEA-1, a 244 KD malaria antigen expressed in schizont-infected RBCs, having a polyA tail of 30 monomers in length is ligated to a donor polyà tail of 10 UNA Monomers in length to give an UNA-mRNA product having a polyA30Ã10 tail of 40 monomers in length. The UNA-mRNA has an increased lifetime and markedly increased translational activity in fibroblasts. The UNA-mRNA is found to induce an antibody response in an animal model.
-
FIG. 7 shows the primary structure of a functional mRNA transcript in the cytoplasm. The mRNA includes a 5′ methylguanosine cap, a protein coding sequence flanked by untranslated regions (UTRs), and a polyadenosine (polyA) tail bound by polyA binding proteins (PABPs). -
FIG. 8 shows the 5′ cap and PABPs cooperatively interacting with proteins involved in translation to facilitate the recruitment and recycling of ribosome complexes. - DNA splint oligomers were made for splint-mediated ligation of of a donor oligomer to an acceptor RNA. As shown in the scheme of
FIG. 8 , a short mRNA acceptor oligomer and a 5′-monophosphate-bearing polyA donor oligomer can be ligated in the presence of a DNA splint oligomer. -
FIG. 9 shows the splint-mediated ligation scheme, in which an acceptor RNA with a 30-monomer stub polyA tail (A(30)) was ligated to a 30-monomer donor oligomer (A(30)). The splint-mediated ligation used a DNA oligomer splint which was complementary to the 3′ UTR sequence upstream of the stub polyA tail, and included a 60-monomer oligo(dT) 5′ heel (T(60)) to splint the ligation. The anchoring region of the splint was complementary to the UTR sequence to ensure that a 5′ dT30 overhang was presented upon hybridization to the acceptor. This brings the donor oligomer into juxtaposition with the 3′ terminus of the stub tail, dramatically improving the kinetics of ligation. -
FIG. 10 shows the results of ligation using 2 ug of a 120-monomer acceptor with an A30 stub tail that was ligated to a 5′-phosphorylated A30 RNA donor oligomer usingT4 RNA Ligase 2. The reaction was incubated overnight at 37° C. The ligation and a mock reaction done without enzyme were purified, treated with DNAse I for 1 hour to degrade and detach the splint oligomers, and re-purified in a volume of 30 uL. The ligation efficiency was nearly 100%. The absence of a size shift in the mock-reaction prep shows that the acceptor and donor were truly ligated and not simply held together by undigested splint oligomers. - Following the same protocol with a short incubation period, high efficiency ligation of the short acceptor mRNA proceeded to nearly 100% completion.
FIG. 11 shows the results of splint-mediated ligation using an acceptor RNA with a 30-monomer stub polyA tail (A(30)). The ligation reactions were performed with three different donor oligomer species: A(30), A(60), and A(120). Based on the gel shifts, the ligations attained nearly 100% efficiency. - A protocol used for a 100 ul splint-mediated ligation reaction included the following materials, reagents, and steps.
- 100 pmol UNA-PolyA UNA Oligomer donor.
- 100 pmol TAIL-60 splint oligomer.
- 50 pmol purified RNA acceptor.
- 10 uL
T4 RNA Ligase 2 10× Buffer. - 2 uL
T4 RNA Ligase 2. - Nuclease-free Water to 100 uL.
- Mix and incubate for 1-2 hours at 37 degrees, then purify the RNA in a total of ˜90 uL RNAse-free water.
- Add 10
uL 10× DNase buffer to eluent and 2 ul DNase I, mix and incubate for 1 hour at 37 degrees to digest splint DNA. - Repurify the RNA using RNeasy spin columns, eluting in water or TE pH 7.0.
- Reagents.
- NEB M0239
T4 RNA Ligase 2. - NEB M0303 DNase I (RNase-free).
- Qiagen 74104RNeasy Mini Kit.
- TAIL-60 splint oligomer sequence:
-
(SEQ ID NO: 165) CTTCCTACTCAGGCTTTATTCAAAGACCA. - Notes:
- (a) The splint oligomer sequence includes an anchor that is specific to the 3′ UTR used for making mRNA.
