miR-34 Regulated Genes and Pathways as Targets for Therapeutic Intervention
The present invention concerns methods and compositions for identifying genes or genetic pathways modulated by miR-34, using miR-34 to modulate a gene or gene pathway, using this profile in assessing the condition of a patient and/or treating the patient with an appropriate miRNA.
1 . A method of modulating gene expression in a cell comprising administering to the cell an amount of an isolated nucleic acid comprising a miR-34 nucleic acid sequence in an amount sufficient to modulate the expression of one or more genes identified in Table 1, 3, 4, or 5.
2 . The method of claim 1 , wherein the cell is in a subject having, suspected of having, or at risk of developing a metabolic, an immunologic, an infectious, a cardiovascular, a digestive, an endocrine, an ocular, a genitourinary, a blood, a musculoskeletal, a nervous system, a congenital, a respiratory, a skin, or a cancerous condition.
3 . (canceled)
4 . The method of claim 2 , wherein the cancerous condition is astrocytoma; anaplastic large cell lymphoma; acute lymphoblastic leukemia; acute myeloid leukemia; angiosarcoma; breast carcinoma; B-cell lymphoma; bladder carcinoma; cervical carcinoma; carcinoma of the head and neck; chronic lymphocytic leukemia; chronic myeloid leukemia; colorectal carcinoma; endometrial carcinoma; glioma; glioblastoma; gastric carcinoma; gastrinoma; hepatoblastoma; hepatocellular carcinoma; Hodgkin lymphoma; Kaposi's sarcoma; leukemia; lung carcinoma; leiomyosarcoma; laryngeal squamous cell carcinoma; melanoma; mucosa-associated lymphoid tissue B-cell lymphoma; medulloblastoma; mantle cell lymphoma; meningioma; myeloid leukemia; multiple myeloma; high-risk myelodysplastic syndrome; mesothelioma; neurofibroma; non-Hodgkin lymphoma; non-small cell lung carcinoma; ovarian carcinoma; esophageal carcinoma; oropharyngeal carcinoma; osteosarcoma; pancreatic carcinoma; papillary carcinoma; prostate carcinoma; pheochromocytoma; rhabdomyosarcoma; squamous cell carcinoma of the head and neck; schwannoma; small cell lung cancer; salivary gland tumor; sporadic papillary renal carcinoma; thyroid carcinoma; testicular tumor; urothelial carcinoma wherein the modulation of one or more gene is sufficient for a therapeutic response.
5 . The method of claim 4 , wherein the cancerous condition is lung carcinoma
6 . The method of claim 5 , wherein lung carcinoma is non-small cell lung carcinoma.
7 . (canceled)
8 . The method of claim 4 , wherein the cancerous condition is prostate carcinoma.
9 . The method of claim 8 , wherein prostate carcinoma is associated with detectable prostate-specific antigen (PSA).
10 . The method of claim 8 , wherein prostate carcinoma is androgen independent.
11 . The method of claim 1 , wherein the expression of a gene is down-regulated.
12 . The method of claim 1 , wherein the expression of a gene is up-regulated.
13 - 16 . (canceled)
17 . The method of claim 1 , wherein the isolated miR-34 nucleic acid is a recombinant nucleic acid.
18 - 22 . (canceled)
23 . The method of claim 1 , wherein the miR-34 nucleic acid is a synthetic nucleic acid.
24 . The method of claim 23 , wherein the nucleic acid is administered at a dose of 0.01 mg/kg of body weight to 10 mg/kg of body weight.
25 . (canceled)
26 . The method of claim 1 , wherein the miR-34 is miR-34a, miR-34b, or miR-34c.
27 . The method of claim 1 , wherein the nucleic acid is administered enterally or parenterally.
28 . (canceled)
29 . (canceled)
30 . The method of claim 1 , wherein the nucleic acid is comprised in a pharmaceutical formulation.
31 . The method of claim 30 , wherein the pharmaceutical formulation is a lipid composition or a nanoparticle composition.
32 . (canceled)
33 . The method of claim 30 , wherein the pharmaceutical formulation consists of biocompatible and/or biodegradable molecules.
34 - 52 . (canceled)
53 . A method of selecting a miRNA to be administered to a subject with, suspected of having, or having a propensity for developing a pathological condition or disease comprising:
(a) determining an expression profile of one or more genes selected from Table 1, 3, 4, or 5;
(b) assessing the sensitivity of the subject to miRNA therapy based on the expression profile; and
(c) selecting one or more miRNA based on the assessed sensitivity.
54 - 56 . (canceled)
57 . A method of assessing a cell, tissue, or subject comprising assessing expression of miR-34 in combination with assessing expression of one or more gene from Table 1, 3, 4, or 5 in at least one sample.
58 . (canceled)