Methods and Compositions for the Treatment of Medical Conditions Involving Cellular Reprogramming

• US 20120156138A1
• Filed: 04/14/2009
• Published: 06/21/2012
• Est. Priority Date: 04/14/2009
• Status: Abandoned Application

• Current Assignee: Larry J. Smith
• Original Assignee: Larry J. Smith
• Inventors: Smith, Larry J.
• Application Number:
  US13/264,482
• Publication Number:
  US 20120156138A1
• Time in Patent Office: Days
• US Class Current: 424/9.2
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/158 Expression markers

Abstract

The present invention provides a variety of nucleic acid based therapeutics and methods of use thereof which are effective to beneficially reprogram diseased cells such that they exhibit more desirable phenotypes. Also provided are compositions and methods to reprogram normal cells for medical and commercial purposes.

Claims

1. A composition, comprising in a biologically acceptable carrier, at least one nucleic acid based therapeutic (NABT) for down modulating target gene expression, said NABT comprising a nucleic acid sequence which inhibits production of at least one gene product encoded by said target gene, said sequence optionally comprising one or more modifications selected from the group consisting of

i) at least one modification to the phosphodiester backbone linkage;

ii) at least one modification to a sugar in said nucleic acid;

iii) a support;

iv) at least one cellular penetrating peptide or a cellular penetrating peptide mimetic;

v) an endosomal lytic moiety;

vi) at least one specific binding pair member or targeting moiety; and

viii) operable linkage to an expression vector,

wherein said nucleic acid sequence is selected from the group of sequences in Table 8, with the proviso that when i, ii, iii, iv, v, vi, viii are absent, said nucleic acid is not SEQ ID NOS;

1, 2, 3, 4, or 2265-2293.

2. The composition of claim 1, wherein said nucleic acid comprises at least one modified linkage selected from the group consisting of phosphorothioate linkages, methylphosphonate linkages, ethylphosphonate linkages, boranophosphate linkages, sulfonamide, carbonylamide, phosphorodiamidate, phosphorodiamidate linkages comprising a positively charged side group, phosphorodithioates, aminoethylglycine, phosphotriesters, aminoalkylphosphotriesters;

3′

-alkylene phosphonates;

5′

-alkylene phosphonates, chiral phosphonates, phosphinates, 3′

-amino phosphoramidate, aminoalkylphosphoramidates, thionophosphoramidates;

thionoalkyl-phosphonates, thionoalkylphosphotriesters, selenophosphates, 2′

-5′

linked boranophosphonate analogs, linkages having inverted polarity, abasic linkages, short chain alkyl linkages, cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, short chain heteroatomic or heterocyclic internucleoside linkages with siloxane backbones, sulfide, sulfoxide, sulfone, formacetyl linkages, thioformacetyl linkages, methylene formacetyl linkages, thioformacetyl linkages, riboacetyl linkages, alkene linkages, sulfamate backbones, methyleneimino linkages, methylenehydrazino linkages, sulfonate linkages, and amide linkages.

3. The composition of claim 1 or 2, which comprises at least one modified sugar selected from the group consisting of 2′

fluoro, 2′

fluoro substituted ribose, 2-fluoro-D-arabinonucleic acid, 2′

-O-methoxyethyl ribose, 2′

-O-methoxyethyl deoxyribose, 2′

-O-methyl substituted ribose, a morpholino, a piperazine, and a locked nucleic acid.

4. The composition of claim 1, 2 or 3 wherein said nucleic acid is a conventional antisense nucleic acid which functions via a steric hindrance mechanism.

5. The composition of claim 1 or 2, or 3, wherein said nucleic acid is a modified antisense nucleic acid which functions by triggering RNAse H activity.

6. The composition of claim 5, wherein said nucleic acid is a gapmer which promotes RNAse H activity and exhibits increased binding affinity for said target nucleic acid.

7. The composition of claim 1, wherein said nucleic acid is an RNAi.

8. The composition of claim 1 or 2, or 7 wherein said nucleic acid sequence is operably linked to an expression vector which produces an NABT which inhibit expression of said target gene upon introduction of said vector into a cell.

9. The composition of claim 5 or 6, comprising a modification selected from the group consisting of a LNA modification, a FANA modification, a 2′

fluoro substituted ribose, at least one morpholino, or at least one piperazine, wherein NABT is a 14-22mer with phosphorothioate linkages and a 4-18 nucleoside core comprising deoxyribose or a functional analog thereof.

