Methods of using hcn genes to treat cardiac arrhythmias

Abstract

The subject invention is directed to methods of treating cardiac pacing dysfunction by administering HCN genes, alone or in combination with other genes.

1 - 23 . (canceled) 
     
     
         24 . A nucleic acid construct comprising:
 a heterologous regulatory sequence operably linked to a nucleotide sequence encoding a truncated human hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) protein,   wherein the truncated human HCN4 protein is a truncated version of an un-truncated wild-type human HNC4 protein that encodes a cyclic nucleotide binding domain (CNBD) and is truncated 16 amino acids after the coding sequence of the CNBD, and   wherein expression of the human HCN4 truncated polynucleotide in an isolated cell results in a channel responsive to cyclic adenosine monophosphate (cAMP) over a broader range of potentials than the un-truncated wild-type human HCN4 protein.   
     
     
         25 . An isolated purified cell comprising the construct of  claim 24 , wherein expression of the human HCN4 truncated polynucleotide in the cell results in a channel responsive to cAMP over a broader range of potentials than the un-truncated wild-type human HCN4 protein. 
     
     
         26 . A pharmaceutical composition comprising the cell of  claim 25  and a pharmaceutically acceptable carrier. 
     
     
         27 . A method comprising administering the pharmaceutical composition of  claim 25  to a patient in need thereof. 
     
     
         28 . The method of  claim 27 , wherein the patient is suffering from a cardiac dysfunction. 
     
     
         29 . The method of  claim 28 , wherein the cardiac dysfunction is arrhythmia. 
     
     
         30 . The method of  claim 28 , wherein the cardiac dysfunction is bradyarrhythmia. 
     
     
         31 . The method of  claim 28 , wherein the cardiac dysfunction is tachyarrhythmia. 
     
     
         32 . A pharmaceutical composition comprising the construct of  claim 24  and a pharmaceutically acceptable carrier. 
     
     
         33 . The pharmaceutical composition of  claim 32 , further comprising a nucleic acid construct comprising a heterologous regulatory sequence operably linked to a nucleotide sequence encoding a protein selected from the group consisting of human hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) protein, human hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) protein, and human hyperpolarization-activated cyclic nucleotide-gated 3 (HCN3). 
     
     
         34 . The pharmaceutical composition of  claim 33 , further comprising a nucleic acid construct comprising a heterologous regulatory sequence operably linked to a nucleotide sequence encoding a protein selected from the group consisting of beta-1 adrenergic receptor, beta-2 adrenergic receptor, T-type calcium channel (CACNA1H, I ca,T ), human L-type calcium channel (CACNA1C, I ca,L ), mink-related peptide 1 (KCNE2-beta, MiRP1, HCN-beta subunit), voltage-gated channel (KCNE2, I Kr ), cholinergic receptor, acetylcholine-activated K+ channel (KCNJ3, KCNJ4, I K(Ach) ), muscarinic 2 receptor (CHRM2), muscarinic 3 receptor (CHRM3), inwardly-rectifying K+ channel (KCNJ2, I K1 ), transient outward K+ channel voltage-gated channel (KCND3, T t0  and Kv channel interacting proteins 2 (KchIP2.x). 
     
     
         35 . The pharmaceutical composition of  claim 32 , further comprising a nucleic acid construct comprising a heterologous regulatory sequence operably linked to a nucleotide sequence encoding a protein selected from the group consisting of beta-1 adrenergic receptor, beta-2 adrenergic receptor, T-type calcium channel (CACNA1H, I ca,T ), human L-type calcium channel (CACNA1C, I ca,L ), mink-related peptide 1 (KCNE2-beta, MiRP1, HCN-beta subunit), voltage-gated channel (KCNE2, I Kr ), cholinergic receptor, acetylcholine-activated K+ channel (KCNJ3, KCNJ4, I K(Ach) ), muscarinic 2 receptor (CHRM2), muscarinic 3 receptor (CHRM3), inwardly-rectifying K+ channel (KCNJ2, I K1 ), transient outward K+ channel voltage-gated channel (KCND3, T t0 ) and Kv channel interacting proteins 2 (KchIP2.x). 
     
     
         36 . A method comprising administering the pharmaceutical composition of  claim 32  to a patient in need thereof. 
     
     
         37 . The method of  claim 36 , wherein the patient is suffering from a cardiac dysfunction. 
     
     
         38 . The method of  claim 37 , wherein the cardiac dysfunction is arrhythmia. 
     
     
         39 . The method of  claim 37 , wherein the cardiac dysfunction is bradyarrhythmia. 
     
     
         40 . The method of  claim 37 , wherein the cardiac dysfunction is tachyarrhythmia.