METHOD OF REGULATING CFTR EXPRESSION AND PROCESSING
The present invention relates to therapeutic agents comprising miR-138, a miR-138 mimic, a SIN3A RNAi molecule, or a an anti-SIN3A RNAi molecule, and/or an anti-SIN3A antisense oligonucleotide (ASO) or other agent that suppresses SIN3A expression, a small molecule drug that interferes with SIN3A activity or whose actions mimic the biological effects of SIN3A suppression and methods of use of these therapeutic agents to treat cystic fibrosis.
1 . A method comprising of inhibiting translation of SIN3A in a CF cell, increasing CFTR mRNA expression in a cell, generating a CFTR anion channel in a cell, enhancing anion transport in an epithelial cell, and/or enhancing CFTR protein processing in a cell, comprising contacting the cell with a therapeutic agent, wherein the agent comprises miR-138, a miR-138 mimic, an anti-SIN3A RNAi molecule, and/or an anti-SIN3A antisense oligonucleotide (ASO) or other agent that suppresses SIN3A expression, a small molecule drug that interferes with SIN3A activity or whose actions mimic the biological effects of SIN3A suppression.
2 . The method of claim 1 , wherein the method comprises inhibiting translation of SIN3A in the CF cell by at least about 10%.
3 . (canceled)
4 . (canceled)
5 . (canceled)
6 . (canceled)
7 . A method of increased surface display of ΔF508-CFTR protein on a cell by knocking down a gene product level in the cell comprising contacting the cell with a therapeutic agent, wherein the agent comprises miR-138, a miR-138 mimic, an anti-SIN3A RNAi molecule, and/or an anti-SIN3A antisense oligonucleotide (ASO) or other agent that suppresses SIN3A expression, a small molecule drug that interferes with SIN3A activity or whose actions mimic the biological effects of SIN3A suppression, wherein the gene product is produced by a gene listed in Table 6:
TABLE 6
Ref. No.
Gene ID
1
DERL1
2
HSPA8
3
HSPA5
4
DNAJB12
5
BAG1
6
NHERF1 (SLC9A3R1)
7
CAPNS1
8
HSPB1
9
HSPA1A
10
MARCH2
11
HAP90B1
12
RNF128
13
CANX
14
GRIP1
15
SYVN1
16
DAB2
17
RCN2
18
GOPC
19
HSPA9
20
MARCH3
21
PPP2R1B
22
RCN1
23
BAG2
24
ATP6V1A
25
DNAJC3
8 . The method of claim 7 , wherein the gene product level in the cell is decreased by 10%.
9 . The method of claim 1 , wherein the cell is a CF epithelial cell.
10 . The method of claim 9 wherein the CF epithelial cell is an airway epithelial cell.
11 . The method of claim 10 , wherein the airway epithelial cell is a lung cell, a nasal cell, a tracheal cell, a bronchial cell, a bronchiolar or alveolar epithelial cell.
12 . The method of claim 10 , wherein the airway epithelial cells are present in a mammal.
13 . The method of claim 12 , wherein the agent is administered orally.
14 . The method of claim 12 , wherein the agent is administered by inhalation.
15 . The method of claim 9 , wherein the epithelial cells are intestinal, pancreatic epithelia, liver, gallbladder, reproductive tract, or sweat gland cells.
16 . The method of claim 15 , wherein the intestinal epithelial cells are present in a mammal.
17 . The method according to claim 16 , wherein the therapeutic agent is administered orally.
18 . The method of claim 1 , wherein the therapeutic agent is present within a pharmaceutical composition.
19 . A method of claim 1 , wherein the cell produces a CFTR protein having a deletion at position 508.
20 . A method of treating a subject having cystic fibrosis (CF) comprising administering to the subject an effective amount of a therapeutic agent to alleviate the symptoms of CF, wherein the agent comprises miR-138, a miR-138 mimic, an anti-SIN3A RNAi molecule, and/or an anti-SIN3A antisense oligonucleotide (ASO) or other agent that suppresses SIN3A expression, a small molecule drug that interferes with SIN3A activity or whose actions mimic the biological effects of SIN3A suppression.
21 . The method of claim 20 , wherein the method increases chloride ion conductance in airway epithelial cells of the subject, and wherein the subject's CFTR protein has a deletion at position 508.
22 . The method of claim 20 , wherein the subject is a mammal.
23 . (canceled)
24 . The method of claim 20 , wherein the administration is via aerosol, dry powder, bronchoscopic instillation, intra-airway (tracheal or bronchial) aerosol or orally.
25 . The method of claim 20 , wherein the therapeutic agent is present within a pharmaceutical composition.
26 . The method of claim 20 , wherein the therapeutic agent is Aminoglutethimide, Biperiden, Diphenhydramine, Rottlerin, Midodrine, Thioridazine, Sulfadimethoxine, neostigmine bromide, Pyridostigmine, pizotifen, tyrophostin (AG-1478), valproic acid, Scriptaid or neomycin.
27 . The method of claim 1 , wherein the therapeutic agent is not genistein.
28 . A pharmaceutical composition for treatment of cystic fibrosis, comprising miR-138, a miR-138 mimic, an anti-SIN3A RNAi molecule, and/or an anti-SIN3A antisense oligonucleotide (ASO) or other agent that suppresses SIN3A expression, a small molecule drug that interferes with SIN3A activity or whose actions mimic the biological effects of SIN3A suppression in combination with a pharmaceutically acceptable carrier, where the composition does not comprise genistein as an active ingredient, and wherein the composition further comprises a CF therapeutic agent.
29 . The pharmaceutical composition of claim 28 , wherein the therapeutic agent is Aminoglutethimide, Biperiden, Diphenhydramine, Rottlerin, Midodrine, Thioridazine, Sulfadimethoxine, neostigmine bromide, Pyridostigmine, pizotifen, tyrophostin (AG-1478), valproic acid, Scriptaid or neomycin.
30 . (canceled)
31 . (canceled)