Protein activity modification

• US 8,548,583 B2
• Filed: 05/04/2006
• Issued: 10/01/2013
• Est. Priority Date: 03/10/2004
• Status: Active Grant

• Current Assignee: Impulse Dynamics NV
• Original Assignee: Impulse Dynamics NV
• Inventors: Rousso, Benny, Mika, Yuval, Ben-Haim, Shlomo, Sabbah, Hani N.
• Primary Examiner(s): Koharski, Christopher D
• Assistant Examiner(s): VOORHEES, CATHERINE M
• Application Number:
  US11/919,491
• Publication Number:
  US 20100016923A1
• Time in Patent Office: 2,707 Days
• Field of Search: 607/9, 607/22, 607/59, 607/62, 607 50- 52, 607/92, 607/164, 607 1- 5, 600 9- 15
• US Class Current: 607/3
• CPC Class Codes: A61N 1/205 for promoting a biological process
• CPC Class Codes: A61N 1/32 alternating or intermittent currents applying electric fields by inductive or capacitive coupling A61N1/40; microwave apparatus A61N5/02
• CPC Class Codes: A61N 1/3627 for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy
• CPC Class Codes: A61N 1/3628 using sub-threshold or non-excitatory signals
• CPC Class Codes: A61N 1/3629 in combination with non-electric therapy
• CPC Class Codes: A61N 2/004 specially adapted for a specific therapy
• CPC Class Codes: C12N 13/00 Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/112 Disease subtyping, staging or classification
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2800/325 Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

A method of modifying tissue behavior, comprising:

• • determining a desired modification of tissue behavior for at least one of treatment of a disease, short or long term modification of tissue behavior, assessing tissue state and assessing tissue response to stimulation;
  • selecting an electric field having an expected effect of modifying protein activity of at least one protein as an immediate response of a tissue to the field, said expected effect correlated with said desired modification; and
  • applying said field to said tissue.

Claims

1. A method of modifying tissue behavior, comprising:

determining a desired modification of tissue behavior for at least one of treatment of a disease, short or long term modification of tissue behavior, assessing tissue state and assessing tissue response to stimulation;

selecting an electric field having an expected effect of modifying protein activity of at least one protein, previously existing in the cell, by electrically inducing chemical modification thereof, as an immediate response of a tissue to the field, said expected effect correlated with said desired modification; and

applying said field to said tissue,

wherein modifying protein activity comprises attaching or detaching a cofactor to at least one of said at least one protein; and

wherein said immediate response comprises a response within less than 1 minute.

2. A method according to claim 1, wherein said tissue comprises cardiac tissue.

3. A method according to claim 1, wherein said at least one protein comprises phospholamban.

4. A method according to claim 1, wherein said attaching or detaching comprises phosphorylation.

5. A method according to claim 1, wherein said attaching or detaching comprises dephosphorylation.

6. A method according to claim 1, wherein said modification of protein activity comprises a long term modification which comprises changes in protein expression levels.

7. A method according to claim 1, wherein said treatment of a disease comprises reversing a heart failure state in said tissue.

8. A method according to claim 1, comprising:

programming a controller of a therapeutic device to apply said electric field as a sequence of electric field applications.

9. A method according to claim 1, comprising

selectively applying a therapy material to said tissue prior to said applying said field and wherein said applying said field interacts with said material.

10. A method according to claim 1, comprising

stopping said applying for a length of time which is a function of an expected washout time of said expected effect of said field.

11. A method according to claim 10, wherein said desired modification is a long-term modification.

12. A method according to claim 1, wherein said desired modification is a non-immediate modification measured by a change in one or more of ejection fraction, cardiac muscle dimension, cardiac chamber dimension, quality of life as measured by a questionnaire, peak oxygen consumption, anaerobic threshold, 6 minute walk distance, fluid retention, sleep apnea severity, and exercise tolerance.

13. A method according to claim 1, wherein said applying, comprises:

applying a test therapy at a therapy location placement to the tissue; and

deciding on suitability of the therapy location placement based on an effect on protein activity levels of said test therapy.

14. A method according to claim 13, wherein said deciding comprises

deciding on suitability of the therapy location placement based on an effect on protein activity levels of said test therapy, even if an improvement in organ function is sought and not detected.

