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Compositions and methods for treating neurodegenerative diseases and cardiomyopathy

a neurodegenerative disease and cardiomyopathy technology, applied in the field of compositions and methods for treating neurodegenerative diseases and cardiomyopathy, can solve the problem that no disease modifying therapy is currently approved to treat, and achieve the effect of increasing the activity of pink1

Inactive Publication Date: 2016-04-21
MITOKININ INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a way to increase the activity of a protein called PINK1 in cells. This may be useful for developing therapies for certain neurological conditions. The method involves using a new substance that can activate PINK1, and it appears to be effective in mouse cells.

Problems solved by technology

Parkinson's Disease (PD) is one of the most common neurodegenerative disorders, however no disease modifying therapies are currently approved to treat PD.

Method used

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  • Compositions and methods for treating neurodegenerative diseases and cardiomyopathy
  • Compositions and methods for treating neurodegenerative diseases and cardiomyopathy
  • Compositions and methods for treating neurodegenerative diseases and cardiomyopathy

Examples

Experimental program
Comparison scheme
Effect test

example 6.1

Characterize Amplification of PINK1 Kinase Activity in Cardiomyocyte Cell Lines

[0401]Kinetin mediated PINK1 activity amplification was characterized using a variety of cell lines and primary cells. The HL-1 cell line, an established cardiomyocyte cell line that retains characteristic properties of differentiated cardiac tissue (Claycomb et al., 1998) as well as freshly isolated cardiomyocytes from PINK1 wt or PINK1− / − mice. Infected HL-1 cells with a lentivirus expressing shRNA targeting PINK1, were developed to generate a PINK1 knockdown control. To analyze the amplification of PINK1 kinase activity we analyzed the phosphorylation level of Bcl-xL, Mfn2, and Parkin following treatment of PINK1wt and PINK1 knockdown or − / −cell lines with DMSO or 25 μM adenine, kinetin or 9-methyl kinetin (9MK negative control) and fCCCP for three to twenty-four hours following published protocols (Arena et al., 2013; Chen and Dorn, 2013; Kondapalli et al., 2012). Neuronal cell lines treated with kine...

example 6.2

Characterize Amplification of PINK1 Kinase Activity in Animal Models of Heart Failure

[0404]PINK1 expression is protective in several mouse models of heart failure. PINK1 wt expression will block pathological hypertrophy, increase heart fractional shortening, and prevent ischemia induced death of heart tissue. To assay the effect of kinetin PINK1wt or PINK1− / − mice were treated with vehicle, adenine or kinetin from birth following published protocols for administration of kinetin (Hims et al., 2007; Shetty et al., 2011). The mice were sacrificed and whole hearts analyzed, and isolated cardiomyocytes from mice at appropriate time periods (e.g. 2 and 6 months). O2 consumption, mitochondrial integrity (mtDNA abundance, mitochondrial capacity and JC-1 fluorescence) caspase 3 / 7 cleavage activity and TUNEL staining were measured to assess the health of these tissues. According to published results (Billia et al., 2011; Chen and Dorn, 2013), PINK1 activity is essential for normal 02 consump...

example 6

REFERENCES (EXAMPLE 6)

[0408]Arena, G., Gelmetti, V., Torosantucci, L., Vignone, D., Lamorte, G., De Rosa, P., Cilia, E., Jonas, E. A., and Valente, E. M. (2013). PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage. Cell Death Differ., in press.[0409]Billia, F., Hauck, L., Konecny, F., Rao, V., Shen, J., and Mak, T. W. (2011). PTEN-inducible kinase 1 (PINK1) / Park6 is indispensable for normal heart function. Proc Natl Acad Sci USA 108, 9572-9577.[0410]Chen, Y., and Dorn, G. W., 2nd (2013). PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471-475.[0411]Chen, Y., Liu, Y., and Dorn, G. W., 2nd (2011). Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109, 1327-1331.[0412]Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., and Guo, M. (2006). Drosophila pink1 i...

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Abstract

Disclosed herein inter alia are compositions and methods useful in the treatment neurodegenerative diseases and cardiomyopathy, and for modulating the activity of PINK1.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a continuation of international application PCT / US2014 / 015863, filed Feb. 11, 2014, which claims priority to U.S. Patent Application No. 61 / 763,444, filed Feb. 11, 2013 and to U.S. Patent Application No. 61 / 845,529, filed Jul. 12, 2103.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with government support under grant no. R01 EB1987, awarded by the National Institutes of Health. The government has certain rights in the invention.REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE[0003]The Sequence Listing written in file 48536-533N01_ST25.TXT, created Oct. 21, 2015, 13,356 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference.BACKGROUND OF THE INVENTION[0004]Studies have correlated mitochondrial function with the disease of cardiomyopathy and for n...

Claims

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Application Information

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IPC IPC(8): C07D473/34
CPCC07D473/34A61P25/00A61P9/00
Inventor HERTZ, NICHOLAS T.SHOKAT, KEVAN M.DEVITA, ROBERT
Owner MITOKININ INC
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