US2010172966A1PendingUtilityA1
Methods and compositions for cellular reprogramming
Est. expiryAug 23, 2011(expired)· nominal 20-yr term from priority
Inventors:Larry J. Smith
A61P 31/22A61P 31/16A61P 31/18A61P 9/10A61P 37/00A61P 25/28C12Q 1/6886C12N 15/113C12N 15/1135A61P 19/02C12Q 2600/106C12N 2310/11
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Claims
Abstract
Compositions and methods useful for the treatment of aberrant programming diseases, particularly those associated with aberrant apoptosis are disclosed
Claims
exact text as granted — not AI-modified1 - 28 . (canceled)
29 . A composition comprising at least one isolated nucleic acid which hybridizes to a target nucleic acid, wherein said at least one isolated nucleic acid is selected from the group consisting of an oligoribonucleotide, a double-stranded oligoribonucleotide, and a chimeric RNA/DNA oligonucleotide, wherein said target nucleic acid is selected from the group consisting of,
FAS/APO-1, SGP2, TRPM-2,5-alpha reductase, AP-4, Apolipoprotein epsilon 4, Beta Amyloid Precursor Protein, Bax-alpha, BCL-X, BCL-XL, BCL-2-alpha, BCL-2-beta, BSAP, CDK-1, CDK-2, CDK-3, CDK-4, CDK-4 inhibitor, COX-2, CREBP-alpha, CREM, CTF, Cyclin A, Cyclin B, Cyclin D2, Cyclin D3, Cyclin D1, DAD-1, DB-1, Dopamine D 2 Receptor, Delta-max, DP-1, E2F-1, E2F-2, E2F-like protein, E4BP4, E4TF1, EGFR, ELK-1, EN-2, ERG-1, ERG-2, ERK, ERK-3, ERM, EVX-1, EVX-2, EVX-associated, FLT-1, FLT-4, Fra-1, Fra-2, GADD-153, GADD-45, GATA-2, GATA-4, HGPx1, HLX-1, HLX-1 poly-A tail, Hox 1.8, Hox 1.3, Hox 2G, Hox 21, Hox 3D, Hox 4A, Hox 4B, Hox 4C, Hox 4D, Hox 7, Hox 8, Hox A1, Hox A10, Hox B2, Hox B6, Hox C6, cp19, p40, HTF4a, 1-rel, ICE, ICH-1L, ICH-1S, 1D-1, ID-2, ID-3, IRF-1, IRF-2, KDR/FLK-1, MAD-1, MAD-3, MADS/MEF-2, MCL-1, MSX-2, MTF-1, MTS-1, MTS-2, Mxi-1, NET, NF-ATC, NF-IL6-beta, Oct-T1, Oct-T2, Oct-6, OTF-3, OTF-3C, OZF, p107, p34cdc2, PDEGF, PDGFR, PES, Pim-1, PKC-α, PKC-β, PKC-δ, PKC-ε, PKC-τ, PKC-i, PKC-μ, PKC-Θ, PKC-z, Rb-2, RBAP-1, RBP-1, Ref-1, SAP-1, SP3, SP4, Spi-1, Spi-B, TGF-beta, TNF-alpha, TNF-beta, TR3, TR4, USF, VEGF, WAF-1, WT-1, and YY-1, said at least one isolated nucleic acid optionally comprising a modification and a carrier.
