Method and apparatus for device controlled gene expression for cardiac protection

• US 20070054871A1
• Filed: 09/06/2005
• Published: 03/08/2007
• Est. Priority Date: 09/06/2005
• Status: Active Grant

• Current Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Original Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Inventors: Spinelli, Julio, Pastore, Joseph, Salo, Rodney, Ross, Jeffrey, Kramer, Andrew, Baynham, Tamara
• Granted Patent: US 7,774,057 B2
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• 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 1/36514 controlled by a physiological quantity other than heart potential, e.g. blood pressure controlled by two or more physical parameters A61N1/36585

Abstract

A gene regulatory system detects ischemia events and is capable of delivering a biologic therapy in response to the detection of an ischemic event or the reception of a command. The biologic therapy protects the heart from ischemic damage by regulating the expression of an exogenously introduced gene product. In one embodiment, the gene regulatory system includes an implantable system that emits at least one gene regulatory signal in response to the detection of the ischemic event or the reception of the command. The gene regulatory signal directly or indirectly regulates gene expression of the gene product.

Claims

1. A gene regulatory system, comprising:

a sensing circuit to sense one or more parameters indicative of an ischemic event;

an ischemia detector, coupled to the sensing circuit, to detect the ischemic event from the one or more parameters;

a gene regulatory signal delivery device adapted to emit at least one gene regulatory signal that directly or indirectly regulates a regulatable transcriptional control element without inducing cardiac depolarization; and

a controller coupled to the ischemia detector and the gene regulatory signal delivery device, the controller being a microprocessor-based control circuit including;

a gene regulatory initiator adapted to initiate one or more cardiac protection biologic therapies in response to the detection of the ischemic event, the one or more cardiac protection biologic therapies each including alternating signaling periods and non-signaling periods, the signaling periods each having a signaling duration during which the at least one gene regulatory signal is emitted, the non-signaling periods each having a non-signaling duration during which the at least one gene regulatory signal is not emitted; and

a gene regulatory timer adapted to time the one or more cardiac protection biologic therapies.

2. The system of claim 1, wherein the gene regulatory signal delivery device comprises an electric field generator adapted to generate an electric field having frequency and strength parameters selected for regulating the regulatable transcriptional control element.

3. The system of claim 1, wherein the gene regulatory signal delivery device comprises an electromagnetic field generator adapted to generate an electromagnetic field having frequency and strength parameters selected for regulating the regulatable transcriptional control element.

4. The system of claim 1, wherein the gene regulatory signal delivery device comprises an optical emitter adapted to emit a light having wavelength and intensity parameters selected for regulating the regulatable transcriptional control element.

5. The system of claim 1, wherein the gene regulatory signal delivery device comprises an acoustic emitter adapted to emit an acoustic signal having frequency and intensity parameters selected for regulating the regulatable transcriptional control element.

6. The system of claim 1, wherein the gene regulatory signal delivery device comprises a drug delivery device adapted to emit one or more chemical agents regulating the regulatable transcriptional control element.

7. The system of claim 1, wherein the gene regulatory signal delivery device comprises a thermal radiator adapted to emit a thermal energy for regulating the regulatable transcriptional control element.

8. The system of claim 1, wherein the gene regulatory initiator comprises a postconditioning initiator adapted to initiate at least one postconditioning cardiac biologic therapy after an end of the ischemic event is detected by the ischemia detector, the postconditioning cardiac biologic therapy being one of the one or more cardiac protection biologic therapies.

9. The system of claim 8, wherein the postconditioning initiator is adapted to initiate the at least one postconditioning cardiac biologic therapy when a post-ischemia time interval expires, the post-ischemia time interval starting when the end of the ischemic event is detected by the ischemia detector.

10. The system of claim 8, wherein the gene regulatory initiator comprises a preconditioning initiator adapted to initiate a plurality of preconditioning cardiac biologic therapies in response to the detection of the ischemic event, the preconditioning cardiac biologic therapies each being one of the one or more cardiac protection biologic therapies.

11. The system of claim 10, wherein the preconditioning initiator is adapted to initiate the preconditioning cardiac biologic therapies on a periodic basis using a predetermined period.

12. The system of claim 10, wherein the preconditioning initiator is adapted to initiate the preconditioning cardiac biologic therapies in response to one or more preconditioning commands.