- (b) This protocol requires an mRNA transcript with a pre-incorporated 30-nt polyA tail.
- A full-length synthetic mRNA acceptor and a 5′-monophosphate-bearing polyA donor were ligated in the presence of a DNA splint oligomer. On ligating a 30-monomer length tail to a ˜1 Kb nGFP transcript, a size shift was apparent on a 2% agarose gel, providing a direct indication that bulk ligation was achieved.
FIG. 12 shows the results of one-hour splint-mediated ligations that were performed on nGFP-A30 transcripts. The resulting ligation products were compared to untreated transcripts and native nGFP-A60 IVT products. The native nGFP-A60 and the ligated products were up-shifted on the gel relative to the untreated nGFP-A30 transcripts and mock-ligated material. - A UNA-PolyA UNA Oligomer donor was made having the following structure:
-
(SEQ ID NO: 166) 5′-(rAp)-AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA ÃÃÃÃÃ-(3′-C3 Spacer), wherein 5′-(rAp) is 5′-Phosphorylation and à is UNA-A. - An nGFP transcript with a polyA tail of 30-monomers in length (untreated A30 mRNA) was ligated to a donor polyA tail of 30-monomers in length to give an mRNA product having a polyA tail of 60-monomers in length (A60-bearing ligation product) by splint-mediated ligation.
-
FIG. 13 shows increased lifetime and translational activity for the nGFP-A60 ligation product. As shown inFIG. 13 , nuclearized transcripts were transfected into fibroblasts for comparison of nGFP-A30, mock-ligated nGFP-A30, and an nGFP-A60 ligation product (FIG. 13 , left to right). The significantly higher fluorescence signal observed for the nGFP-A60 ligation product shows that it has markedly increased translational activity. - A wild-type T4 RNA ligase was used to ligate a
donor 5′ phosphorylated oligomer to a short IVT transcript. Short synthetic RNAs were generated by IVT, and the outcome of ligation reactions was evaluated on high-resolution 4% agarose gels. The increase in transcript size from ligation of asynthetic oligomer 30 monomers in length to a full-sized mRNA of 1-2 Kb is too small to clearly visualize on a gel. Thus, short synthetic RNAs of 100-180 monomers were generated by IVT. The 3′ terminal sequence of these short synthetic RNAs was identical to that in the 3′ UTRs of synthetic mRNAs. - A synthetic oligomer having an
adenylated 5′ end was prepared. Theadenylated 5′ end, normally formed as a catalytic intermediate by the ligase, pre-activated the synthetic oligomer for ligation. Use of the pre-adenylated synthetic oligomer obviated the need for ATP in the reactions, and allowed the use of a mutant ligase that was active exclusively on adenylated substrates. Pre-adenylation of the synthetic oligomer increased ligation efficiency and minimized side-product formation. - A KQ mutant variant of
T4 RNA Ligase 2 was used to ligate a pre-adenylated donor oligomer to a short IVT transcript. -
FIG. 14 shows the results of a ligation performed with a 100-monomer acceptor RNA that was treated for 3 hours at room temperature with T4 RNA Ligase 2 (truncated KQ mutant) using a 10 uM concentration of a polyA tail 30-monomer donor oligomer. 15% PEG 8000 was included in the reaction as a volume excluder to promote efficient ligation. The ligation reaction showed that a high molecular weight product was formed, having a size in between the 100-monomer acceptor RNA and a 180-monomer RNA transcript included as a size standard. These results show that the ligation reaction produced a predominant product having high molecular weight with nearly 100% ligation of the donor to the acceptor. Additional experiments performed with concentrations of the polyA tail at 10 uM, 20 uM , and 40 uM showed that at least half of the acceptor RNA was ligated in all cases. - All publications, patents and literature specifically mentioned herein are incorporated by reference for all purposes.
- It is understood that this invention is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which will be encompassed by the appended claims.