10. The composition of claim 9, wherein said gapmer comprises at least one base modification selected from the group consisting of 4′

-C-hydroxymethyl-DNA, 3′

-C-hydroxymethyl-arabinonucleic acid, piperazino-functionalized C3′

,02′

-linked arabinonucleic acid, wherein said modified base is inserted near the center of the NABT within 4 nucleosides of either the 5′

or 3′

end of said NABT.

11. The composition of claim 9 or 10 comprising at least one modified nucleotide selected from the group consisting of 2′

fluoro-arabinonucleotides, abasic nucleotides, tetrahydrofurans (THF), bases shown in Formulas I, II and III wherein each of _R1-8 is independently selected from H, halogen, and C_1-3 alkyl, R₈ may also be independently selected from fluorine and methyl, and bases selected from Formulas IV-XII.

12. The composition of claim 1 to claim 11, comprising a support selected from the group consisting of nanoparticles, dendrimers, nanocapsules, nanolattices, microparticles, micelles, Hemagglutinating virus of Japan (HVJ) envelope, spiegelmers, and liposomes.

13. The composition of claim 1 to claim 12 wherein said NABT is operably linked to a cellular penetrating peptide or mimetic thereof selected from the group consisting of one or more of

14. The composition of claim 1 to claim 13, comprising an endosomal lytic component.

15. The composition of claim 1 to claim 14 comprising at least one member of a specific binding pair or targeting moiety.

16. The composition of claim 15 wherein said binding pair member or targeting moiety is selected from the group consisting of ligands for leptin receptor, ligands for lipoprotein receptor, peptides that target the LOX-1 receptor, LFA-1 targeting moieties, NL4-10K, IFG-1 targeting peptides, ligands for the transferrin receptor, ligands for transmembrane domain protein 30A, ligands for asialoglycoprotein receptor, Trk targeting ligands, an actively transported nutrient, RVG peptide, heart homing peptides, peptide for ocular delivery, and PH-50.

17. The composition of claim 1 to claim 16, operably linked to an expression vector, said vector facilitating cellular uptake and expression of said NABT encoding sequences within the cell resulting in down modulation of the sequence targeted by said NABT.

18. The composition as claimed in claim 7 or 16, wherein said NABT is a double stranded dicer substrate RNA comprising a passenger strand and a guide strand 25-30-nucleotides in length which is cleaved intracellularly to form substantially double stranded 21-mers with a two nucleotide (2-nt) overhang on each 3′

end.

19. The composition of claim 18, wherein the 5′

end of a passenger strand RNA is blocked with an alkyl group, thereby increasing guide strand loading into the RISC complex.

20. The composition of claim 19, wherein said passenger strand is nicked or comprises a gap.

21. The composition of claim 18, wherein a 5′

end of the passenger strand is modified at 1, 2, 3 or 4 positions, thereby increasing Tm of duplex formation with a corresponding guide strand.

22. The composition of claim 18, wherein the affinity of the four nucleotides at the 3′

end of the passenger stand for the 5′

end of the guide strand is decreased relative to the opposite end of the duplex.

23. A formulation, comprising the composition of claim 1 to claim 22, suitable for systemic, aerosolized, oral and topical formulations.

24. The formulation of claim 23, selected from the group consisting of oral, intrabuccal, intrapulmonary, rectal, intrauterine, intratumor, intracranial, nasal, intramuscular, subcutaneous, intravascular, intrathecal, inhalable, transdermal, intradermal, intracavitary, implantable, iontophoretic, ocular, vaginal, intraarticular, otical, intravenous, intramuscular, intraglandular, intraorgan, intralymphatic, implantable, slow release, and enteric coating formulations.

25. A method for down modulating expression of a target gene for the treatment of an aberrant programming disease in a target cell, said method comprising administration of an effective amount of at least one composition comprising an NABT as claimed in any one of the preceding claims, thereby reprogramming said target cell, said reprogramming altering the aberrant programming disease phenotype thereby providing a beneficial therapeutic or commercial effect.

26. The method of claim 25, wherein said NABT down modulates expression of a transcriptional regulator.

27. The method of claim 25, wherein said NABT down modulates expression of a direct modifier of a transcriptional regulator.

28. The method of claim 25, wherein said reprogramming is therapeutically beneficial to diseased cells and normal cells are not adversely affected.

29. The method of claim 25 to claim 28, wherein said cell is in a patient.

30. The method of claim 25 to claim 29, further comprising administration of an augmentation agent, selected from the group consisting of antioxidants, polyunsaturated fatty acids, chemotherapeutic agents, genome damaging agents and ionizing radiation.

