Targeted epigenetic therapy against distal regulatory element of TGFβ2 expression
The instant disclosure provides methods and compositions for the diagnosis, treatment and prevention of a TGFβ2-associated disease, disorder and/or condition, including, e.g., Scleroderma, other fibrotic disease, grade 4 glioblastoma (GBM) and/or Primary Open-Angle Glaucoma (POAG). The disclosure further provides pharmaceutical compositions and kits for the diagnosis, treatment and prevention of TGFβ2-associated diseases, disorders and/or conditions.
1. A method for treating a subject having or at risk of developing a transforming growth factor β2-associated disease, disorder and/or condition comprising:
administering to the subject an effective amount of one or more agents that inhibit transforming growth factor β2 (TGFβ2) expression by inhibiting occupancy, of an enhancer sequence, by CBP/P300 and bromodomain-containing protein 4 (BRD4), wherein an inhibitor of CBP/P300 is selected from the group consisting of bromodomain inhibitor SGC-CBP30, C646, C375 and C146, and wherein the enhancer sequence is located 15 kb downstream of the TGFβ2 3′UTR, said transforming growth factor β2-associated disease, disorder and/or condition is Scleroderma and/or a fibrotic disease,
thereby treating the subject.
2. The method of claim 1 , wherein the one or more agents modulate activity of one or more molecules at the enhancer sequence and/or inhibit binding to the enhancer sequence and/or inactivate the enhancer functions and/or activities.
3. The method of claim 2 , wherein the one or more agents: increase histone deacetylase activity, inhibit histone acetyltransferase activity, inhibit BRD4 activity or combinations thereof, as compared to a normal control at the enhancer sequence.
4. The method of claim 3 , wherein the agent that inhibits acylation of a TGFβ2 enhancer sequence or promotes deacetylation of a TGFβ2 enhancer sequence is an inhibitor of CBP/P300.
5. The method of claim 1 , wherein the agent that inhibits acylation of a TGFβ2 enhancer sequence or promotes deacetylation of a TGFβ2 enhancer sequence is a histone deacetylase (HDAC).
6. The method of claim 3 , wherein an inhibitor of BRD4 is JQ1.
7. The method of claim 1 , further comprising an agent that modulates NF-κB activity.
8. The method of claim 6 , wherein the agent inhibits NF-κB activity.
9. The method of claim 1 wherein the subject has a transforming growth factor β2-associated disease, disorder and/or condition.
10. The method of claim 9 , wherein a fibrotic synthetic repertoire (FSR) comprising one or more pro-fibrotic markers, is diagnostic of a transforming growth factor β2-associated disease, disorder and/or condition.
11. The method of claim 9 , wherein an FSR comprises expression of one or more markers comprising COL1A1, SERPINH1 or combinations thereof, and/or TGFβ2 expression.
12. The method of claim 9 , wherein the transforming growth factor β2-associated disease, disorder and/or condition is Scleroderma and/or a fibrotic disease.