- It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprises,” “comprising”, “containing,” “including”, and “having” can be used interchangeably.
- Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
- All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose.
Claims (40)
1. A mUNA molecule, comprising one or more UNA monomers, and comprising nucleic acid monomers, wherein the mUNA molecule is translatable to express a polypeptide or protein.
2. The molecule of claim 1 , wherein the molecule comprises from 200 to 12,000 monomers.
3. The molecule of claim 1 , wherein the molecule comprises from 200 to 4,000 monomers.
4. The molecule of claim 1 , wherein the molecule comprises from 1 to 8,000 UNA monomers.
5. The molecule of claim 1 , wherein the molecule comprises from 1 to 100 UNA monomers.
6. The molecule of claim 1 , wherein the molecule comprises from 1 to 20 UNA monomers.
7. The molecule of claim 1 , wherein the molecule comprises one or more modified nucleic acid nucleotides, or one or more chemically-modified nucleic acid nucleotides.
8. The molecule of claim 1 , wherein the molecule comprises a 5′ cap, a 5′ untranslated region of monomers, a coding region of monomers, a 3′ untranslated region of monomers, and a tail region of monomers.
9. The molecule of claim 8 , wherein the molecule comprises a translation enhancer in a 5′ or 3′ untranslated region.
10. The molecule of claim 1 , wherein the molecule is translatable in vivo.
11. The molecule of claim 1 , wherein the molecule is translatable in vitro.
12. The molecule of claim 1 , wherein the molecule is translatable in a mammalian cell.
13. The molecule of claim 1 , wherein the molecule is translatable in a human in vivo.
14. The molecule of claim 1 , wherein a translation product of the molecule is an active peptide or protein.
15. The molecule of claim 1 , wherein a translation product of the molecule is human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
16. The molecule of claim 1 , wherein the molecule exhibits at least 2-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
17. The molecule of claim 1 , wherein the molecule exhibits at least 3-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
18. The molecule of claim 1 , wherein the molecule exhibits at least 5-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
19. The molecule of claim 1 , wherein the molecule exhibits at least 10-fold increased translation efficiency in vivo as compared to a native mRNA that encodes the same translation product.
20. The molecule of claim 1 , wherein the molecule has a cytoplasmic half-life in a cell at least 2-fold greater than a native mRNA of the cell that encodes the same translation product.
21. The molecule of claim 1 , wherein the molecule is a therapeutic agent for a rare disease, a liver disease, or a cancer.
22. The molecule of claim 1 , wherein the molecule is an immunization agent or vaccine component for a rare disease, a liver disease, or a cancer.
23. The molecule of claim 1 , wherein the molecule comprises a sequence selected from SEQ ID NOs: 1-164.
24. A composition comprising a mUNA molecule of claim 1 and a pharmaceutically acceptable carrier.
25. A vaccine or immunization composition comprising a mUNA molecule of claim 1 .
26. The composition of claim 24 , wherein the carrier is a nanoparticle or liposome.
27. A method for ameliorating, preventing or treating a disease or condition in a subject comprising administering to the subject a composition of claim 24 .
28. The method of claim 27 , wherein the disease or condition is a rare disease, liver disease, or cancer.
29. The method of claim 27 , wherein the disease or condition is described in Table 1.
30. A method for producing a polypeptide or protein in vivo, the method comprising administering to a mammal a composition of claim 24 .
31. The method of claim 30 , wherein the polypeptide or protein is deficient in a disease or condition described in Table 1.
32. The method of claim 30 , wherein the protein is human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
33. A method for producing a polypeptide or protein in vitro, the method comprising transfecting a cell with a mUNA molecule of claim 1 .
34. The method of claim 33 , wherein the transfecting is done with a transfection reagent.
35. The method of claim 33 , wherein the polypeptide or protein is deficient in a disease or condition described in Table 1.
36. The method of claim 33 , wherein the protein is human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
37. A method for ameliorating, preventing or treating a rare disease or condition in a subject associated with a deficiency in a peptide or protein, the method comprising administering to the subject a mUNA molecule encoding the peptide or protein.