31. A method as claimed in claim 25 to claim 30, wherein said disease is selected from the group consisting of Cancer, AIDS, Alzheimer'"'"'s disease, Amyotrophic lateral sclerosis, Atherosclerosis, Autoimmune Diseases, Cerebellar degeneration, Cancer, Diabetes Mellitus, Glomerulonephritis, Heart Failure, Macular Degeneration, Multiple sclerosis, Myelodysplastic syndromes, Parkinson'"'"'s disease, Prostatic hyperplasia, Psoriasis, Asthma, Retinal Degeneration, Retinitis pigmentosa, Rheumatoid arthritis, Rupture of atherosclerotic plaques, Systemic lupus erythematosis, Ulcerative colitis, viral infection, ischemia reperfusion injury, cardiohypertrophy, and Diamond Black Fan anemia.

32. The method as claimed in claim 31, wherein said disease is a viral disease and said NABT is effective to reduce viral replication, load or spread.

33. The method as claimed in claim 32, wherein said viral disease is HIV and said target is selected from the group consisting of at least one of USF, Ap-2, Ap-4, Sp-1, Sp-3, Sp-4, p53, NF-κ

β

, and C/EBP.

34. An anti-viral composition effective against HIV for use in the method of claim 32, comprising at least one NABT having a sequence selected from the group consisting of USF (SEQ ID NOS:

3484-3508), Ap-2 (SEQ ID NOS;

48-84), Ap-4 (SEQ ID NOS;

85-107), Sp-1 (SEQ ID NOS;

3198-3208), Sp-3 (SEQ ID NOS;

3209-3212), Sp-4 (SEQ ID NOS;

3213-3219), p53 (SEQ ID NOS;

4, 2806-2815, 3606-3626, and 3786-3798), (NF-κ

β

SEQ ID NOS;

2524-2620), and C/EBP (SEQ ID NOS;

336-345) in pharmaceutically acceptable carrier.

35. The method as claimed in claim 32, wherein said viral disease is CMV and said target is selected from the group consisting of at least one of SRF, NF-κ

β

, p53, and C/EBP.

36. An anti-viral composition effective against CMV for use in the method of claim 35, comprising an effective amount of at least one NABT having a sequence selected from the group consisting of at least one of SRF (SEQ ID NOS:

3260-3290), NF-κ

β

(SEQ ID NOS;

2524-2620), p53 (SEQ ID NOS;

4, 2806-2815, 3606-3626, and 3786-3798), and C/EBP (SEQ ID NOS;

336-345) in a pharmaceutically acceptable carrier.

37. The method as claimed in claim 32, wherein said viral disease is herpesvirus and said target is USF, Spi-1, Spi-B, ATF, CREB, C/EBP, E2F, YY-1, Oct-1, Ap-1, Ap-2, c-myb, and NF-κ

β

.

38. An anti-viral composition effective against herpes virus infection for use in the method of claim 37, comprising an effective amount of at least one NABT having a sequence selected from the group consisting of USF (SEQ ID NOS:

3484-3508), Spi-1 (SEQ ID NOS;

3220-3240), Spi-B (SEQ ID NOS;

3241-3259), ATF (SEQ ID NOS;

194-205), CREB (SEQ ID NOS;

515-577), C/EBP (SEQ ID NOS;

336-345), E2F (SEQ ID NOS;

846-888), YY-1 (SEQ ID NOS;

3596-3601), Oct-1 (SEQ ID NOS;

2631-2653), Ap-2 (SEQ ID NOS;

48-84), c-myb (SEQ ID NOS;

382-387), and NF-κ

β

(SEQ ID NOS;

2524-2620) in a pharmaceutically acceptable carrier suitable for topical administration.

39. The method as claimed in claim 32, wherein said viral disease is hepatitis virus and said target is NF-1, Ap-1, Sp-1, RFX-1, RFX-2, RFX-3, NF-κ

β

, Ap-2 and C/EBP.

40. An anti-viral composition effective against hepatitis virus for use in the method of claim 39, comprising an effective amount of at least one NABT having a sequence selected from the group consisting of Sp-1 (SEQ ID NOS 3198-3208), NF-κ

β

(SEQ ID NOS;

2524-2620), Ap-2 (SEQ ID NOS;

48-84) and C/EBP (SEQ ID NOS;

336-345).

