Posttranslational control of a cardiac ion channel transgene in vivo: clarithromycin-hMiRP1-Q9E interactions.
The present study investigates a novel gene therapy approach for atrial arrhythmias, using a clarithromycin-responsive ion channel subunit mutation, hMiRP1-Q9E, cloned into an expression plasmid; wild-type expression plasmids encoding human minK-related protein 1 (hMiRP1) were also used as controls. In a series of pig studies, right atrial myocardium was injected at one site with hMiRP1-Q9E plasmid DNA; a separate site in the same right atrium was injected with wild-type plasmid or was sham injected. Two weeks after transfection intravenous clarithromycin administration resulted in a site-specific, dose-dependent prolongation of the repolarization phase of the right atrial epicardial monophasic action potential (MAP) only at the hMiRPQ9E sites, but not at sham or wild-type sites. MAP recordings before clarithromycin administration did not differ between hMiRP1-Q9E and control sites. These studies show that regional control of atrial myocardial repolarization by site-specific transfection with plasmid DNA encoding an antibiotic-responsive ion channel subunit is feasible and, because hMiRP1-Q9E-transfected sites were affected only if clarithromycin was given, provide proof of concept for a posttranslational, controllable gene therapy strategy for atrial arrhythmias.
Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Itay
I
Perlstein
Denise Y
DY
Burton
Kenneth
K
Ryan
Suzanne
S
Defelice
Erin
E
Simmers
Barry
B
Campbell
Jeanne M
JM
Connolly
Amnon
A
Hoffman
Robert J
RJ
Levy
D000200:Action Potentials; D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000628:therapy; D017291:Clarithromycin / Q000494:pharmacology*; D004452:Echocardiography; D004594:Electrophysiology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006325:Heart Atria / Q000378:metabolism*; D009154:Mutation; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D013552:Swine; D014162:Transfection; D019076:Transgenes
C489619:KCNE2 protein, human; D024642:Potassium Channels, Voltage-Gated; D049452:Green Fluorescent Proteins; D017291:Clarithromycin