Use of a small native peptide activator of SERCA pump for treatment of heart failure and other disorders characterized by cytosolic calcium overload
The present disclosure describes a new native peptide designated herein as Dwarf Open Reading Frame, or DWORF. This peptide enhances the apparent activity of the SERCA pump, is positively inotropic and lusitropic, and therefore is provided as a therapeutic agent for disorders characterized by cytosolic calcium overload.
1. A method of promoting the activity of the SERCA calcium pump in a cardiac cell in a subject in need thereof comprising contacting said SERCA pump with Dworf open reading frame (DWORF) or the sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7 and SEQ ID NO: 9, wherein said subject suffers from a disorder characterized by or comprised of cytosolic calcium overload.
2. The method of claim 1 , wherein DWORF has a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7 and SEQ ID NO: 9.
3. The method of claim 1 , wherein DWORF is linked to a heterologous peptide or polypeptide segment.
4. The method of claim 1 , wherein DWORF is contacted as a peptide or polypeptide.
5. The method of claim 1 , wherein DWORF is contacted by expression of a nucleic acid segment encoding DWORF, said nucleic acid segment being under the control of a promoter active in eukaryotic cells.
6. The method of claim 1 , further comprising contacting the SERCA calcium pump with a second SERCA activating agent.
7. The method of claim 1 , wherein contacting occurs at least a second time.
8. The method of claim 1 , wherein DWORF is provided to said subject intravenously, intradermally, intraarterially, intraperitoneally, intranasally, topically, intramuscularly, subcutaneously, mucosally, intrapericardially, intraumbilically, orally, via injection, via infusion, via continuous infusion, via a catheter, via a lavage, in creams, or in lipid compositions.
9. The method of claim 3 , wherein the heterologous peptide or polypeptide segment is HIV TAT.
10. The method of claim 5 , wherein said nucleic acid segment is provided as naked DNA or modified mRNA.
11. The method of claim 5 , wherein said nucleic acid segment is provided in a viral particle.
12. The method of claim 5 , wherein said nucleic acid segment is provided as a non-viral expression construct in a nanoparticle, microparticle or lipid vehicle.
13. The method of claim 1 , wherein said subject is a non-human mammal.
14. The method of claim 1 , wherein the said subject is a human.
15. The method of claim 1 , wherein contacting occurs more than one.
16. The method of claim 1 , wherein said disorder is selected from the group consisting of heart failure, restenosis and muscular dystrophy.
17. The method of claim 16 , further comprising administering to said subject a second therapy for heart failure, restenosis or muscular dystrophy.