30 . The composition of claim 29 , wherein said nucleic acid is a double stranded oligonucleotide comprising a strand which specifically hybridizes to a sequence selected from the group consisting of
FAS/APO-1 (SEQ ID NOS: 1139-1145); SGP2 (SEQ ID NOS: 3175-3197; TRPM-2 (SEQ ID NOS: 3419-3483); 5-alpha reductase (SEQ ID NOS: 7-45); AP-4 (SEQ ID NOS: 85-1078); Apolipoprotien epsilon 4 (SEQ ID NOS:108-175); Beta Amyloid Precursor Protein (SEQ ID NOS: 216-238); Bax-alpha (SEQ ID NOS: 239-253); BCL-X (SEQ ID NOS: 254-263); BCL-XL (SEQ ID NOS: 264-278); BCL-2-alpha (SEQ ID NOS: 279-312); BCL-2-beta (SEQ ID NOS: 313-317); BSAP (SEQ ID NOS: 318-335); CDK-1 (SEQ ID NOS: 408-414); CDK-2 (SEQ ID NOS: 415-420); CDK-3 (SEQ ID NOS: 421-433); CDK-4 (SEQ ID NOS: 434-437); CDK-4 inhibitor (SEQ ID NOS: 438-460); COX-2, (SEQ ID NOS: 496-514); CREBP-alpha (SEQ ID NOS: 538-549); CREM (SEQ ID NOS: 578-588); CTF (SEQ ID NOS: 589-621); Cyclin A (SEQ ID NOS: 622-643); Cyclin B (SEQ ID NOS: 644-652); Cyclin D2 (SEQ ID NOS: 653-673); Cyclin D3 (SEQ ID NOS: 674-687); Cyclin D1 (SEQ ID NOS: 688-699); DAD-1 (SEQ ID NOS: 700-738); DB-1 (SEQ ID NOS: 739-748); Dopamine D 2 Receptor (SEQ ID NOS: 749-795); Delta-max (SEQ ID NOS: 796-801); DP-1 (SEQ ID NOS: 802-808); E2F-1 (SEQ ID NOS: 846-860); E2F-2 (SEQ ID NOS: 861-874); E2F-like protein (SEQ ID NOS: (875-888); E4BP4 (SEQ ID NOS: 895-903); E4TF1 (SEQ ID NOS: 904-940); EGFR (SEQ ID NOS: 941-950); ELK-1 (SEQ ID NOS: 951-961); EN-2 (SEQ ID NOS: 962-969); ERG-1 (SEQ ID NOS: 993-1006); ERG-2 (SEQ ID NOS: 1007-1020); ERK (SEQ ID NOS:1021-1060); ERK-3 (SEQ ID NOS: 1061-1070); ERM (SEQ ID NOS: 1071-1080); EVX-1 (SEQ ID NOS: 1106-1120); EVX-2 (SEQ ID NOS:1121-1130); EVX-associated (SEQ ID NOS: 1131-1138); FLT-1 (SEQ ID NOS:1146-1161); FLT-4 (SEQ ID NOS: 1162-1197); Fra-1 (SEQ ID NOS: 1198-1203); Fra-2 (SEQ ID NOS: 1204-1215); GADD-153 (SEQ ID NOS: 1216-1224); GADD-45 (SEQ ID NOS: 1225-1272); GATA-2 (SEQ ID NOS: 1273-1289); GATA-4 (SEQ ID NOS: 1308-1321); HGPx1 (SEQ ID NOS: 1423-1468); HLX-1 (SEQ ID NOS: 1469-1539); HLX-1 poly-A tail 1540-1541); Hox 1.8 (SEQ ID NOS: 1542-1552); Hox 1.3 (SEQ ID NOS: 1570-1586); Hox 2G (SEQ ID NOS: 1671-1676); Hox 21 (SEQ ID NOS: 1677-1684); Hox 3D (SEQ ID NOS: 1685-1701); Hox 4A (SEQ ID NOS: 1702-1715); Hox 4B (SEQ ID NOS: 1716-1726); Hox 4C (SEQ ID NOS: 1727-1734); Hox 4D (SEQ ID NOS: 1735-1744); Hox 7 (SEQ ID NOS: 1769-1793); Hox 8 (SEQ ID NOS: 1794-1805); Hox A1 (SEQ ID NOS: 1806-1811); Hox A10 (SEQ ID NOS: 1815-1818); Hox B2 (SEQ ID NOS: 1819-1826); Hox B6 (SEQ ID NOS: 1827-1832); Hox C6 (SEQ ID NOS: 1833-1836); cp19 (SEQ ID NOS: 1837-1853); p40 (SEQ ID NOS: 1854-1863); HTF4a (SEQ ID NOS: 1883-1895); I-rel (SEQ ID NOS: 1896-1918); ICE (SEQ ID NOS: 1919-1933); ICH-1L (SEQ ID NOS: 1934-1950); ICH-1S (SEQ ID NOS: 1951-1964); ID-1 (SEQ ID NOS: 1965-1980); ID-2 (SEQ ID NOS: 1981-1996); ID-3 (SEQ ID NOS: 1997-2015); IRF-1 (SEQ ID NOS: 2016-2033); IRF-2 (SEQ ID NOS: 2034-2054); KDR/FLK-1 (SEQ ID NOS: 2105-2125); MAD-1 (SEQ ID NOS: 2164-2179); MAD-3 (SEQ ID NOS: 2180-2204); MADS/MEF-2 (SEQ ID NOS: 2205-2220); MCL-1 (SEQ ID NOS: 2231-2264); MSX-2 (SEQ ID NOS: 2294-2303); MTF-1 (SEQ ID NOS: 2304-2321); MTS-1 (SEQ ID NOS: 2322-2340); MTS-2 (SEQ ID NOS: 2341-2361); Mxi-1 (SEQ ID NOS: 2362-2375); NET (SEQ ID NOS: 2397-2425); NF-ATC (SEQ ID NOS: 2426-2442); NF-IL6-beta (SEQ ID NOS: 2493-2523); Oct-T1 (SEQ ID NOS: 2663-2711); Oct-T2 (SEQ ID NOS: 2712-2720); Oct-6 (SEQ ID NOS: 2721-2738); OTF-3 (SEQ ID NOS: 2739-2755); OTF-3C (SEQ ID NOS: 2756-2761); OZF (SEQ ID NOS: 2762-2769); p107 (SEQ ID NOS: 2770-2781); p34 cdc2 (SEQ ID NOS: 2782-2805); PDEGF Platelet Derived Endothelial Growth Factor (SEQ ID NOS: 2816-2839); PDGFR Platelet Derived Growth Factor Receptor (SEQ ID NOS: 2840-2862); PES (Prostaglandin Endoperoxide synthase) (SEQ ID NOS:2863-2878); Pim-1 (SEQ ID NOS: 2879-2909); PKC-α (Protein kinase C alpha) (SEQ ID NOS: 2910-2922); PKC-β (Protein kinase C beta-1) (SEQ ID NOS: 2923-2927); PKC-δ (Protein kinase C delta) (SEQ ID NOS: 2928-2947); PKC-ε (Protein kinase C epsilon) (SEQ ID NOS: 2948-2964); PKC-γ (Protein kinase C gamma) (SEQ ID NOS: 2965-2973); PKC-i (Protein kinase C iota) (SEQ ID NOS: 2974-2992); PKC-μ (Protein kinase C mu) (SEQ ID NOS: 2993-3010 PKC-Θ (Protein kinase C theta) (SEQ ID NOS: 3011-3021); PKC-z (Protein kinase C zeta) (SEQ ID NOS: 3022-3045); Rb-2 (SEQ ID NOS: 3046-3070); RBAP-1 (SEQ ID NOS: 3086-3108); RBP-1 (SEQ ID NOS: 3109-3120); Ref-1 (SEQ ID NOS: 3121-3142); SAP-1 (SEQ ID NOS: 3155-3162); SP3 (SEQ ID NOS: 3209-3212); SP4 (SEQ ID NOS: 3213-3219); Spi-1 (SEQ ID NOS: 3220-3240); Spi-B (SEQ ID NOS: 3241-3259); TGF-beta (SEQ ID NOS: 3291-3314) TNF-α (tumor necrosis factor-alpha) (SEQ ID NOS: 3315-3342); TNF-β (tumor necrosis factor-beta) (SEQ ID NOS: 3343-3374); TR3 (SEQ ID NOS: 3375-3399); TR4 (SEQ ID NOS: 3400-3418); USF (SEQ ID NOS: 3484-3508); VEGF (Vascular endothelial Growth Factor) (SEQ ID NOS: 3509-3563); WAF-1 (SEQ ID NOS: 3564-3577); WT-1 (SEQ ID NOS: 3578-3595); and YY-1 (SEQ ID NOS: 3596-3601).
31 . The composition of claim 30 , comprising at least one modification selected from the group consisting of a 2′-0-methyl modified ribose sugar, an ethylphosphonate modified backbone, a methylphosphonate modified backbone, a phosphorothioates modified backbone, a dithioate modified backbone and alpha-oligodeoxynucleotide.
32 . The composition of claim 31 wherein said nucleic acid is a double-stranded ribonucleotide, comprising between 10 and 35 nucleotides in a pharmaceutically acceptable carrier.
33 . The composition of claim 29 or 30 or 31 or 32 , wherein said nucleic acid is operably linked to an expression vector to inhibit expression of said target gene upon introduction of said vector into a cell.
34 . The composition of claim 33 comprising a lipophilic carrier.
