The aptamer BC 007 for treatment of dilated cardiomyopathy: evaluation in Doberman Pinschers of efficacy and outcomes

Werner, Sabine; Wallukat, Gerd; Becker, Niels-Peter; Wenzel, Katrin; Müller, Johannes; Schimke, Ingolf und Wess, Gerhard (2020): The aptamer BC 007 for treatment of dilated cardiomyopathy: evaluation in Doberman Pinschers of efficacy and outcomes. In: ESC Heart Failure, Bd. 7, Nr. 3: S. 844-855

Abstract

Aims: Aptamer BC 007, a 15-mer single-strand DNA oligonucleotide (5'-GGTTGGTGTGGTTGG-3'), was developed to neutralize functional autoantibodies that bind to the extracellular domains of G protein-coupled receptors (GPCR-AAB), leading to the modulation of receptor-mediated signalling cascades that induce pathophysiological states. Among the GPCR-AAB, there are those directed against the beta 1-adrenergic receptor (beta 1-AAB) that are highly present in patients with dilated cardiomyopathy (DCM) and are increasingly accepted as disease drivers. Using Doberman Pinschers (DP) with DCM, which possess similarities with human DCM among these beta 1-AAB positivity for that the disease-driving role in DP DCM was demonstrated, the safety of BC 007, efficacy for neutralizing beta 1-AAB, and the DP's outcome were investigated. Methods and results Fourteen client-owned beta 1-AAB-positive DP with electrocardiographically and echocardiographically indicated DCM were treated with BC 007. For controlling, two groups were created: 14 beta 1-AAB-positive DP with DCM not treated with BC 007 (Control 1) and 14 DP with DCM closely matched to the BC 007-treated DP (Control 2), retrospectively selected from the institutional database of DP. After treatment, DP were monitored both echocardiographically, and for beta 1-AAB, and survival curves were calculated. Based on clinical and laboratory examination, no adverse effects associated with BC 007 treatment were observed during the study. Forty-eight hours after treatment, the DP's blood was free of beta 1-AAB, which led to a reduction or stabilization of left ventricular end-systolic volume (ESVI) during beta 1-AAB free time in 10 of the treated DP. In one DP, where beta 1-AAB returned after 3 months and ESVI worsened again, a second BC 007 treatment after 9 months again cleared the blood from beta 1-AAB and improved the ESVI. Compared with the controls, DP treated with BC 007 showed a significantly longer survival time [572 days, interquartile range (IQR) 442-840 days] vs. Control group 1 (266 days, IQR 97-438 days;logrank: P = 0.009) and Control group 2 (229 days, IQR 174-319 days;logrank: P = 0.012). Conclusions: Treatment with BC 007 for beta 1-AAB neutralization was safe, resulted in a long-lasting reduction of beta 1-AAB combined with improved cardiac function and prolonged the survival of DP with DCM. Using a natural large animal model of DCM considered superior to small animal models of immunization-induced cardiomyopathy, combined with a study design comparable with clinical trials, we believe that our results provide the basis for optimism that treatment with BC 007 might also be effective in human patients with DCM.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Tiermedizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2055-5822
• Sprache: Englisch