Method and apparatus for controlled gene or protein delivery

• US 7,729,761 B2
• Filed: 07/14/2004
• Issued: 06/01/2010
• Est. Priority Date: 07/14/2004
• Status: Expired due to Fees

• Current Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Original Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Inventors: Girouard, Steven D., Ross, Jeffrey
• Primary Examiner(s): Layno; Carl H
• Assistant Examiner(s): Gedeon; Brian T
• Application Number:
  US10/890,825
• Publication Number:
  US 20060015146A1
• Time in Patent Office: 2,148 Days
• Field of Search: 607/3, 607/4, 607/14, 604/93.01, 604/20, 604/21
• US Class Current: 607/3
• CPC Class Codes: A61N 1/306 Arrangements where at least part of the apparatus is introduced into the body
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

An implantable system which includes a gene/protein delivery device and a pulse generator, as well as method of preparing the gene/protein delivery device and using the system, are provided. In one embodiment, the implantable system detects a predetermined condition or event and, in response, delivers gene(s) and/or protein(s) in conjunction with delivering pacing and/or defibrillation pulses.

Claims

1. A system, comprising:

an implantable pulse generator including;

a sensor to sense a physiological signal indicative of a predetermined cardiac condition;

an event detector, coupled to the sensor, to detect the predetermined cardiac condition from the physiological signal;

an implant telemetry module to receive an external command transmitted to the implantable pulse generator; and

an implant controller coupled to the event detector and the implant telemetry module, the implant controller including a gene or protein delivery control module configured to produce an electrical signal to control iontophoretic gene or protein delivery in response to the predetermined cardiac condition and the external command;

an implantable lead system including one or more leads, the lead system configured to transmit the electrical signal; and

an implantable gene or protein delivery device electrically wired to the implantable pulse generator through the implantable lead system, the implantable gene or protein delivery device configured to receive the electrical signal and including a polymer matrix and isolated nucleic acid which encodes at least one gene product or binds at least one selected mRNA, or isolated protein, the nucleic acid or protein contained in the polymer matrix and released from the implantable gene or protein delivery device in response to an electric field applied to the polymer matrix, the electric field created by the electrical signal.

2. The system of claim 1, wherein the sensor comprises an electrogram sensing circuit, and the event detector comprises an arrhythmia detector.

3. The system of claim 2, wherein the arrhythmia detector comprises one or more of a bradycardia detector, a tachycardia detector, and a fibrillation detector.

4. The system of claim 3, wherein the fibrillation detector comprises an atrial fibrillation detector.

5. The system of claim 3, wherein the fibrillation detector comprises a ventricular fibrillation detector.

6. The system of claim 1, wherein the sensor comprises a sensor sensing an physiological signal indicative of ischemia, and the event detector comprises an ischemia detector.

7. The system of claim 1, wherein the sensor comprises a metabolic sensor adapted to sense a signal indicative of a cardiac metabolic level.

8. The system of claim 7, wherein the sensor comprises at least one of a pH sensor, an oxygen pressure (PO₂) sensor, a carbon dioxide pressure (PCO₂) sensor, a glucose sensor, a creatine sensor, a C-creative protein sensor, a creatine kinase sensor, and a creatine kinase-MB sensor.

9. The system of claim 1, wherein the sensor comprises an impedance sensor to sense tissue impedance.

10. The system of claim 9, wherein the impedance sensor comprises a pulmonary impedance sensor.

11. The system of claim 10, wherein the impedance sensor comprises a respiratory sensor.

12. The system of claim 1, wherein the sensor comprises a pressure sensor to sense a pressure in a cardiovascular system.

13. The system of claim 12, wherein the pressure sensor comprises at least one of a left atrial pressure sensor, a left ventricular pressure sensor, an artery pressure sensor, and a pulmonary arterial pressure sensor.

14. The system of claim 13, wherein the event detector comprises a systolic dysfunction detector.

15. The system of claim 13, wherein the event detector comprises a diastolic dysfunction detector.

16. The system of claim 1, wherein the sensor comprises a stroke volume sensor.

17. The system of claim 1, wherein the sensor comprises a neural activity sensor.

18. The system of claim 17, wherein the neural activity sensor comprises a neurohormone sensor to sense a neurohormone level.