13. The system of claim 1, wherein the controller is adapted to detect an arrhythmia and to suspend the one or more cardiac protection biologic therapies in response to the detection of the arrhythmia.

14. The system of claim 1, further comprising an implantable medical device including at least the ischemia detector and the controller, the ischemia detector adapted to produce an ischemia alert signal indicative of the detection of the ischemic event, the implantable medical device adapted to produce an audible alarm signal in response to the ischemia alert signal.

15. The system of claim 1, further comprising:

an implantable medical device including at least the ischemia detector and the controller, the ischemia detector adapted to produce an ischemia alert signal indicative of the detection of the ischemic event; and

an external system communicatively coupled to the implantable medical device, the external system comprises;

an external controller adapted to receive the ischemia alert signal; and

a presentation device configured to present at least one of an alarm signal and a warning message in response to the ischemia alert signal.

16. The system of claim 15, wherein the external system comprises a user input device to receive one or more gene regulatory commands, and the gene regulatory initiator is adapted to initiate the one or more cardiac protection biologic therapies in response to the detection of the ischemic event and the one or more gene regulatory commands.

30. A method to control expression of at least one exogenously introduced expression cassette which includes a regulatable transcriptional control element operably linked to an open reading frame in a mammal at risk of an ischemic event, comprising:

providing a mammal comprising the system of claim 1 or 17, which mammal is at risk of an ischemic event;

introducing to the mammal at least one expression cassette which includes a transcriptional control element directly or indirectly regulated by the emitted signal operably linked to an open reading frame, the expression of which in an effective amount is capable of preventing, inhibiting or treating an ischemic event; and

directing signal emission in response to detection of the event so as to control expression of the open reading frame.

31. A method to control expression of at least one exogenously introduced expression cassette which includes a regulatable transcriptional control element operably linked to an open reading frame in a mammal at risk of an ischemic event, comprising:

providing a mammal comprising at least one exogenously introduced expression cassette which includes a transcriptional control element directly or indirectly regulated by a signal operably linked to an open reading frame, the expression of which in an effective amount is capable of preventing, inhibiting or treating an ischemic event, which mammal is at risk of the event;

introducing to the mammal the system of claim 1 or 17, wherein the emitted signal directly or indirectly regulates the transcriptional control element and thereby the expression of the open reading frame; and

directing signal emission in response to detection of the event so as to control expression of the open reading frame.

17. A system, comprising:

an implantable medical device system including;

an implant telemetry module to receive an external command;

a gene regulatory signal delivery device adapted to emit at least one gene regulatory signal which directly or indirectly regulates a regulatable transcriptional control element without inducing cardiac depolarization; and

an implant controller coupled to the ischemia detector and the implant telemetry module, the implant controller including a gene regulatory control module adapted to initiate and control the emission of the at least one gene regulatory signal based on the external command, the gene regulatory control module including;

a gene regulatory initiator adapted to initiate one or more cardiac protection biologic therapies in response to the reception of the external command, the one or more cardiac protection biologic therapies each including at least one signaling period and at least one non-signaling period, wherein each signaling period has a signaling duration during which the at least one gene regulatory signal is emitted and each non-signaling period has a non-signaling duration during which the at least one gene regulatory signal is not emitted; and

a gene regulatory timer adapted to time the one or more cardiac protection biologic therapies; and

an external system including an external telemetry module to transmit the external command to the implant telemetry module.

18. The system of claim 17, further comprising:

a sensor to sense a physiological parameter indicative of an ischemic event; and

an ischemia detector, coupled to the sensor, to detect the ischemic event from the sensed physiological parameter, and

wherein the gene regulatory control module is adapted to initiate and control the emission of the at least one gene regulatory signal based on one or more of the sensed physiological parameter and the external command, and the gene regulatory initiator is adapted to initiate the one or more cardiac protection biologic therapies in response to one or more of the reception of the external command and the detection of the ischemic event.

