| Genetic modification of targeted regions of the cardiac conduction system -> Monitor Keywords |
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Genetic modification of targeted regions of the cardiac conduction systemRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.)Genetic modification of targeted regions of the cardiac conduction system description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070021375, Genetic modification of targeted regions of the cardiac conduction system. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10/424,080-filed Apr. 25, 2003, by Vinod Sharma and entitled "GENETIC MODIFICATION OF TARGETED REGIONS OF THE CARDIAC CONDUCTION SYSTEM." FIELD OF THE INVENTION [0002] The present invention relates to compositions, apparatus, and methods for providing curative therapy for cardiac dysfunction, and more particularly to biological systems and methods relating to implementing curative therapeutic agents and systems for arrhythmias and cardiac pacing dysfunction. BACKGROUND [0003] In a normal, healthy heart, cardiac contraction is initiated by the spontaneous excitation of the sinoatrial ("SA") node, located in the right atrium. The electrical impulse generated by the SA node travels to the atrioventricular ("AV") node where it is transmitted to the bundle of His and Purkinje network, which branches in many directions to facilitate simultaneous contraction of the left and right ventricles. [0004] In certain disease states, the heart's ability to pace properly is compromised. Currently, such dysfunction is commonly rectified by the implantation of implantable pacemakers. While improving the lives of many patients, implantable pacemakers have a limited lifetime and hence, may expose a patient to multiple surgeries to replace the implantable pacemaker. Moreover, implantable pacemakers may not be capable of directly responding to the body's endogenous signaling that interacts with the SA node to increase or decrease its pacing rate. [0005] Recently, biological methods of influencing the pacing rate of cardiac cells have been developed, including the use of various drugs and pharmaceutical compositions. Developments in genetic engineering have resulted in methods for genetically modifying cardiac cells to influence their intrinsic pacing rate. For example, U.S. Pat. No. 6,214,620 describes a method for suppressing excitability of ventricular cells by overexpressing (e.g. K.sup.+ channels) or underexpressing certain ion channels (e.g. Na.sup.+ and Ca.sup.2+ channels). PCT Publication No. WO 02/087419 describes methods and systems for modulating electrical behavior of cardiac cells by genetic modification of inwardly rectifying K.sup.+ channels (I.sub.K1) in quiescent ventricular cells. PCT Publication No. WO 02/098286 describes methods for regulating pacemaker function of cardiac cells with HCN molecules (HCN 1, 2, 3, or 4 isoforms of the pacemaker current I.sub.f). [0006] A need remains, however, to implement a system of genetic modification therapy (biopacing) in cooperation with an implantable medical device (IMD) to insure successful curative therapy for cardiac dysfunction. SUMMARY OF THE INVENTION [0007] The present invention provides a biological pacemaker ("bio-pacemaker") that is capable of responding to physiological signals as well as facilitating and restoring synchronous contractions of the ventricles to thus mimic the function of a healthy heart. The bio-pacemaker is generated through the genetic modification of myocardial cells in a targeted region of the cardiac conduction system, through use of a bio-pacemaker composition. [0008] In one aspect of the invention, a bio-pacemaker composition includes at least two coding sequences that encode one or more molecules in myocardial cells of the cardiac conduction system to increase the pacemaking rate of the cells. The coding sequences include a coding sequence that encodes a channel or subunit thereof that produces funny current, a coding sequence that encodes a T-type Ca.sup.2+ channel or subunit thereof, and a coding sequence that encodes one or more molecules that suppresses the expression of the wild type potassium channel. [0009] Preferably, cells of the conduction system are genetically modified using the bio-pacemaker composition to increase their pacing rate to a level resembling the intrinsic pacing rate of the SA nodal cells in a normal heart. [0010] Preferably, the bio-pacemaker composition of the invention generates a bio-pacemaker in the cardiac conduction system cells by altering two or more characteristics of the cell to obtain the following: 1) increased inward Ca.sup.2+ current, 2) increased inward funny current (I.sub.f), and/or 3) decreased outward K.sub.+ current. [0011] Increased inward Ca.sup.2+ current may be obtained by genetically modifying the target cells to overexpress T-type Ca.sup.2+ channels or subunits thereof, and in one embodiment, the .alpha..sub.1H subunits of the T-type Ca.sup.2+ channels are overexpressed. [0012] Increased funny current (I.sub.f) may be obtained by increasing the expression of funny current channels or subunits thereof. Preferably, the channels expressed are an isoform of the hyperpolarization-activated cation channel gene (HCN). The isoform chosen will be related to the mammalian species of cells being modified. [0013] Decreased outward K+current may be obtained by delivering a bio-pacemaker composition to the target cells including a coding sequence designed to encode a molecule or protein that will suppress the expression of the wildtype potassium channels responsible for producing rapid potassium current (I.sub.Kr). In one embodiment, the protein expressed is a dominant-negative form of the potassium channel protein. [0014] In one further embodiment of the invention, a bio-pacemaker of the invention is used in combination with an implantable pacemaker. Specifically, the implantable pacemaker is programmed to work in cooperation with the genetically engineered bio-pacemaker to prevent cardiac dysfunction or to sense and monitor the pacemaking action of the genetically engineered bio-pacemaker. Further, the implantable pacemaker operates to pace the heart when the pacemaking action of the bio-pacemaker is not as expected. For example, two possible triggers for resorting to the implantable pacemaker are 1) a bio-pacemaker pacing rate less than a certain predetermined threshold value and 2) an intermittent but presumably normal function of the bio-pacemaker. Implantable pacemaker can be switched to the role of a primary pacemaker if one or more attempts to engineer a biological pacemaker fail in a patient. [0015] In case the bio-pacemaker location is the AV node, the top portions of the SA node may be ablated to isolate the atria from the AV node. When the bio-pacemaker is located in the Purkinje network, the entire AV node may be ablated. BRIEF DESCRIPTION OF THE DRAWINGS [0016] FIG. 1 is a diagram of a human heart. [0017] FIG. 2 is a schematic diagram of a right side of a heart, similar to FIG. 1, in which a guiding catheter is positioned for delivery of the genetic construct of the invention. [0018] FIGS. 3A and 3B are schematics illustrating how an embodiment of the invention operates. [0019] FIGS. 4A and 4B show the action potential (AP) characteristics of the AV nodal cells (one location of the bio-pacemaker) before and after genetic modification in accordance with a method of this invention. 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