15. A method according to claim 1, comprising:

selecting at least one location of treatment for said applying, according to a desired propagation of biochemical effect of said treatment in said tissue.

16. A method according to claim 1, wherein said applying comprises

applying said field at a first location of said tissue, comprising:

determining if the field is having a first effect by measuring a short term response at said first location; and

determining if the field is having a second, desired, effect by measuring a long-term response at a second, untreated, location of said tissue.

17. A method according to claim 1, wherein said tissue is cardiac tissue, comprising:

selecting said tissue to be tissue with reduced oxygen transport thereto, wherein said applying comprises

applying said field to said tissue, such that said field does not reduce activity thereof.

18. A method according to claim 1, wherein said tissue is cardiac tissue and wherein said modifying tissue behavior comprises treating cardiac dysfunction and wherein said applying comprising applying an electric field to a heart which is sufficient to have a significant normalization effect on protein phosphorylation levels without significant effect on contractility.

19. A method according to claim 1, wherein said selecting comprises selecting an electric field according to its not being expected to increase mean oxygen consumption;

and wherein said applying comprises applying said electric field with said signal to cardiac tissue, which field does not reduce activity thereof.

20. A method according to claim 1, wherein said modifying protein activity comprises improving protein activity of in vivo diseased cardiac tissue.

21. A method according to claim 1, wherein said modifying protein activity comprises normalizing protein activity of in vivo diseased cardiac tissue.

22. A method according to claim 1, wherein said applying comprises applying by an implanted device to tissue which is part of an in-vivo heart.

23. A method according to claim 1, wherein said selecting comprises selecting said field to increase contractility in immediate response to said field.

24. A method according to claim 1, wherein said selecting comprises selecting said field and applying said field in a manner which does not provide a significant acute effect on contractility.

25. A method according to claim 1, wherein said field comprises a field of between 3 and 10 Volts, comprises of a train of at least 2 biphasic pulses, each phase having a duration of about 5.5 milliseconds.

26. A method according to claim 25, wherein said field is applied for less than 100 milliseconds per beat.

27. A method according to claim 1, wherein said field comprises a train of at least 4 pulses, each with an energy of at least 2000 microjoules, applied in an absolute refractory period.

28. A method according to claim 1, wherein said at least one protein comprises a plurality of proteins.

29. A method according to claim 28, wherein said plurality of proteins belong to at least 2 separate biochemical control pathways.

30. A method according to claim 1, wherein said modifying is a persistent modification lasting at least 100 times the length of said applying.

31. A method according to claim 1, wherein said modifying comprises modifying a ratio between protein configurations of different activation levels of at least one of said at least one protein by a factor of at least 1.2.

32. A method according to claim 1, wherein said selecting comprises selecting an electric field having an expected effect of modifying protein activity of at least one non-ion transport protein, as an immediate response of a tissue to the field, said expected effect correlated with said desired modification.

33. A method of modifying tissue behavior, comprising:

determining a desired modification of tissue behavior for at least one of treatment of a disease, short or long term modification of tissue behavior, assessing tissue state and assessing tissue response to stimulation;

selecting a tissue modifying activity having an expected effect of modifying protein activation levels of at least one protein, previously existing in the cell, by electrically inducing chemical modification thereof, as an immediate response of a tissue to the activity, said expected effect correlated with said desired modification; and

applying said activity to said tissue,

wherein modifying protein activation comprises attaching or detaching a cofactor to at least one of said at least one protein; and

wherein said immediate response comprises a response within less than 1 minute.

34. A method of treating cardiac dysfunction, comprising:

determining a desired effect on protein activity, comprising electrically induced chemical modification of a protein; and

applying an electric, electro-magnetic or electrostatic field to cardiac tissue to cause such desired change,

wherein modifying protein activity comprises attaching or detaching a cofactor to at least one of said at least one protein; and

wherein said modifying includes an immediate response comprises a response within less than 1 minute.

35. A method of treating tissue, comprising:

determining a desired effect on levels of phosphorylation of phospholamban; and

applying an electric, electro-magnetic or electrostatic field to tissue for which said effect on levels of phosphorylation of phospholamban is desired, said applying configured to cause such desired effect including an effect of changing levels of phosphorylation of phospholamban within less than 1 minute.