19. A method for cardiac protection, the method comprising:

sensing one or more parameters indicative of an ischemic event in a mammal;

detecting the ischemic event from the one or more parameters;

initiating one or more cardiac protection biologic therapies in response to the detection of the ischemic event, the one or more cardiac protection biologic therapies each including at least one signaling and non-signaling period, the at least one signaling period having a signaling duration during which at least one gene regulatory signal is delivered, the at least one non-signaling period having a non-signaling duration during which the at least one gene regulatory signal is not delivered, the at least one gene regulatory signal is capable of directly or indirectly regulating a regulatable transcriptional control element without inducing cardiac depolarization, the regulatable transcriptional control element is operably linked to an open reading frame forming an expression cassette, wherein the expression cassette is present in the mammal, and wherein expression of the open reading frame in an effective amount inhibits damage to tissue in the mammal resulting from ischemia; and

delivering the at least one gene regulatory signal during at least one of the signaling periods.

20. The method of claim 19, wherein the one or more cardiac protection biologic therapies comprise at least one postconditioning cardiac biologic therapy, and further comprise initiating the at least one postconditioning cardiac biologic therapy after an end of the ischemic event is detected.

21. The method of claim 20, wherein initiating the at least one postconditioning cardiac biologic therapy comprises initiating the at least one postconditioning cardiac biologic therapy when a post-ischemia time interval expires, the post-ischemia time interval starting when the end of the ischemic event is detected and is up to approximately 10 minutes.

22. The method of claim 20, further comprising timing the at least one postconditioning cardiac biologic therapy including alternating postconditioning signaling and non-signaling periods, the at least one postconditioning cardiac biologic therapy having a postconditioning therapy duration in a range of approximately 30 seconds to 1 hour, the postconditioning signaling period having a postconditioning signal duration in a range of approximately 5 seconds to 10 minutes during which the at least one gene regulatory signal is delivered, the postconditioning non-signaling period having a postconditioning non-signal duration in a range of approximately 5 seconds to 10 minutes during which the at least one gene regulatory signal is not delivered.

23. The method of claim 20, wherein the one or more cardiac protection biologic therapies further comprise a plurality of preconditioning cardiac biologic therapies, and further comprising initiating the preconditioning cardiac biologic therapies after the postconditioning cardiac biologic therapy is completed.

24. The method of claim 23, wherein initiating the preconditioning cardiac biologic therapies comprises initiating the preconditioning cardiac biologic therapies on a periodic basis using a predetermined period in a range of approximately 24 hours to 72 hours.

25. The method of claim 23, wherein initiating the preconditioning cardiac biologic therapies comprises initiating the preconditioning cardiac biologic therapies in response to one or more preconditioning commands.

26. The method of claim 23, further comprising timing the plurality of preconditioning cardiac biologic therapies each including alternating preconditioning signaling and non-signaling periods, the preconditioning cardiac biologic therapies each having a preconditioning therapy duration in a range of approximately 2 minutes to 1 hour, the preconditioning signaling period each having a preconditioning signal duration in a range of approximately 1 minute to 30 minutes during which the at least one gene regulatory signal is delivered, the preconditioning non-signaling period having a preconditioning non-signal duration in a range of approximately 1 minute to 30 minutes during which the at least one gene regulatory signal is not delivered.

27. The method of claim 19, further comprising:

detecting an arrhythmia; and

suspending the one or more cardiac protection biologic therapies when the arrhythmia is detected.

28. A method for cardiac protection, the method comprising:

receiving a command;

initiating one or more cardiac protection biologic therapies in response to the reception of the command, the one or more cardiac protection biologic therapies each including at least one signaling and non-signaling period, the at least one signaling period having a signaling duration during which at least one gene regulatory signal is delivered, the at least one non-signaling period having a non-signaling duration during which the at least one gene regulatory signal is not delivered, the at least one gene regulatory signal is capable of directly or indirectly regulating a regulatable transcriptional control element without inducing cardiac depolarization, the regulatable transcriptional control element is operably linked to an open reading frame forming an expression cassette, wherein the expression cassette is present in the mammal, and wherein expression of the open reading frame in an effective amount inhibits damage to cardiac tissue resulting from ischemia; and

delivering the at least one gene regulatory signal during at least one of the signaling periods.

29. The method of claim 28, further comprising:

sensing one or more parameters indicative of an ischemic event; and

detecting the ischemic event from the one or more parameters,

wherein initiating the one or more cardiac protection biologic therapies comprise initiating the one or more cardiac protection biologic therapies in response to one or more of the reception of the command and the detection of the ischemic event.