BIOLOGIC DEVICE FOR REGULATION OF GENE EXPRESSION AND METHOD THEREFOR

• US 20070036771A1
• Filed: 03/27/2006
• Published: 02/15/2007
• Est. Priority Date: 08/12/2005
• Status: Active Grant

• Current Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Original Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Inventors: Qu, Jihong, Sih, Haris, Ross, Jeffrey, Girouard, Steven, Wagner, Darrell, Heil, Ronald
• Granted Patent: US 9,031,792 B2
• Time in Patent Office: Days
• US Class Current: 424/93.210
• CPC Class Codes: A61K 48/0008 characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61N 1/05 for implantation or insertion into the body, e.g. heart electrode A61N1/06 takes precedence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A system and device are provided which include a gene regulatory system controlling expression of one or more expression cassettes present in or released by the device, by emitting one or more stimulations. An expression cassette includes a regulatable transcription control element that is responsive to the emitted stimulations linked to an open reading frame of interest. The system optionally includes a sensor to sense a parameter indicative of a need, a telemetry module to receive an external command, or a programmable device, for regulating gene expression of the open reading frame.

Claims

1. A method, comprising:

providing a lead comprising;

a lead body;

one or more gene regulatory stimulators that emit a regulatory stimulation capable of regulating a regulatable transcription control element; and

one or more gene depositories adapted for transfer of virus or cells and disposed along the lead body, wherein the one or more gene depositories include a porous, biocompatible and substantially nonbiodegradable material which permits the passage of soluble cellular factors but not cells across the material, wherein at least one gene regulatory stimulator is associated with the one or more gene depositories; and

introducing to one or more of the gene depositories recombinant virus comprising an expression cassette which includes the regulatable transcription control element operably linked to an open reading frame of interest, genetically modified donor cells comprising an expression cassette which includes the regulatable transcription control element operably linked to an open reading frame of interest or donor cells which are not genetically modified but which comprise an endogenous gene which includes the regulatable transcription control element operably linked to an open reading frame of interest.

2. A method, comprising:

providing a mammal having i) a system comprising;

a lead including a lead body extending from a proximal end portion to a distal end portion;

one or more gene depositories disposed along the lead body, the one or more gene depositories include a porous, biocompatible and substantially nonbiodegradable material, wherein the material is selected to allow the passage of soluble cellular factors and prevent passage of cells across the material; and

one or more gene regulatory stimulators associated with the one or more gene depositories, the one or more gene regulatory stimulators emit a regulatory stimulation capable of regulating a regulatable transcription control element in an expression cassette including the regulatable transcription control element operably linked to an open reading frame of interest or in an endogenous gene which includes the regulatable transcription control element operably linked to an open reading frame of interest,

wherein the one or more gene depositories comprise recombinant virus comprising the expression cassette, donor cells, genetically modified donor cells comprising the expression cassette, or a combination thereof, or

ii) a lead comprising;

a lead body extending from a proximal end portion to a distal end portion and having an intermediate portion therebetween;

one or more gene depositories disposed along the lead body, the one or more gene depositories include a porous, biocompatible and substantially nonbiodegradable material, wherein the material is selected to allow the passage of soluble cellular factors and prevent passage of cells across the material;

the one or more gene depositories having at least one of a recombinant virus comprising an expression cassette comprising a regulatable transcription control element operably linked to an open reading frame of interest, genetically modified donor cells comprising an expression cassette comprising a regulatable transcription control element operably linked to an open reading frame of interest, donor cells which are not genetically modified but which comprise an endogenous gene which includes a regulatable transcription control element operably linked to an open reading frame of interest, or a combination thereof; and

one or more gene regulatory stimulators associated with the one or more gene depositories, the one or more gene regulatory stimulators emit a regulatory stimulation capable of regulating the regulatable transcription control element; and

delivering a regulatory stimulation from the one or more gene regulatory stimulators in an amount effective to regulate the regulatable transcription control element.

3. The method of claim 2, wherein the regulatory stimulation is delivered in response to a sensed physiological parameter.

4. The method of claim 3, wherein the physiological parameter is sensed by an implanted sensor.

5. The method of claim 2, wherein the regulatory stimulation is delivered in response to a command.

6. The method of claim 5, wherein the command is an external command.

7. The method of claim 5, wherein the command is from an implanted programmable device.

8. The method of claim 2, further comprising ceasing delivery of the regulatory stimulation.

9. The method of claim 8, wherein the delivery ceases in response to receiving a command.

10. The method of claim 9, wherein the command is an external command.

11. The method of claim 9, wherein the command is from an implanted programmable device.

12. The method of claim 6 or 10, wherein the external command is entered by at least one of physician or other caregiver, or a patient through an external system.

13. The method of claim 2, wherein the regulatory stimulation is delivered in response to a sensed physiological parameter indicative of ischemia.

14. The method of claim 13, wherein the regulatory stimulation is delivered in response to a sensed S-T segment deviation from baseline, prolongation of the Q-T interval, T-wave inversion, shortness of breath, chest pain, blood pH of less than 7.0, blood K⁺ concentration of greater than 10 mM, glucose concentration of less than about 80 mg/dl or greater than about 115 mg/dl, or oxygen concentration of less than about 90% pO₂.

15. The method of claim 2, wherein the regulatory stimulation is delivered in response to a sensed physiological parameter indicative of remodeling.

16. The method of claim 15, wherein the regulatory stimulation is delivered in response to a sensed decrease in ejection fraction or QRS complex width of greater than about 120 msec.

17. The method of claim 2, wherein the regulatory stimulation is delivered in response to a sensed physiological parameter indicative of myocardial infarction.

18. The method of claim 17, wherein the regulatory stimulation is delivered in response to a sensed aberrant electrical activation front, S-T segment elevation, Q wave alteration, reduced R wave amplitude, chest pain or shortness of breath.

19. The method of claim 2, wherein expression of the open reading frame prevents, inhibits or treats cardiac ischemia, cardiac remodeling or myocardial infarction.

20. The method of claim 2, wherein expression of the open reading frame enhances preconditioning of the heart for ischemia, repair of infarcted myocardial tissue, or reverse remodeling.

21. The method of claim 2, wherein the regulatory stimulation is delivered in response to a sensed worsening of heart failure, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, or bradycardia.

22. The method of claim 2, further comprising transmitting light energy from a source via a fiber optic wave guide of the lead.

23. The method of claim 2, further comprising placing the lead within an external energy field.