38. The method of claim 37 , wherein the disease or condition described in Table 1.
39. A method for producing a polypeptide or protein in vivo, the method comprising administering to a mammal a mUNA molecule encoding the polypeptide or protein.
40. The method of claim 39 , wherein the polypeptide or protein is human EPO, human Factor IX, human alpha-1-antitrypsin, human CFTR, human ASL, human PAH, human NIS, or human hepcidin.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/929,366 US20160130567A1 (en) | 2014-11-02 | 2015-11-01 | Messenger una molecules and uses thereof |
US15/806,096 US10815463B2 (en) | 2014-11-02 | 2017-11-07 | Messenger UNA molecules and uses thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462074046P | 2014-11-02 | 2014-11-02 | |
US14/929,366 US20160130567A1 (en) | 2014-11-02 | 2015-11-01 | Messenger una molecules and uses thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/806,096 Continuation US10815463B2 (en) | 2014-11-02 | 2017-11-07 | Messenger UNA molecules and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20160130567A1 true US20160130567A1 (en) | 2016-05-12 |
Family
ID=55858532
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/929,366 Abandoned US20160130567A1 (en) | 2014-11-02 | 2015-11-01 | Messenger una molecules and uses thereof |
US15/806,096 Active US10815463B2 (en) | 2014-11-02 | 2017-11-07 | Messenger UNA molecules and uses thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/806,096 Active US10815463B2 (en) | 2014-11-02 | 2017-11-07 | Messenger UNA molecules and uses thereof |
Country Status (6)
Country | Link |
---|---|
US (2) | US20160130567A1 (en) |
EP (1) | EP3212793B1 (en) |
JP (1) | JP6728156B2 (en) |
AU (1) | AU2015338923B2 (en) |
CA (1) | CA2966527C (en) |
WO (1) | WO2016070166A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018222890A1 (en) * | 2017-05-31 | 2018-12-06 | Arcturus Therapeutics, Inc. | Synthesis and structure of high potency rna therapeutics |
WO2018222926A1 (en) * | 2017-05-31 | 2018-12-06 | Ultragenyx Pharmaceutical Inc. | Therapeutics for glycogen storage disease type iii |
CN112023062A (en) * | 2020-09-18 | 2020-12-04 | 北京基因安科技有限公司 | Method for inhibiting allergic reactions using soluble IgE receptors |
US11104887B2 (en) * | 2017-01-03 | 2021-08-31 | Ethris Gmbh | Ornithine transcarbamylase coding polyribonucleotides and formulations thereof |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3469074B1 (en) | 2016-06-13 | 2020-12-09 | Translate Bio, Inc. | Messenger rna therapy for the treatment of ornithine transcarbamylase deficiency |
EP3554554B1 (en) | 2016-12-19 | 2022-09-07 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
LT3554552T (en) | 2016-12-19 | 2022-10-10 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
ES2927079T3 (en) | 2016-12-19 | 2022-11-02 | Sarepta Therapeutics Inc | Exon skipping oligomer conjugates for muscular dystrophy |
JP2020510426A (en) * | 2017-02-28 | 2020-04-09 | アークトゥラス・セラピューティクス・インコーポレイテッドArcturus Therapeutics,Inc. | Translatable molecules and their synthesis |
WO2018222925A1 (en) | 2017-05-31 | 2018-12-06 | Ultragenyx Pharmaceutical Inc. | Therapeutics for phenylketonuria |
EA201991450A1 (en) | 2017-09-22 | 2019-12-30 | Сарепта Терапьютикс, Инк. | OLIGOMER CONJUGATES FOR EXONISM SKIP IN MUSCULAR DYSTROPHY |