35 . The composition of claim 34 , wherein said lipophilic carrier is a liposomic suspension comprising a hydrophobic layer of phospholipids and an ionic surfactant.
36 . The composition of claim 35 , wherein said phospholipids are selected from the group consisting of lecithin and sphingomyelin, said composition optionally comprising a steroid.
37 . The composition of claim 35 , wherein said ionic surfactant is selected from the group consisting of diacetylphosphate, stearylamine, and phosphatidic acid.
38 . The composition as claimed in claim 32 wherein at least one RNA nucleosides is replaced with inosine.
39 . The composition as claimed in claim 32 wherein at least two ribonucleosides are linked by a dithioate or a phosphorothioate.
40 . The composition as claimed in claim 32 comprising a conjugation moiety which modulates at least one parameter selected from the group consisting of oligonucleotide binding, absorption, distribution or clearance.
41 . The composition as claimed in claim 40 for inducing apoptosis in a target cell, comprising an augmentation agent, said agent being selected from the group consisting of a free radical generator, a cytokine, a chemotherapeutic agent, and radiation.
42 . The composition of claim 32 , wherein said oligonucleotide is 2′-O-methyl modified at a single end.
43 . The composition of claim 32 , wherein said oligonucleotide is 2′O-methyl modified at both ends.
44 . The composition of claim 32 wherein said oligonucleotide is a 20 mer comprising between one and five 2′O-methyl modifications.
45 . The composition of claim 31 , wherein said oligonucleotide is a DNA/RNA chimera and said RNA comprises a 2′-O-methyl modification, said chimera optionally comprising at least one dithioate and/or phosphorothioate linkage.
46 . A composition comprising at least one isolated nucleic acid which hybridizes to a target nucleic acid, wherein said at least one isolated nucleic acid is selected from the group consisting of an oligoribonucleotide, a double-stranded oligonucleotide, a single stranded oligonucleotide, a double-stranded oligoribonucleotide, and a chimeric RNA/DNA oligonucleotide, wherein said target nucleic acid is either SGP2 or TRPM-2, said at least one isolated nucleic acid optionally comprising a modification and a carrier where said composition modulates the expression of SGP2 or TRPM-2.
47 . The composition of claim 46 , comprising a modification selected from the group consisting of a 2′-0-methyl modified ribose sugar, an ethylphosphonate modified backbone, a methylphosphonate modified backbone, a phosphorothioates modified backbone, and a dithioate modified backbone.
48 . The composition of claim 47 , wherein said at least one isolated nucleic acid is a double-stranded ribonucleotide or an antisense oligonucleotide.
49 . The composition of claim 48 , said double-stranded ribonucleotide having a sequence which specifically hybridizes with a nucleic acid selected from the group consisting of SEQ ID NOS: 3175-3197 and SEQ ID NOs: 3419-3483, in a pharmaceutically acceptable carrier.
50 . The composition of claim 48 , said antisense oligonucleotide having a sequence selected from the group consisting of SEQ ID NOS: 3175-3197 and SEQ ID NOs: 3419-3483, in a pharmaceutically acceptable carrier.
51 . The composition of claim 49 or 50 , wherein said nucleic acid is operably linked to an expression vector, expression of said target gene being inhibited upon introduction of said vector into a cell.
52 . The composition of claims 51 , comprising a lipophilic carrier.
53 . The composition of claim 52 , wherein said lipophilic carrier is a liposomic suspension comprising a hydrophobic layer of phospholipids and an ionic surfactant:
54 . The composition of claim 53 , wherein said phospholipids are selected from the group consisting of lecithin and sphingomyelin, said composition optionally comprising a steroid.
55 . The composition of claim 53 , wherein said ionic surfactant is selected from the group consisting of diacetylphosphate, stearylamine, and phosphatidic acid.
56 . The composition of claim 49 further comprising at least one agent selected from the group consisting of chemotherapy, radiation, anti-inflammatory agents cytokines and free-radical generating agents.
57 . A method for modulating apoptosis in a cell or tissue comprising:
contacting said cells or tissue with an effective amount of the composition of claim 21 or claim 22 , which inhibits or promotes SGP2 (SEQ ID NOS: 3175-3197) or TRPM-2 (SEQ ID NOs: 3419-3483) modulated cell death under conditions whereby said agent enters said cells and reduces or promotes apoptosis relative to untreated cells.
