Biologic device for regulation of gene expression and method therefor

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.

Description

CROSS-REFERENCE TO RELATED APPLICATION(S) [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 707,637, filed on Aug. 12, 2005, under 35 U.S.C. § 119(e), which is hereby incorporated by reference.FIELD OF THE INVENTION [0002] This invention relates generally to gene therapy, for example, the use of genetically modified cells or recombinant gene therapy vectors, and particularly, but not by way of limitation, to method and apparatus for direct regulation of gene expression. BACKGROUND [0003] The heart is the center of a person's circulatory system. It includes an electromechanical system performing two major pumping functions. The left portions of the heart draw oxygenated blood from the lungs and pump it to the organs of the body to provide the organs with their metabolic needs for oxygen. The right portions of the heart draw deoxygenated blood from the organs and pump it into the lungs where the blood gets oxygenated. The body's metabolic need for oxyge...

AI Technical Summary

Benefits of technology

[0010] Recombinant virus or genetically modified donor cells for use with the implantable device contain an expression cassette that has a regulatable transcription control element operably linked to an open reading frame of interest, the expression of which open reading frame in a mammal has a desirable (beneficial) effect. Donor cells which are not genetically modified for use with the implantable device express a gene product with a desirable (beneficial) effect, where the native (endogenous) gene includes a regulatable transcriptional control element linked to an open reading frame. In one embodiment, the regulatable transcriptional control element is regulated by light or an electric field. In one embodiment, the open reading frame encodes a gene product which is secreted (released into the extracellular environment) from donor cells which express the gene product, and which gene product is capable of passing through the porous, biocompatible and substantially nonbiodegradable material that forms at least a part of a gene depository. In another embodiment, the gene product alters, e.g., increases, expression of one or more other gene products in the donor cells, which one or more other gene products are released, e.g., secreted, from the cells and pass through the porous, biocompatible and substantially nonbiodegradable material. Therefore, in one embodiment, the beneficial effect of the expression of the open reading frame is direct, e.g., the expression results in a therapeutic soluble factor(s), while in another embodiment, the beneficial effect of the expression of the desirable open reading frame is indirect, e.g., the encoded gene product alters the expression of at least one other gene encoding a soluble factor in the donor cells, while in yet another embodiment the expression of the open reading yields a soluble factor which alters the expression of one or more genes in host cells, thereby resulting in a soluble factor(s) which has a beneficial effect on cells in the host.

[0015] Also provided is a method of using the system or lead of the invention. The method includes providing to a mammal having the system or lead of the invention, and delivering a regulatory stimulation from the one or more gene regulatory stimulation devices in an amount effective to regulate the regulatable transcription control element, thereby regulating the gene product encoded by the open reading frame linked to the regulatable transcription control element. In one embodiment, the mammal is at risk of or has a cardiac condition and the open reading frame of interest in the expression cassette is selected so that expression of the open reading frame in the mammal prevents, inhibits or treats the condition or at least one symptom thereof. In one embodiment, the method includes sensing a physiological parameter indicative of a predetermined cardiac condition in a mammal having a lead of the invention and delivering a regulatory stimulation from the one or more gene regulatory stimulation devices in the lead in response to at least the sensed physiological parameter. In another embodiment, a regulatory stimulation is delivered from the one or more gene regulatory stimulation devices in the lead in response to a command, e.g., an external command or one from an implanted programmable device.

Problems solved by technology

A blocked or otherwise damaged electrical conduction system causes the myocardium to contract at a rhythm that is too slow, too fast, and / or irregular.

Arrhythmia reduces the heart's pumping efficiency and hence, diminishes the blood flow to the body.

A deteriorated myocardium has decreased contractility, also resulting in diminished blood flow.

A heart failure patient usually suffers from both a damaged electrical conduction system and a deteriorated myocardium.

The diminished blood flow results in insufficient blood supply to various body organs, preventing these organs to function properly and causing various symptoms.

Without effective treatment, acute decompensated heart failure cause rapid deterioration of the cardiovascular and general health and significantly shortened life expectancy.

Strong viral promoters can drive a high level of expression in a wide range of tissues and cells, however, constitutive expression is an open loop system and the encoded gene product may induce cellular toxicity or tolerance, or down regulation of expression through negative feedback.

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