US20210145852A1 (en) | 2017-09-28 | 2021-05-20 | Sarepta Therapeutics, Inc. | Combination Therapies for Treating Muscular Dystrophy |
US20200254002A1 (en) | 2017-09-28 | 2020-08-13 | Sarepta Therapeutics, Inc. | Combination therapies for treating muscular dystrophy |
US20200248178A1 (en) | 2017-09-28 | 2020-08-06 | Sarepta Therapeutics, Inc. | Combination therapies for treating muscular dystrophy |
JP7423522B2 (en) * | 2017-11-22 | 2024-01-29 | モダーナティエックス・インコーポレイテッド | Polynucleotide encoding ornithine transcarbamylase for the treatment of urea cycle disorders |
WO2019104160A2 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria |
CA3084061A1 (en) | 2017-12-20 | 2019-06-27 | Translate Bio, Inc. | Improved composition and methods for treatment of ornithine transcarbamylase deficiency |
US10758629B2 (en) | 2018-05-29 | 2020-09-01 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
EP3806868A4 (en) | 2018-06-13 | 2022-06-22 | Sarepta Therapeutics, Inc. | Exon skipping oligomers for muscular dystrophy |
TW202020153A (en) | 2018-07-27 | 2020-06-01 | 美商薩羅塔治療公司 | Exon skipping oligomers for muscular dystrophy |
AU2019394996A1 (en) | 2018-12-06 | 2021-07-29 | Arcturus Therapeutics, Inc. | Compositions and methods for treating ornithine transcarbamylase deficiency |
SG11202104960PA (en) | 2018-12-13 | 2021-06-29 | Sarepta Therapeutics Inc | Exon skipping oligomer conjugates for muscular dystrophy |
EP3955966A1 (en) | 2019-04-18 | 2022-02-23 | Sarepta Therapeutics, Inc. | Compositions for treating muscular dystrophy |
US20230136960A1 (en) * | 2020-03-19 | 2023-05-04 | Nature's Toolbox, Inc. | Novel MRNA-Based COVID-19 Multi-Valent Vaccine and Methods of Scaled Production of the Same |
FI20215508A1 (en) | 2020-04-09 | 2021-10-10 | Niemelae Erik Johan | Mimetic nanoparticles for preventing the spreading and lowering the infection rate of novel coronaviruses |
CA3176844A1 (en) | 2020-05-01 | 2021-11-04 | Carlos G. PEREZ-GARCIA | Nucleic acids and methods of treatment for cystic fibrosis |
KR20240070615A (en) | 2021-09-30 | 2024-05-21 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | Antisense oligonucleotides with one or more non-basic units |
WO2023070086A1 (en) | 2021-10-22 | 2023-04-27 | Sarepta Therapeutics, Inc. | Morpholino oligomers for treatment of peripheral myelin protein 22 related diseases |
WO2024064237A2 (en) | 2022-09-21 | 2024-03-28 | Sarepta Therapeutics, Inc. | Dmd antisense oligonucleotide-mediated exon skipping efficiency |
WO2024104914A1 (en) | 2022-11-14 | 2024-05-23 | BioNTech SE | Rna capping efficiency assay |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0710288B1 (en) * | 1993-06-10 | 2006-04-05 | Genetic Therapy, Inc. | Adenoviral vectors for treatment of hemophilia |
WO2002024932A2 (en) * | 2000-09-18 | 2002-03-28 | Genzyme Corporation | Expression vectors containing hybrid ubiquitin promoters |
EP1739179A1 (en) * | 2005-06-30 | 2007-01-03 | Octapharma AG | Serum-free stable transfection and production of recombinant human proteins in human cell lines |
EP4332227A1 (en) | 2005-08-23 | 2024-03-06 | The Trustees of the University of Pennsylvania | Rna containing modified nucleosides and methods of use thereof |
US9012219B2 (en) | 2005-08-23 | 2015-04-21 | The Trustees Of The University Of Pennsylvania | RNA preparations comprising purified modified RNA for reprogramming cells |
