LIM kinasemodulating agents for neurofibromatoses therapy and methods for screening for same
Disclosed herein are methods of treating a patient at risk of developing or having a neurofibromatosis or a sporadic schwannoma. In exemplary embodiments, the method involves administering to a subject in need an effective amount of a LIMK modulating agent. Also disclosed are compounds newly identified to be inhibitors of Merlin-null Schwann cell proliferation and/or survival.
1. A method for treating a neurofibromatosis in a subject, the method comprising administering to the subject an effective amount of a LIMK modulating agent, wherein the LIMK modulating agent specifically inhibits activity of LIMK-1 (SEQ ID NO. 1), wherein the neurofibromatosis comprises a tumor of Schwann cell origin.
2. The method of claim 1 , wherein the neurofibromatosis is type 1 Neurofibromatosis (NF1).
3. The method of claim 1 , wherein the neurofibromatosis is type 2 Neurofibromatosis (NF2).
4. The method of claim 1 , wherein the neurofibromatosis is Schwannomatosis.
5. The method of claim 1 , wherein the neurofibromatosis includes sporadic Schwannoma.
6. The method of claim 1 , wherein the LIMK modulating agent is selected from the group consisting of a ribozyme, an interfering molecule, a peptide, a small molecule, an antibody targeted to LIMK, and combinations thereof.
7. The method of claim 6 , wherein the LIMK modulating agent comprises BMS-5 or prodrug, analog, derivative, metabolite, and/or pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the LIMK modulating agent comprises an interfering molecule, and wherein the interfering molecule comprises a member selected from the group consisting of a phosphothioate morpholino oligomer (PMO), miRNA, sRNA, methylated sRNA, treated siRNAs, shRNA, antisense RNA, a dicer-substrate 27-mer duplex, and combinations thereof.
9. The method of claim 1 , wherein the subject exhibits a symptom of a neurofibromatosis.
10. The method of claim 9 , wherein the symptom comprises a presence of multiple coffee-colored patches on a skin of the subject, hearing loss or disequilibrium, or a combination thereof.
11. The method of claim 1 , wherein the LIMK modulating agent comprises BMS-5, or prodrug, analog, derivative, metabolite, and/or pharmaceutically acceptable salt thereof.
12. A method of inhibiting Schwann cell proliferation in a subject comprising administering an effective amount of an LIMK modulating agent, or prodrug, analog, derivative, metabolite, and/or pharmaceutically acceptable salt thereof, to the subject to inhibit the expression or action of LIMK (SEQ ID NO. 1).
13. The method of claim 12 , wherein the LIMK modulating agent is selected from the group consisting of a ribozyme, an interfering molecule, a peptide, a small molecule, or an antibody targeted to LIMK.
14. The method of claim 12 , wherein the LIMK modulating agent comprises BMS-5, or prodrug, analog, derivative, metabolite, and/or pharmaceutically acceptable salt thereof.
15. The method of claim 12 , wherein the LIMK modulating agent comprises an interfering molecule.
16. The method of claim 15 , wherein the interfering molecule comprises a member selected from the group consisting of a phosphothioate morpholino oligomer (PMO), miRNA, sRNA, methylated sRNA, treated siRNAs, shRNA, antisense RNA, a dicer-substrate 27-mer duplex, and any combination thereof.