41. The method as claimed in claim 31, wherein said disease in heart failure and said target is selected from the group consisting of p53, BCL-X, Bcl-2-like 1, BCL2L1, BCL2L, Bcl-xS, FAS/APO1, Pro-apoptotic form of gene product, DB-1, (ZNF161;

VEZF1), ICE (CASP1;

Caspase-1), NF-kappaB, PKC alpha, SRF and VEGF, said NABT optionally being linked to a heart homing peptide.

42. A composition useful for the treatment of heart failure for use in the method of claim 41, comprising an effective amount of at least one NABT having a sequence selected from the group consisting of those targeting p53, BCL-X, Bcl-2-like 1, BCL2L1, BCL2L, Bcl-xS, FAS/APO 1, Pro-apoptotic form of gene product, DB-1, (ZNF161;

VEZF1), ICE (CASP1;

Caspase-1), NF-kappaB, PKC alpha, SRF and VEGF, said NABT optionally being operably linked to a heart homing peptide in a pharmaceutically acceptable carrier.

43. The composition of claim 42, comprising a heart homing peptide of SEQ ID NOS 3715-3719.

44. The method as claimed in claim 31, wherein said disease is cancer and said sequence targeted by said NABT is selected from the group consisting of at least one of 5 alpha reductase, A-myb, ATF-3, B-myb, β

-amyloid precursor protein, BSAP, C/EBP, c-fos, c-jun, c-myb, c-myc, CDK-1, CDK-2, CDK-3, CDK-4, CDK-4 inhibitor (Arf), cHF.10, COX-2, CREB, CREBP1, Cyclins A, B, D1, D2, D3, DB-1, DP-1, E12, E2A, E2F-1, E2F-2, E47, ELK-1, Epidermal Growth Factor Receptor, ERM, (ETV5), estrogen receptor, ERG-1, ERK-1, ERK3, ERK subunit A, ERK subunit B, Ets-1, Ets-2, FAS/APO-1, FLT-1, FLT-4, Fra-1, Fra-2, GADD-45, GATA-2, GATA-3, GATA-4, HB9, HB24, h-plk, Hox1.3, Hox 2.3, Hox2.5, Hox4A, Hox 4D, Hox 7, HoxA1, HoxA10, HoxC6, HS1, HTF4a, I-Rel, ICE, ICH-1L, ICH-1S, ID-1, ID-2, ID-3, IRF-1, IRF-2, ISGF3, junB, junD, KDR/FLK-1, L-myc, Lyl-1, MAD-1, MAD-3, MADS/MEF-2, MAX, Mcl-1, MDR-1, MRP, MSX-2, mts1, MXi1, MZF-1, NET, NF-IL6, C/EBPbeta, NF-IL6 beta, NF-kappa B, N-myc, OCT-1, OCT-2, OCT-3, Oct-T1, OCT-T2, OTF-3C, OZF, p53, p107, PDEGF, PDGFR, PES, Pim-1, PKC-alpha, PKC-beta, PKC-delta, PKC-epsilon, PKC-iota, Ref-1, REL, SAP-1, SCL, SGP-2, TRPM-2 Apolipoprotein J;

APOJ, Complement associated protein SP 40,40, Complement cytolysis inhibitor, KUB1;

CL1, testosterone-repressed prostate message

     2), Sp-1, Sp-3, Sp-4, Spi-B, SRF, TGF-beta, TR4, VEGF, Waf-1, WY-1 and YY-1, said method optionally comprising administration of an at least one augmention agent, chemotherapeutic, biologic or anti-proliferative agent.

45. The method as claimed in claim 44, wherein said cancer is selected from the group consisting of brain cancer, lung cancer, ovarian cancer, breast cancer, testicular cancer, kidney cancer, liver cancer, skin cancer, pancreatic cancer, esophageal cancer, stomach cancer, bladder cancer, uterine cancer, prostate cancer, glaucomas, sarcomas, myelomas, lymphomas, and leukemias.