58 . The method of claim 57 , wherein said cell is a cancer cell and said composition promotes apoptosis.
59 . The method of claim 57 , wherein said cell is stem cell and said composition inhibits apoptosis.
60 . A method of reprogramming normal cells comprising administration of an effective amount of an agent selected from the group consisting of an antisense oligonucleotide, an oligoribonucleotide, a double-stranded oligoribonucleotide, and a chimeric RNA/DNA oligonucleotide, said agent inhibiting expression of a target nucleic acid selected from the group consisting of AP-4, BSAP, CDK-1, CDK-2, CDK-3, CDK-4, CDK-4 inhibitor, CREBP-alpha, CREM, CTF, Cyclin A, Cyclin B, Cyclin D2, Cyclin D3, Cyclin D1, DB-1, Delta-max, DP-1, E2F-1, E2F-2, E2F-like protein, E4BP4, E4TF1, ELK-1, ERG-1, ERG-2, ERK, ERK-3, ERM, EVX-1, EVX-2, Fra-1, Fra-2, GADD-153, GADD-45, GATA-2, GATA-4, HLX-1, Hox 1.8, Hox 1.3, Hox 2G, Hox 21, Hox 3D, Hox 4A, Hox 4B, Hox 4C, Hox 4D, Hox 7, Hox 8, Hox A1, Hox A10, Hox B2, Hox B6, Hox C6, cp19, p40, HTF4a, I-rel, ID-1, ID-2, ID-3, IRF-1, IRF-2, MAD-I, MAD-3, MADS/MEF-2, MSX-2, MTF-1, Mxi-1, NET, NF-ATC, NF-IL6-beta, Oct-T1, Oct-T2, Oct-6, OTF-3, OTF-3C, OZF, p107, RBAP-1, RBP-1, Ref-1, SAP-1, SP3, SP4, Spi-1, Spi-B, TR3, TR4, USF, WAF-1, WT-1, and YY-1 and being effective to modulate at least one of cellular differentiation, proliferation, cellular apoptosis and/or viability.
61 . The method of claim 60 , wherein said agent specifically hybridizes to a target nucleic acid selected from the group consisting of cyclin D1, cyclin D2, CDK-4 inhibitor, DP-1, E2F, ID-1 and Spi-1.
62 . The method of claim 60 or claim 61 , wherein said agent is effective to modulate to expand normal cell numbers.
63 . The method of claim 60 or claim 61 , wherein said agent is effective to modulate apoptosis or inhibit programmed cell death.
64 . The method of claim 60 or claim 61 wherein said agent is effective to modulate cellular differentiation.
65 . The method of claim 60 or claim 61 , wherein said agent is, or comprises a strand which hybridizes to a sequence selected from the group consisting of
AP-4 (SEQ ID NOS: 85-1078); BSAP (SEQ ID NOS: 318-335); CDK-1 (SEQ ID NOS: 408-414); CDK-2 (SEQ ID NOS: 415-420); CDK-3 (SEQ ID NOS: 421-433); CDK-4 (SEQ ID NOS: 434-437); CDK-4 inhibitor (SEQ ID NOS: 438-460); CREBP-alpha (SEQ ID NOS: 538-549); CREM (SEQ ID NOS: 578-588); CTF (SEQ ID NOS: 589-621); Cyclin A (SEQ ID NOS: 622-643); Cyclin B (SEQ ID NOS: 644-652); Cyclin D2 (SEQ ID NOS: 653-673); Cyclin D3 (SEQ ID NOS: 674-687); Cyclin D1 (SEQ ID NOS: 688-699); DB-1 (SEQ ID NOS: 739-748); Delta-max (SEQ ID NOS: 796-801); DP-1 (SEQ ID NOS: 802-808); E2F-1 (SEQ ID NOS: 846-860); E2F-2 (SEQ ID NOS: 861-874); E2F-like protein (SEQ ID NOS: (875-888); E4BP4 (SEQ ID NOS: 895-903); E4TF1 (SEQ ID NOS: 904-940); ELK-1 (SEQ ID NOS: 951-961); ERG-1 (SEQ ID NOS: 993-1006); ERG-2 (SEQ ID NOS: 1007-1020); ERK (SEQ ID NOS: 1021-1060); ERK-3 (SEQ ID NOS: 1061-1070); ERM (SEQ ID NOS: 1071-1080); EVX-1 (SEQ ID NOS: 1106-1120); EVX-2 (SEQ ID NOS: 1121-1130); Fra-1 (SEQ ID NOS: 1198-1203); Fra-2 (SEQ ID NOS: 1204-1215); GADD-153 (SEQ ID NOS: 1216-1224); GADD-45 (SEQ ID NOS: 1225-1272); GATA-2 (SEQ ID NOS: 1273-1289); GATA-4 (SEQ ID NOS: 1308-1321); HLX-1 (SEQ ID NOS: 1469-1539); Hox 1.8 (SEQ ID NOS: 1542-1552); Hox 1.3 (SEQ ID NOS: 1570-1586); Hox 2G (SEQ ID NOS: 1671-1676); Hox 21 (SEQ ID NOS: 1677-1684); Hox 3D (SEQ ID NOS: 1685-1701); Hox 4A (SEQ ID NOS: 1702-1715); Hox 4B (SEQ ID NOS: 1716-1726); Hox 4C (SEQ ID NOS: 1727-1734); Hox 4D (SEQ ID NOS: 1735-1744); Hox 7 (SEQ ID NOS: 1769-1793); Hox 8 (SEQ ID NOS: 1794-1805); Hox A1 (SEQ ID NOS: 1806-1811); Hox A10 (SEQ ID NOS: 1815-1818); Hox B2 (SEQ ID NOS: 1819-1826); Hox B6 (SEQ ID NOS: 1827-1832); Hox C6 (SEQ ID NOS: 1833-1836); cp19 (SEQ ID NOS: 1837-1853); p40 (SEQ ID NOS: 1854-1863); HTF4a (SEQ ID NOS: 1883-1895); I-rel (SEQ ID NOS: 1896-1918); ID-1 (SEQ ID NOS: 1965-1980); ID-2 (SEQ ID NOS: 1981-1996); ID-3 (SEQ ID NOS: 1997-2015); IRF-1 (SEQ ID NOS: 2016-2033); IRF-2 (SEQ ID NOS: 2034-2054); MAD-1 (SEQ ID NOS: 2164-2179); MAD-3 (SEQ ID NOS: 2180-2204); MADS/MEF-2 (SEQ ID NOS: 2205-2220); MSX-2 (SEQ ID NOS: 2294-2303); MTF-1 (SEQ ID NOS: 2304-2321); Mxi-1 (SEQ ID NOS: 2362-2375); NET (SEQ ID NOS: 2397-2425); NF-ATC (SEQ ID NOS: 2426-2442); NF-IL6-beta (SEQ ID NOS: 2493-2523); Oct-T1 (SEQ ID NOS: 2663-2711); Oct-T2 (SEQ ID NOS: 2712-2720); Oct-6 (SEQ ID NOS: 2721-2738); OTF-3 (SEQ ID NOS: 2739-2755); OTF-3C (SEQ ID NOS: 2756-2761); OZF (SEQ ID NOS: 2762-2769); p107 (SEQ ID NOS: 2770-2781); RBAP-1 (SEQ ID NOS: 3086-3108); RBP-1 (SEQ ID NOS: 3109-3120); Ref-1 (SEQ ID NOS: 3121-3142); SAP-1 (SEQ ID NOS: 3155-3162); SP3 (SEQ ID NOS: 3209-3212); SP4 (SEQ ID NOS: 3213-3219); Spi-1 (SEQ ID NOS: 3220-3240); Spi-B (SEQ ID NOS: 3241-3259); TR3 (SEQ ID NOS: 3375-3399); TR4 (SEQ ID NOS: 3400-3418); USF (SEQ ID NOS: 3484-3508); WAF-1 (SEQ ID NOS: 3564-3577); WT-1 (SEQ ID NOS: 3578-3595); and YY-1 (SEQ ID NOS: 3596-3601).
66 . The method of claim 60 , wherein said cell is selected from the group consisting of a stem cell, an epithelial cell, a mesenchymal cell, a hematopoietic cell, a pancreatic islet cell, a neutral progenitor cell.
67 . The method of claim 60 , wherein said method further comprises subjecting cells to a Reprogramming test.
68 . The method of claim 60 , further comprising administration of said cells to a patient in need thereof, said cells being effective for use in a procedure selected from the group consisting of tissue transplantation, regeneration of liver cells, regeneration of gastrointestinal cells, and expansion of hematopoietic cell lineages.
