MODULATION OF SIRTUINS BY VAGUS NERVE STIMULATION

• US 20130079834A1
• Filed: 12/27/2011
• Published: 03/28/2013
• Est. Priority Date: 09/23/2011
• Status: Active Grant

• Current Assignee: Setpoint Medical Corporation
• Original Assignee: Setpoint Medical Corporation
• Inventors: Levine, Jacob A.
• Granted Patent: US 9,833,621 B2
• Time in Patent Office: Days
• US Class Current: 607/3
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61N 1/36053 adapted for vagal stimulation A61N1/36114 takes precedence
• CPC Class Codes: A61N 1/36146 specified by the stimulation parameters

Abstract

Systems, devices and methods for modulation of sirtuins by neurostimulation. In particular, sirtuins may be modulated by stimulation of the vagus nerve. Further described herein generally are methods, systems and devices, for specifically modulating sirtuins, including sub-sets (types or localized regions) of sirtuins by vagus nerve stimulation (VNS).

Claims

1. A method of modulating SIRT activity and/or level in a patient, the method comprising modulating SIRT activity and/or level by applying stimulation to a subject'"'"'s vagus nerve from an implanted micro stimulator.

2. The method of claim 1, wherein applying comprises applying stimulation from the microstimulator to the vagus nerve to modulate SIRT activity and/or level to treat cancer, to enhance longevity, to treat a metabolic syndrome, to treat or prevent liver cirrhosis/fatty liver, to treat or prevent muscle disorders such as Sarcopenia or disuse atrophy, to treat a circadian rhythm disorder, to treat insomnia, and/or to treat a CNS disorder including Alzheimer'"'"'s, Parkinson'"'"'s, or Huntington'"'"'s diseases.

3. The method of claim 1, further comprising applying stimulation in conjunction with one or more active agents selected from the group consisting of:

drugs, medical food, probiotics.

4. The method of claim 1, wherein applying stimulation comprises applying electrical VNS having an amplitude of greater than about 1000 μ

A.

5. The method of claim 1, wherein applying stimulation comprises applying electrical VNS having an amplitude of between about 150 μ

A and 5 mA, a pulse width of between about 50 μ

sec and 1 msec, a frequency of between about 1 Hz and 100 Hz, a duration of between about 1 sec and 5 min, an interpulse interval of between about 10 μ

sec and about 950 μ

sec.

6. The method of claim 1, wherein applying stimulation comprises applying electrical stimulation sufficient to modulate only a sub-set of SIRTs without substantially modulating another sub-set of SIRTs.

7. The method of claim 1, wherein applying stimulation comprises applying repeated electrical stimulation separated by an off-time of greater than about 8 hours.

8. The method of claim 1, wherein applying comprises applying extremely low duty cycle electrical energy.

9. The method of claim 1, wherein applying comprises applying stimulation from the microstimulator to the vagus nerve to modify the patient'"'"'s circadian cycles by modulating SIRT activity and/or level.

10. A method of treating a disorder by modulating SIRT activity and/or level in a patient, the method comprising modulating SIRT activity and/or level by applying stimulation from a stimulator to stimulate the vagus nerve.

11. The method of claim 10, further comprising modifying the stimulation based on feedback from one or more biomarker.

12. The method of claim 11, wherein the feedback is feedback from one or more of:

SIRT and circadian rhythm biomarkers.

13. The method of claim 11, wherein modifying the stimulation comprises modifying one or more of the time, duration, frequency, intensity, and/or interval of an electrical stimulation.

14. The method of claim 10, further comprising applying stimulation in conjunction with one or more active agents selected from the group consisting of:

drugs, medical food, probiotics.

15. The method of claim 10, wherein applying stimulation comprises applying electrical VNS having an amplitude of greater than about 1000 μ

A.

16. The method of claim 10, wherein applying stimulation comprises applying electrical VNS having an amplitude of between about 150 μ

A and 5 mA, a pulse width of between about 50 μ

sec and 1 msec, a frequency of between about 1 Hz and 100 Hz, a duration of between about 1 sec and 5 min, an interpulse interval of between about 10 μ

sec and about 950 μ

sec.

17. The method of claim 10, wherein applying stimulation comprises applying electrical stimulation sufficient to modulate only a sub-set of SIRTs without substantially modulating another sub-set of SIRTs.

18. The method of claim 10, wherein applying stimulation comprises applying repeated electrical stimulation separated by an off-time of greater than about 8 hours.

19. The method of claim 10, wherein applying comprises applying extremely low duty cycle electrical energy.

20. The method of claim 10, wherein applying comprises applying stimulation from an implanted microstimulator to the vagus nerve.

21. The method of claim 10, further comprising coordinating the application of stimulation from the stimulator based on the patient'"'"'s circadian rhythm.

22. The method of claim 21, wherein coordinating comprises synchronization or asynchronization of stimulation with circadian rhythm to modulate disease.

23. The method of claim 10, wherein modulating SIRT activity and/or level includes modifying the activity and/or level of a plurality of different sirtuins.

24. The method of claim 23, wherein the plurality of different sirtuins includes SIRT1, SIRT3, SIRT4 and SIRT6.

25. The method of claim 10, wherein modulating SIRT activity and/or level includes increasing the activity and/or level of a first sirtuin and decreasing the activity and/or level of a second sirtuin.

26. A system for treating a disorder in a patient buy modulating SIRT, the system comprising:

a stimulator configured to apply a low duty-cycle stimulation to a vagus nerve; and

a controller configured to set a dose for the stimulator wherein the dose comprises a supra-threshold pulse followed by an off-period of greater than four hours configured to modulate SIRT level and/or activity.

27. The system of claim 26, wherein the stimulator comprises an implantable microstimulator.

28. The system of claim 26, further comprising a controller configured to synchronize the applied stimulation with the patient'"'"'s circadian rhythms.

29. The system of claim 26, further comprising a feedback configured to indicate a subject'"'"'s circadian rhythm.