46. The method of claim 44, wherein said agent is selected from the group consisting of at least one of a toxin, saporin, ricin, abrin, ethidium bromide, diptheria toxin, Pseudomonas exotoxin, an alkylating agent, a nitrogen mustards, chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, uracil mustard;

aziridines, thiotepa;

a methanesulphonate ester, busulfan;

carmustine, lomustine, streptozocin;

cisplatin, carboplatin;

mitomycin, procarbazine, dacarbazine and altretamine, bleomycin, amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, teniposide, plicamydin, methotrexate, trimetrexate;

fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, floxuridine;

mercaptopurine, 6-thioguanine, fludarabine, pentostatin;

asparginase, hydroxyurea, vincristine, vinblastine, paclitaxel (Taxol), estrogens;

conjugated estrogens;

ethinyl estradiol;

diethylstilbesterol;

chlortrianisen;

idenestrol;

hydroxyprogesterone caproate, medroxyprogesterone, megestrol;

testosterone, testosterone propionate, fluoxymesterone, methyltestosterone, abarelix abiraterone acetate, Degarelix, prednisone, dexamethasone, methylprednisolone, and prednisolone, leuprolide acetate, goserelin acetate, tamoxifen, flutamide, mitotane, and aminoglutethimide.

47. The method of claim 46 wherein said chemotherapeutic agent is selected from the group consisting of:

pacitaxel (Taxol®

), cisplatin, docetaxol, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11, 5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, adriamycin (doxorubicin), etoposide, arsenic trioxide, irinotecan, and epothilone derivatives.

48. The method of claim 44 to claim 47, wherein said NABT and said anti-cancer or anti-proliferative agent act synergistically.

49. The method of claim 44 to claim 47, wherein said cancer is prostate cancer, said at least one NABT is selected from the group consisting of those targeting 5 alpha-reductase, β

amyloid precursor protein, cyclin A, cyclin D3, Oct-T1, p53, Pim-1, Ref-1, SAP-1, SGP2, SRF, TGF-beta, TRPM-2, clusterin and said chemotherapeutic agent is selected from the group consisting of Abarelix, abiraterone acetate, and Degarelix.

50. The method of claim 49 further comprising administration of an augmentation agent.

51. The method of claim 31, wherein said disease is Alzheimer'"'"'s disease and said sequence targeted by said NABT is selected from the group consisting of apolipoprotein epsilon 4, β

amyloid precursor protein, CDK-2, Cox-2, CREB, CREBP, Cyclin B, ICH-1L (also known as caspase 2L), PKC genes, PDGFR, SGP2, SRF, and TRPM-2, said NABT optionally comprising a cellular peneratrating peptide (CPP) to facilitate penetration of the blood brain barrier, thereby enhancing uptake of said NABT into cells of the CNS.

52. The method of claim 31, wherein said disease is Multiple sclerosis and said target is selected from the group consisting of p53, COX-2 TNF-α

, and TNF-β and

said composition is administered nasally.

53. The method of claim 31 wherein said disease is diabetes and said NABT targets a gene selected from the group consisting of androgen receptor, CDK-4 inhibitor, MTS-2, and p53.

54. The method of claim 53 further comprising administration of at least one agent selected from the group consisting of Glucophage®

, Avandia®

, Actos®

, Januvia® and

Glucovance®

).

55. The method of claim 31 wherein said disease is asthma and said target is selected from the group consisting of ISGF3, PES, REF-1, and TNF-alpha.

56. The method of claim 55, further comprising administration of at least one agent selected from the group consisting of cortisone, hydrocortisone, prednisone, prednylidene, prednisolone, methylprednisolone, beclomethasone, flunisolide, triamcinolone, deflazacort, betamethasone and dexamethasone.

57. The method of claim 31, wherein said disease is atherosclerosis and said target is selected from the group consisting of at least one of DB-1, DP-1, E2F-1, ERG-1, FLT-4, ICH-1L, ISGF3, NF-IL6, OCT-1, p53, Sp-1, PDEGF, and PDGFR.

58. The method of claim 31, wherein said disease is psoriasis and said target is selected from the group consisting of at least one of Bcl-xL, cyclin A, cyclin B, Flt-1, ICE, ID-1, ISGF3, junB, p53, sp1, TNF-alpha, VEGF, and NF-kappa B and said NABT is administered topically.

59. The method of claim 31, wherein said disease is Diamond Blackfan anemia and said target is p53.

60. The method of claim 59, wherein said NABT has a sequence selected from the group consisting of at least one of SEQ ID NOS:

2806-2818, 3606-3626, 3786-3798 and modified SEQ ID NO;

4.

61. The method of claim 60, wherein SEQ ID NO:

4 comprises a 2′

fluoro gapmer which acts via a steric hindrance mechanism.

62. The method of claim 60, wherein at least two NABTs directed to p53, said pair of NABTs being selected from those in Table 23.

63. The method for the treatment of prostate cancer as claimed in claim 49 or 50 comprising administration of a pair of NABTs directed to SGP-2 or clusterin.

