Calmodulin inhibitors for the treatment of ribosomal disorders and ribosomapathies
The present invention relates generally to methods, compositions and kits for treatment of ribosomal disorders and ribosomopathy, e.g. Diamond Blackfan anemia (DBA). In some embodiments, the invention relates to methods for the use of calmodulin inhibitors and calcium channel blockers for treatment of ribosomal disorders and ribosomopathy, e.g. Diamond Blackfan anemia (DBA).
1. A method of treating a subject with Diamond Blackfan Anemia (DBA), comprising administering an effective amount of a phenothiazine compound or CGS-9343 (zaldaride maleate) or a functional derivative or analog thereof to the subject to decrease p53 or p21 in at least one of CD34+ cells, erythroid cells or erythroid differentiated cells in the subject.
2. The method of claim 1 , wherein the phenothiazine compound is trifluoperazine (TFP) or a functional derivative or analog of a compound with the following structure:
3. The method of claim 1 , wherein the phenothiazine compound is fluphenazine or a functional derivative or analog of a compound with the following structure:
4. The method of claim 1 , wherein the phenothiazine compound is perphenazine or a functional derivative or analog of a compound with the following structure:
5. The method of claim 1 , wherein the functional derivative or analog of CGS-9343 (zaldaride maleate) is a functional derivative or analog of a compound with the following structure:
wherein the functional derivative or analog of CGS-9343 decreases p53 or p21 in at least one of CD34+ cells, erythroid cells or erythroid differentiated cells in the subject.
6. The method of claim 1 , wherein the subject has DBA1, DBA2, DBA3, DBA4, DBA5, DBA6, DBA7, or DBA8.
7. The method of claim 1 , wherein the subject has a mutation in ribosomal protein 19 (RPS19).
8. The method of claim 1 , wherein the subject has a mutation in ribosomal protein selected from RPS7, RPS10, RPS19, RPS24, PRS26, RPS17, PRS27L RPS29, RPL35A, PRL5 and PPL11.
9. The method of claim 1 , wherein the subject has a mutation in a ribosomal protein selected from the group consisting of: rPL2A, rPL2B, rPL3, rpL4A, rPL4B, rPL7A, rPL7B, rPL10, rPL11, rPL16A, rPL17A, rPL17B, rPL18A, rPL18B, Rp119A, rPL19, rPL25, rPL29, rpL31A, rpL31B, rPL36A, rPL40A, rPS1A, rPS6A, rPS6B, rPS14A, rPS15, rPS19, rPS23B, rPS25A, rPS26B, rPS29, rPS29B and rPS31.
10. The method of claim 1 , wherein the subject is administered another therapeutic agent to treat the ribosomal protein defect, selected from the group consisting of: corticosteroids, blood transfusions.
11. The method of claim 1 , wherein the phenothiazine compound increases the number of CD71+ erythroid cells in the subject, or increase the hemoglobin levels in the subject, or both.