19. The system of claim 17, wherein the neural activity sensor comprises an action potential recorder to sense neural electrical activities.

20. The system of claim 1, wherein the sensor comprises a heart rate variability detector.

21. The system of claim 1, wherein the sensor comprises a renal function sensor.

22. The system of claim 21, wherein the renal function sensor comprises at least one of a renal output sensor, a filtration rate sensor, and an angiotensin II level sensor.

23. The system of claim 1, wherein the sensor comprises an acoustic sensor adapted to sense at least one of heart sounds and respiratory sounds.

24. The system of claim 23, wherein the event detector to detect the predetermined cardiac condition when third hear sound (S3) amplitude exceeds a predetermined threshold.

25. The system of claim 1, wherein the sensor comprises a remodeling sensor to sense a signal indicative a degree of myocardial remodeling.

26. The system of claim 25, wherein the remodeling sensor comprises two or more piezoelectric crystals to sense a size of an injured myocardial region.

27. The system of claim 1, wherein the implantable gene or protein delivery device comprises an epicardial patch including the polymer matrix.

28. The system of claim 1, wherein the nucleic acid or protein is released at a rate controlled by the strength of the electric field.

29. The system of claim 1, wherein the implantable pulse generator further comprises a pacing circuit coupled to the implant controller, and wherein the implant controller includes a pacing control module adapted to control a delivery of pacing pulses in conjunction with the release of the nucleic acid or protein.

30. The system of claim 29, further comprising at least one atrial pacing lead coupled to the pacing circuit to deliver atrial pacing pulses.

31. The system of claim 29, further comprising at least one ventricular pacing lead coupled to the pacing circuit to deliver ventricular pacing pulses.

32. The system of claim 29, wherein the implantable pulse generator further comprises a cardiac resynchronization therapy (CRT) circuit coupled to the implant controller, and wherein the implant controller includes a CRT control module adapted to control a delivery of CRT in conjunction with the release of the nucleic acid or protein.

33. The system of claim 29, wherein the implantable pulse generator further comprises a remodeling control therapy (RCT) circuit coupled to the implant controller, and wherein the implant controller includes an RCT therapy control module adapted to control a delivery of RCT therapy in conjunction with the release of the nucleic acid or protein.

34. The system of claim 29, wherein the implantable pulse generator further comprises defibrillation circuit coupled to the implant controller, and wherein the implant controller includes a defibrillation control module adapted to control a delivery of defibrillation shocks in conjunction the release of the nucleic acid or protein.

35. The system of claim 34, further comprising at least one atrial defibrillation lead coupled to the defibrillation circuit to deliver the defibrillation shocks to one or more atria, and wherein the defibrillation control module comprises an atrial defibrillation control module.

36. The system of claim 34, further comprising at least one ventricular defibrillation lead coupled to the defibrillation circuit to deliver the defibrillation shocks to one or more ventricles, and wherein the defibrillation control module comprises a ventricular defibrillation control module.

37. The system of claim 1, further comprising an external system communicatively coupled to the implantable pulse generator, the external system including:

a presentation device to present one or more of the sensed physiological signal and the detected predetermined cardiac condition;

a user input device to receive the external command; and

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

38. The system of claim 37, wherein the external system comprises a programmer.

39. The system of claim 38, wherein the external system comprises an advanced patient management system including:

an external device wirelessly coupled to the implantable pulse generator via telemetry;

a remote device to provide for access to the implantable pulse generator from a distant location; and

a network connecting the external device and the remote device.

40. The system of claim 39, wherein the external device comprises the user input.

41. The system of claim 39, wherein the remote device comprises the user input.

42. The system of claim 1, wherein the polymer matrix comprises a synthetic nonbiodegradable polymer.

43. The system of claim 1, wherein the implantable gene or protein delivery device comprises an implantable iontophoresis gene or protein delivery device, and the nucleic acid or protein contained in the polymer matrix is released from the implantable gene or protein delivery device by iontophoresis.

80. A method to transiently deliver isolated nucleic acid which encodes at least one gene product or binds at least one selected mRNA, or isolated protein to a mammal being at risk of a predetermined cardiac condition, comprising:

programming the timing of the electric signal produced from the system of claim 1 implanted in the mammal at risk of the predetermined condition, in response to detection of the condition so as to transiently deliver the nucleic acid or protein via iontophoresis in an amount effective to inhibit or treat the condition or at least one symptom thereof.

81. The method of claim 80, wherein the system is in or on the heart of the mammal.

82. The method of claim 80, wherein the system is in or on a blood vessel of the mammal.

83. The method of claim 80, wherein the condition is atrial fibrillation, heart failure, ventricular fibrillation, ischemia, brachycardia or hyperplasia.

84. The method of claim 80, wherein the nucleic acid or protein is delivered to at least one of the atria.

85. The method of claim 80, wherein the nucleic acid or protein is delivered to at least one of the ventricles.

86. The method of claim 80, wherein the nucleic acid or protein delivered is a connexin nucleic acid or protein.

87. The method of claim 80, wherein the nucleic acid or protein delivered is an atrial-specific ion channel gene or protein.

88. The method of claim 87, wherein the nucleic acid or protein delivered is associated with I_f.

89. The method of claim 80, wherein the nucleic acid or protein delivered is a non- specific ion channel gene or protein.

90. The method of claim 89, wherein the nucleic acid or protein delivered is associated with I_K1, I_CaL, I_to, I_Kr, I_Kur, I_KATP, I_Na or I_Na/Ca.

91. The method of claim 80, wherein the gene product or protein regulates gap junctions.

92. The method of claim 80, wherein the gene product or protein alters conduction in the myocardium.

93. The method of claim 80, wherein the protein is or the nucleic acid encodes a regulatory protein that blocks ion channels, upregulates ion channels, downregulates ion channels, or alters ion channel kinetics.

44. A method for operating an implantable gene or protein delivery system coupled to an implantable device, comprising:

sensing a physiological signal indicative of a predetermined cardiac condition using an implantable sensor;

detecting the predetermined cardiac condition from the physiological signal;

receiving an external command transmitted to the implantable device from an external system;

producing an electrical signal in response to the predetermined cardiac condition and the external command using the implantable device;

transmitting the electrical signal from the implantable device to an implantable gene or protein delivery device through an implantable lead system;

creating an electric field using the electrical signal; and

applying the created electric field to a polymer matrix of the implantable gene or protein delivery device, the polymer matrix containing isolated nucleic acid which encodes at least one gene product or binds at least one selected mRNA or isolated protein, wherein the created electrical field is effective to release the nucleic acid or protein from the polymer matrix via iontophoresis.

45. The method of claim 44, wherein the nucleic acid or protein is released at a rate controlled by the strength of the electric field.

46. The method of claim 44, wherein sensing the physiological signal comprises sensing at least one electrogram, and detecting the predetermined cardiac condition comprises detecting an arrhythmia.

47. The method of claim 46, wherein detecting the predetermined cardiac condition comprises detecting an atrial fibrillation.

48. The method of claim 46, wherein detecting the predetermined cardiac condition comprises detecting a ventricular fibrillation.

49. The method of claim 44, wherein sensing the physiological signal comprises sensing an physiological signal indicative of ischemia, and detecting the predetermined cardiac condition comprises detecting an ischemia.

50. The method of claim 44, wherein sensing the physiological signal comprises sensing a signal indicative of a cardiac metabolic level.

51. The method of claim 50, wherein sensing the signal indicative of the cardiac metabolic level comprises sensing at least one of a pH value, an oxygen pressure (PO2), a carbon dioxide pressure (PCO2), a glucose level, a creatine level, a C-creative protein level, a creatine kinase level, and a creatine kinase-MB level.

52. The method of claim 44, wherein sensing the physiological signal comprises sensing tissue impedance.

53. The method of claim 52, wherein sensing the tissue impedance comprises sensing pulmonary impedance.

54. The method of claim 52, wherein sensing the tissue impedance comprises sensing an impedance indicative of minute ventilation.

