title: Aptamer neutralization of beta1-adrenoceptor autoantibodies isolated from patients with cardiomyopathies.
abstract: BACKGROUND
  Autoantibodies directed against the beta1-adrenoceptor (beta1-AABs) have been proposed to drive the pathogenesis of idiopathic dilated cardiomyoparthy (DCM), Chagas' cardiomyopathy, and peripartum cardiomyopathy. For disease treatment, aptamers that bind and neutralize beta1-AABs could be significant.
  
  
  OBJECTIVE
  We determined whether oligonucleotide-aptamers, selected to target human beta1-AABs directed against the second extracellular loop of the beta1-AAB, can neutralize these AABs and modulate their function in vitro.
  
  
  RESULTS
  Using Monolex technology, we identified an ssDNA aptamer that targets human beta1-AABs. The neutralization potential of this aptamer against beta1-AABs isolated from patients with DCM, Chagas' cardiomyopathy, and peripartum cardiomyopathy was analyzed using cultured neonatal rat cardiomyocytes by monitoring beta1-AAB induced cell toxicity and chronotropic cell responses. Aptamer addition reduced beta1-AAB induced cell toxicity and neutralized chonotropic beta1-AAB function in a dose-dependent manner. In the presence of aptamer neutralized beta1-AABs, cells remained fully responsive to agonists and antagonists, such as isoprenaline and bisoprolol. Both aptamer pretreated with a complementary (antisense) aptamer and a control scrambled-sequence aptamer were ineffective at beta1-AAB neutralization. Beta1-AABs directed against the first extracellular loop of the beta1-receptor and AABs directed against other G-protein coupled receptors were not affected by the selected aptamer.
  
  
  CONCLUSIONS
  A specific aptamer that can neutralize cardiomyopathy associated human beta1-AABs in vitro has been identified and characterized, providing a framework for future in vivo testing of this treatment option in animal experiments.
authors.affiliation: Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Annekathrin
authors.initials: A
authors.lastname: Haberland
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Claudia
authors.initials: C
authors.lastname: Dahmen
authors.forename: Andreas
authors.initials: A
authors.lastname: Kage
authors.forename: Ingolf
authors.initials: I
authors.lastname: Schimke
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D001323:Autoantibodies / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D017298:Bisoprolol / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000276:immunology*; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D052157:Aptamers, Nucleotide; D001323:Autoantibodies; D018342:Receptors, Adrenergic, beta-1; D007545:Isoproterenol; D017298:Bisoprolol