64. The method of claim 63, wherein said NABT directed to SGP-2 or clusterin are selected from those set forth in Tables 18-22.

65. The method as claimed in claim 31, wherein said disease is pulmonary fibrosis and said at least one NABT is aerosolized and targets a gene selected from the group consisting of Fra-2, PDEGF, PDGFR, and SRF.

66. The method as claimed in claim 31, wherein said disease is systemic lupus erythematosis and said at least one NABT targets a gene selected from the group consisting of CREM, Fas/APO-1, HS1, Oct-T1 and p53.

77. The composition as claimed in claim 1, 2, or 3 wherein said NABT acts via a steric hindrance mechanism and also triggers RNAse H activity.

67. A method for optimizing the efficacy of NABT for treatment of aberrant programming diseases:

a) selecting a target gene sequence which regulates cellular programming and a sequence which hybridizes therewith from Table 8;

b) incubating the aberrantly programmed diseased cells in the presence and absence of said at least one NABT molecule, said NABT comprising one or more modifications selected from the group consisting of

i) at least one modification to the phosphodiester backbone linkage;

ii) at least one modification to a sugar in said nucleic acid;

iii) a support;

iv) at least one cellular penetrating peptide or a cellular penetrating peptide mimetic;

v) an endosomal lytic moiety;

vi) at least one specific binding pair member or targeting moiety; and

viii) operable linkage to an expression vector,

c) identifying those NABT which exhibit improved effects on cellular reprogramming relative to cells treated NABT lacking at least one modification of step b);

thereby identifying efficacious modified NABT for the treatment of aberrant programming disorders.

68. The method of claim 67, comprising contacting normal cells with the NABT identified in step c) thereby identifying those NABTs which differentially affect cellular programming in aberrantly programmed cells versus normal cells.

69. The method as claimed in claim 67 or claim 68 wherein said aberrant programming disease is selected from the group consisting of AIDS, Alzheimer'"'"'s disease, Amylotrophic lateral schlerosis, Atherosclerosis, restenosis, Cerebellar degeneration, cancer, Diamond Blackfan anemia, immune-mediated glomerulonephritis, toxin-induced liver disease, multiple organ dysfunction syndrome, multiple sclerosis, myelodysplastic syndrome, myocardial infarction, heart failure, psoriasis, rupture of aortic plaques, Parkinson'"'"'s disease, ischemia-reperfusion injury, retinitis pigmentosa, arthritis, asthma, stroke, systemic lupus erythematosis,

70. The method of claim 67 to claim 69, wherein said disease comprises aberrant apoptosis and said NABT is directed to bcl-2α

or bcl-2β

.

71. The method of claim 67 to claim 70 wherein said NABT is directed to a transcriptional regulator selected from the group consisting of

p34 (cdc2), SEQ ID NOS:

944-966;

p53 (SEQ ID NOS;

4, 2806-2815, 3606-3626, and 3786-3798)

fas/Apo 1, SEQ ID NOS;

3287-3293.

mts-1, SEQ ID NOS;

2454-2472;

mts-2, SEQ ID NOS;

2100-2120;

Nfκ

B, SEQ ID NOS;

1720-1739, 1741-1774, and 2166-2205;

WAF1 (p21), SEQ ID NOS;

2440-2453;

RB, (SEQ ID NOS;

400, 402, 404, 406, 408, 410, 411, 413, 415, 417 and

     419);

ref-1, (SEQ ID NOS;

2657-2678);

c-myc, (SEQ ID NOS;

657-676);

n-myc, (SEQ ID NOS;

639-648);

SGP-2, (SEQ ID NOS;

3175-3197, 3746-3785) and

TRPM-2, (SEQ ID NOS;

3419-3483.

72. The method as claimed in claim 67 to claim 71, further comprising the step of assessing the oligonucleotide so identified for efficacy and toxicity in an in vivo animal model.

73. The method as claimed in claim 72, wherein said animal model is a non-human primate model for AIDS.

74. The method as claimed in claim 67, wherein disease is cancer and said modified NABT is assessed in an immunocompromised tumor bearing animal.

75. The method as claimed in claim 74, wherein said NABT targets at least one region in the p53 gene sequence.

76. The method as claimed in claim 67, wherein said NABT is selected from the group consisting of an antisense NABT, a modified antisense NABT, an siRNA NABT, a modified siRNA NABT, a ribozyme NABT, each of the NABT optionally being encoded by an expression vector suitable for expressing said NABT in a target cell.