US8454948B2 (en) * | 2006-09-14 | 2013-06-04 | Medgenics Medical Israel Ltd. | Long lasting drug formulations |
WO2008068879A1 (en) * | 2006-12-06 | 2008-06-12 | Jcr Pharmaceuticals Co., Ltd. | Method for production of human erythropoietin |
US7700734B2 (en) * | 2007-01-09 | 2010-04-20 | Shu-Wha Lin | Recombinant human factor IX and use thereof |
BRPI0811170B8 (en) * | 2007-05-22 | 2021-05-25 | Arcturus Therapeutics Inc | RNA oligonucleotides and hydroxymethyl substituted RNA complexes |
EP3165234B1 (en) | 2009-07-31 | 2019-04-03 | ethris GmbH | Rna with a combination of unmodified and modified nucleotides for protein expression |
ES2661680T3 (en) * | 2011-04-21 | 2018-04-03 | University Of Massachusetts | Compositions based on VAAr and methods for treating alpha-1 anti-trypsin deficiencies |
EP3492109B1 (en) | 2011-10-03 | 2020-03-04 | ModernaTX, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
WO2013101690A1 (en) * | 2011-12-29 | 2013-07-04 | modeRNA Therapeutics | Modified mrnas encoding cell-penetrating polypeptides |
EP2830595B1 (en) * | 2012-03-29 | 2019-10-16 | Translate Bio, Inc. | Ionizable cationic lipids |
US8999380B2 (en) * | 2012-04-02 | 2015-04-07 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
JP2015522277A (en) * | 2012-06-28 | 2015-08-06 | カルドラ ヘルス リミテッドCaldera Health Ltd | Prostate cancer diagnosis method and diagnostic substance |
US20160022774A1 (en) | 2013-03-12 | 2016-01-28 | Moderna Therapeutics, Inc. | Diagnosis and treatment of fibrosis |
US20160032316A1 (en) | 2013-03-14 | 2016-02-04 | The Trustees Of The University Of Pennsylvania | Purification and Purity Assessment of RNA Molecules Synthesized with Modified Nucleosides |
WO2015051169A2 (en) | 2013-10-02 | 2015-04-09 | Moderna Therapeutics, Inc. | Polynucleotide molecules and uses thereof |
EP3071547B1 (en) | 2013-11-18 | 2024-07-10 | Arcturus Therapeutics, Inc. | Ionizable cationic lipid for rna delivery |
FI3690056T3 (en) | 2014-01-31 | 2023-03-19 | Factor Bioscience Inc | Methods and products for nucleic acid production and delivery |
WO2015196128A2 (en) | 2014-06-19 | 2015-12-23 | Moderna Therapeutics, Inc. | Alternative nucleic acid molecules and uses thereof |
EP3256585A4 (en) | 2015-02-13 | 2018-08-15 | Factor Bioscience Inc. | Nucleic acid products and methods of administration thereof |
-
2015
- 2015-11-01 JP JP2017523216A patent/JP6728156B2/en active Active
- 2015-11-01 US US14/929,366 patent/US20160130567A1/en not_active Abandoned
- 2015-11-01 AU AU2015338923A patent/AU2015338923B2/en active Active
- 2015-11-01 CA CA2966527A patent/CA2966527C/en active Active
- 2015-11-01 EP EP15855964.1A patent/EP3212793B1/en active Active
- 2015-11-01 WO PCT/US2015/058534 patent/WO2016070166A2/en active Application Filing
-
2017
- 2017-11-07 US US15/806,096 patent/US10815463B2/en active Active
Non-Patent Citations (4)
Title |
---|
Campbell et al. (Chem. Soc. Rev, 2011, 40, 5680-5689) * |
Collins (Mammalian Gene Collection Program Team, Proc. Natl. Acad. Sci. U.S.A. 99 (26), 16899-16903 (2002)) * |
Lucchiari et al. (Human Mutation, #564, 2002) * |
Seth et al. (Molecular Therapy, vol. 19, no. 5, 2011, 928-935) * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11104887B2 (en) * | 2017-01-03 | 2021-08-31 | Ethris Gmbh | Ornithine transcarbamylase coding polyribonucleotides and formulations thereof |