69 . The method of claim 68 , wherein said hematopoietic cells are administered to reconstitute immune function.
70 . A method of reprogramming normal cells comprising administration of an effective amount of an agent selected from the group consisting of an antisense oligonucleotide, an oligoribonucleotide, a double-stranded oligoribonucleotide, and a chimeric RNA/DNA oligonucleotide, said agent inhibiting expression of a target nucleic acid selected from the group consisting of p53 and c-myc and being effective to modulate at least one of cellular differentiation, proliferation, and/or viability.
71 . The method of claim 70 , wherein said agent is, or comprises a sequence which hybridizes to a sequence selected from the group consisting of SEQ ID NOS: 1-4, 2806-2815 and 388-407.
72 . The method of claim 70 or claim 71 , wherein said agent is effective to modulate to expand normal cell numbers.
73 . The method of claim 70 or claim 71 , wherein said agent is effective to inhibit programmed cell death.
74 . The method of claim 70 or claim 71 , wherein said agent is effective to modulate cellular differentiation.
75 . The method of claim 70 or claim 71 , wherein said cell is selected from the group consisting of a stem cell, an epithelial cell, a mesenchymal cell, a hematopoietic cell, a pancreatic islet cell, a neutral progenitor cell.
76 . The method of claim 70 or claim 71 , wherein said method further comprises subjecting cells to a Reprogramming test.
77 . The method of claim 70 or claim 71 further comprising administration of said cells to a patient in need thereof, said cells being effective for use in a procedure selected from the group consisting of tissue transplantation, regeneration of liver cells, regeneration of gastrointestinal cells, and expansion of hematopoietic cell lineages.
78 . The method of claim 70 or claim 71 , wherein said hematopoietic cells are administered to reconstitute immune function.
79 . The method of claim 57 further comprising contacting said cells with an effective amount of a composition which down modulates a target selected from the group consisting of Apo-1, Bax a, Bax, b, Bax c, Bcl-2, Bcl-x, Bcl-xl, Bcl-xs, CD40 ligand, a cyclin, Dad-1, heat shock protein, ICE, ICH-1L, ICH-1S, Mcl-1, TGF, and TNF, said composition entering said cells and modulating the expression of said target gene, thereby inducing or inhibiting apoptosis in said cell.
80 . The method of claim 79 , wherein said cell is a normal cell and apoptosis in inhibited
81 . The method of claim 79 , wherein said cell is a cancer cell and apoptosis is promoted
82 . The method of claim 57 or claim 79 , wherein said nucleic acid molecule optionally comprises at least one modification which improves pharmacologic function.
83 . The method of claim 57 or claim 79 , comprising co-administration of at least one augmentation agent selected from the group consisting of a free radical generator and a redox modifier.
84 . The method of claim 57 or claim 79 , comprising co-administration of at least one augmentation agent selected from the group consisting of an antioxidant, anti-inflammatory agent and a cytokine.
85 . The method of claim 57 or claim 79 , wherein said cells are damaged by a process selected from the group consisting of Alzheimer's disease, autoimmune disease, artherosclerosis, restenosis, ischemia/reperfusion injury, rheumatoid arthritis, arthritis, multiple sclerosis, lupus erythematosus, multiple organ dysfunction syndrome, myocardial infarction, stroke, ionizing radiation, and viral disease.
86 . The method of claim 57 or claim 79 , wherein said cell or tissue exhibits an aberrant programming disease phenotype.
87 . The method of claim 82 , wherein said modification is selected from the group consisting of a ethyl- or methylphosphonate modified oligodeoxynucleotides, phosphorothioate modified oligonucleotides, dithioates, oligonucleotide analogs, oligonucleotides comprising ribozymes, oligoribonucleotides, chimeric oligonucleotides that are composite RNA, DNA analogues, oligonucleotides having a lipophilic backbone, methylphosphonate analogs with ribozyme structures, and oligonucleotides with 2′-O-methyl modified ribose sugars
88 . The method of claim 57 or claim 79 wherein said method is for treatment of apoptosis associated with viral infection, wherein said virus is selected from the group consisting of adenovirus, cytomegalovirus, Epstein-Barr virus, hepatitis C virus, herpes virus, hemorrhagic fever viruses, human immunodeficiency virus, influenza virus, pox virus, and vaccinia virus.Cited by (0)
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