55. The method of claim 44, wherein sensing the physiological signal comprises sensing a pressure in a cardiovascular system.

56. The method of claim 55, wherein sensing the pressure comprises sensing at least one of a left atrial pressure, a left ventricular pressure, an arterial pressure, and a pulmonary arterial pressure.

57. The method of claim 55, wherein detecting the predetermined cardiac condition comprises detecting a systolic dysfunction.

58. The method of claim 55, wherein detecting the predetermined cardiac condition comprises detecting a diastolic dysfunction.

59. The method of claim 44, wherein sensing the physiological signal comprises sensing a stroke volume.

60. The method of claim 44, wherein sensing the physiological signal comprises sensing a neural activity.

61. The method of claim 60, wherein sensing the neural activity comprises sensing a neurohormone level.

62. The method of claim 60, wherein sensing the neural activity comprises sensing neural electrical activities.

63. The method of claim 62, wherein sensing the physiological signal comprises detecting a heart rate variability.

64. The method of claim 44, wherein sensing the physiological signal comprises sensing a renal function.

65. The method of claim 64, wherein sensing the renal function comprises sensing at least one of a renal output, a filtration rate, and an angiotensin II level.

66. The method of claim 44, wherein sensing the physiological signal comprises sensing at least one of heart sounds and respiratory sounds.

67. The method of claim 66, wherein detecting the predetermined cardiac condition comprises detecting a predetermined cardiac condition when third hear sound (S3) amplitude exceeds a predetermined threshold.

68. The method of claim 44, wherein sensing the physiological signal comprises sensing a signal indicative of a degree of myocardial remodeling.

69. The method of claim 68, wherein sensing the signal indicative of the degree of myocardial remodeling comprises sensing a size of an injured myocardial region.

70. The method of claim 44, further comprising delivering pacing pulses in conjunction with releasing the nucleic acid or protein.

71. The method of claim 70, further comprising delivering a cardiac resynchronization therapy (CRT) in conjunction with releasing the nucleic acid or protein.

72. The method of claim 70, further comprising delivering a remodeling control therapy (RCT) in conjunction with releasing the nucleic acid or protein.

73. The method of claim 70, further comprising delivering cardioversion/defibrillation shocks in conjunction with releasing the nucleic acid or protein.

74. The method of claim 73, wherein delivering the cardioversion/defibrillation shocks comprises delivering atrial defibrillation shocks.

75. The method of claim 73, wherein delivering the cardioversion/defibrillation shocks comprises delivering ventricular defibrillation shocks.

76. The method of claim 44, further comprising:

transmitting one or more of the sensed physiological signal and a detection of the predetermined cardiac condition to the external system; and

presenting the one or more of the sensed physiological signal and a detection of the predetermined cardiac condition through the external system.

77. The method of claim 44, wherein receiving the external command comprises receiving the external command entered by a physician or other caregiver through the external system.

78. The method of claim 44, wherein receiving the external command comprises receiving the external command entered by a patient through the external system.

79. The method of claim 44, wherein producing the electrical signal comprises producing an electrical signal that creates an electric field capable of releasing the nucleic acid or protein from the polymer matrix by iontophoresis.

94. A system, comprising:

an implantable pulse generator including;

a sensor to sense a physiological signal indicative of a predetermined cardiac condition;

an event detector, coupled to the sensor, to detect the predetermined cardiac condition from the physiological signal; and

an implant controller coupled to the event detector, the implant controller including a gene or protein delivery control module configured to produce an electrical signal to control iontophoretic gene or protein delivery in response to the predetermined cardiac condition; and

an implantable gene or protein delivery device coupled to the implantable pulse generator, the implantable gene or protein delivery device including an epicardial patch comprising a polymer matrix and isolated nucleic acid which encodes at least one gene product or binds at least one selected mRNA, or isolated protein, the nucleic acid or protein contained in the polymer matrix and released from the implantable gene or protein delivery device in response to an electric field applied to the polymer matrix, the electric field created by the electrical signal.