WO2018222890A1 (en) * | 2017-05-31 | 2018-12-06 | Arcturus Therapeutics, Inc. | Synthesis and structure of high potency rna therapeutics |
WO2018222926A1 (en) * | 2017-05-31 | 2018-12-06 | Ultragenyx Pharmaceutical Inc. | Therapeutics for glycogen storage disease type iii |
US20190002906A1 (en) * | 2017-05-31 | 2019-01-03 | Arcturus Therapeutics, Inc. | Synthesis and structure of high potency rna therapeutics |
CN110719954A (en) * | 2017-05-31 | 2020-01-21 | 奥特吉尼克斯制药公司 | Therapeutic agent for glycogen storage disease type III |
KR20200014319A (en) * | 2017-05-31 | 2020-02-10 | 울트라제닉스 파마수티컬 인코포레이티드 | Therapeutics for Glycogen Accumulation Disease Type III |
US11015204B2 (en) * | 2017-05-31 | 2021-05-25 | Arcturus Therapeutics, Inc. | Synthesis and structure of high potency RNA therapeutics |
US11377643B2 (en) | 2017-05-31 | 2022-07-05 | Ultragenyx Pharmaceutical Inc. | Therapeutics for glycogen storage disease type III |
TWI794237B (en) * | 2017-05-31 | 2023-03-01 | 美商奧特吉尼克斯製藥公司 | Therapeutics for glycogen storage disease type iii |
KR102636537B1 (en) * | 2017-05-31 | 2024-02-15 | 울트라제닉스 파마수티컬 인코포레이티드 | Treatment for Glycogen Storage Disease Type III |
CN112023062A (en) * | 2020-09-18 | 2020-12-04 | 北京基因安科技有限公司 | Method for inhibiting allergic reactions using soluble IgE receptors |
Also Published As
Publication number | Publication date |
---|---|
US20180051262A1 (en) | 2018-02-22 |
CA2966527A1 (en) | 2016-05-06 |
WO2016070166A2 (en) | 2016-05-06 |
AU2015338923A1 (en) | 2017-06-22 |
CA2966527C (en) | 2024-02-06 |
WO2016070166A3 (en) | 2016-08-18 |
US10815463B2 (en) | 2020-10-27 |
JP6728156B2 (en) | 2020-07-22 |
EP3212793A2 (en) | 2017-09-06 |
JP2017537613A (en) | 2017-12-21 |
EP3212793A4 (en) | 2018-05-16 |
EP3212793B1 (en) | 2020-01-08 |
AU2015338923B2 (en) | 2021-10-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10815463B2 (en) | Messenger UNA molecules and uses thereof | |
US20210317468A1 (en) | Synthesis and structure of high potency rna therapeutics | |
US11939363B2 (en) | Translatable molecules and synthesis thereof | |
AU2021206908B2 (en) | Multimeric coding nucleic acid and uses thereof | |
US20220243226A1 (en) | Engineered muscle targeting compositions | |
ES2542015T3 (en) | Systems engineering, methods and guide compositions optimized for sequence manipulation | |
US20220325296A1 (en) | Engineered adeno-associated virus capsids | |
US20230265461A1 (en) | Compositions and methods for targeting, editing, or modifying genes | |
US20180353622A1 (en) | Gene deletion and rescue by crispr-mediated elimination of exon splicing enhancers | |
US20240100136A1 (en) | Chimeric adaptor proteins and methods of regulating gene expression | |
US20220220468A1 (en) | Compositions and methods for homology directed repair | |
WO2024166035A1 (en) | Regulating gene expression in gamma delta t cell receptors expressing cells | |
US20220257677A1 (en) | Engineered adeno-associated virus capsids | |
US20180179502A1 (en) | Nucleic Acid Analogue-Guided Chemical Nuclease System, Methods and Compositions | |
CA3236534A1 (en) | Engineered cardiac muscle compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ARCTURUS THERAPEUTICS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CHIVUKULA, PADMANABH;WARREN, LUIGI;TACHIKAWA, KIYOSHI;AND OTHERS;SIGNING DATES FROM 20170901 TO 20170905;REEL/FRAME:044282/0148 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |