Transcription factor-based generation of pacemaker cells and methods of using same

Abstract

Several embodiments disclosed herein relate generally to methods and compositions for the generation of biological pacemakers. In some embodiments, the methods comprise contacting non-pacemaker cells with one or more transcription factors (in vivo or in vitro) and inducing pacemaker functionality in the cells.

1 - 47 . (canceled) 
     
     
         48 . A method of treating a dysfunction in cardiac electrical activity comprising:
 obtaining cells capable of generating a biological pacemaker, wherein the cells are converted from a population of stem cells and/or progenitor cells; and   administering said converted cells to a subject suffering from a dysfunction in cardiac electrical activity, wherein said converted cells exhibit spontaneous, repetitive electrical activity, thereby treating said dysfunction in cardiac electrical activity.   
     
     
         49 . The method of  claim 48 , wherein the dysfunction in cardiac electrical activity comprises a cardiac arrhythmia. 
     
     
         50 . The method of  claim 49 , further comprising isolating said converted cells prior to said administration. 
     
     
         51 . The method according to  claim 48 , wherein said spontaneous, repetitive electrical activity is within about 65% to about 100% of the normal activity of pacemaker cells. 
     
     
         52 . The method according to  claim 48 , wherein said administration causes a change in the rhythm of the heart. 
     
     
         53 . The method of  claim 52 , wherein the changed rhythm of the heart corresponds to a new heart rate within about 25% to about 35% of a normal heart rate. 
     
     
         54 . The method according to  claim 48 , wherein said administration is to a subject having an implanted pacemaker. 
     
     
         55 . The method of  claim 54 , wherein said administration reduces the dependence of said subject on said implanted pacemaker. 
     
     
         56 . The method of  claim 55 , wherein said reduced dependence is sufficient to allow explanting or replacement of said implanted pacemaker. 
     
     
         57 . The method according to  claim 48 , wherein said administration is into the apex of the heart. 
     
     
         58 . The method according to  claim 48 , wherein said administration is to the right branch of the Bundle of His or the left branch of the Bundle of His. 
     
     
         59 . (canceled) 
     
     
         60 . The method according to  claim 48 , wherein said administration is to the Purkinje fibers. 
     
     
         61 . The method according to  claim 48 , wherein said administration is to the inter-ventricular septum. 
     
     
         62 . The method according to  claim 48 , wherein said administration is to the right ventricular free wall or the left ventricular free wall. 
     
     
         63 . (canceled) 
     
     
         64 . The method according to  claim 48 , wherein said administration is to the SA node. 
     
     
         65 . The method according to  claim 48 , wherein said administration is to the AV node. 
     
     
         66 . The method according to  claim 48 , wherein said administration is via the right ventricle. 
     
     
         67 . The method according to  claim 48 , wherein said administration is via the right atrium. 
     
     
         68 . The method according to  claim 48 , wherein said administration is made by accessing the heart directly. 
     
     
         69 . The method of  claim 68 , wherein said accessing is facilitated by use of one or more of a map guided catheter injection system, fluoroscopy guidance, X-ray guidance, echocardiography guidance, and guidance via magnetic resonance imaging. 
     
     
         70 - 76 . (canceled) 
     
     
         77 . A method of treating a cardiac arrhythmia by generating a biological pacemaker using transcription factors, comprising:
 identifying a subject suffering from cardiac arrhythmia;   obtaining a population of converted stem cells and/or progenitor cells,   wherein, prior to said conversion, said stem cells and/or progenitor cells comprised quiescent cells that did not exhibit spontaneous, repetitive electrical activity;   wherein one or more of Tbx18, Shox-2, Tbx3, Tbx5, functional fragments thereof, or combinations thereof were administered to said quiescent cells to generate converted cells that exhibit spontaneous, repetitive electrical activity; and   administering said converted cells to said subject, wherein said administered converted cells engraft into the cardiac tissue of said subject and continue to exhibit spontaneous, repetitive electrical activity, thereby generating a biological pacemaker and treating said cardiac arrhythmia.   
     
     
         78 . The method of  claim 48 , wherein the cells are converted from a population of stem cells through the use of transcription factors into cells suitable for generation of a biological pacemaker, comprising:
 obtaining a population of stem cells;   culturing said stem cells in vitro;   wherein said cultured stem cells comprise quiescent cells that do not exhibit spontaneous, repetitive electrical activity; and   delivering one or more transcription factors to said quiescent cells to generate converted cells, wherein the one or more transcription factors comprises Tbx18,   wherein the converted cells exhibit spontaneous, repetitive electrical activity; thereby converting said stem cells into cells capable of generating a biological pacemaker.   
     
     
         79 . The method of  claim 48 , wherein the converted cells are capable of generating a biological pacemaker to supplement or obviate the need for an electrically-powered pacemaker. 
     
     
         80 . The method of  claim 48 , wherein the converted cells are capable of the generating a biological pacemaker to serve as a temporary bridge until a replacement or alternative electronic pacemaker can be implanted in the subject.