Neutralization of pathogenic beta1-receptor autoantibodies by aptamers in vivo: the first successful proof of principle in spontaneously hypertensive rats

Abstract

Autoantibodies (AABs) against the second extracellular loop of the beta1-receptor (beta1(II)-AABs) are found as a pathogenic driver in patients with idiopathic dilated cardiomyopathy, Chagas cardiomyopathy, peripartum cardiomyopathy, and myocarditis, and have been increasingly seen as a treatment target. We recently identified an aptamer (single short DNA strand) that specifically binds and neutralizes beta1(II)-AABs. Via application of this aptamer, a new treatment strategy for diseases associated with the cardio-pathogenic beta1(II)-AABs could be developed. Spontaneously hypertensive rats (SHR) positive for beta1(II)-AABs were treated five times at weekly intervals (bolus application of 2 mg/kg body weight followed by an infusion of the same amount over 20 min). SHR responded to aptamer treatment with a strong reduction in the cardio-pathogenic beta1(II)-AABs. The AABs did not substantially return within the study period. No signs for aptamer toxicity were observed by visual examination of the heart, liver, and kidney, or by measurement of plasma CK, ALT, and creatinine. The aptamer's potential for beta1(II)-AAB neutralization and consequently for cardiomyopathy treatment has been shown for the first time in vivo.

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

“…This peptide acts comparable to the second loop mimics COR-1 which was already studied to counteract β1-AAB in patients with DCM (14). The other two substances are aptamers (15,35): the first (aptamer 110; D2) is able to neutralize only β1-AAB due to specific β1-AAB binding, which was demonstrated in vitro and in an animal study (36,37), while the second (BC 007; D3), as demonstrated in animal and human studies, is able to inhibit several GPCR-AAB, including β1-AAB and M2-AAB (38,39). After drug pre-incubation of β1-AAB or M2AAB containing IgG from DP with the drugs (test concentration 1 μmol/l), the mixture was added to the bioassay for measurement of the chronotropic activity of IgG.…”

The interstitium in cardiac repair: role of the immune–stromal cell interplay

“…3) Over the past decade, aptamers have been used in several experimental cardiovascular applications, including amelioration of cardiotoxicity, biomarker discovery, and improvement of cardiac muscle contractility [160][161][162] . Other examples include osteopontin RNA aptamers that reduced cardiac hypertrophy and fibrosis in a mouse model of heart failure induced by pressure overload 163 and aptamers designed to neutralize G-coupled receptor autoantibodies for potential treatment of cardiomyopathies 164 or to neutralize β1-adrenergic receptor autoantibodies as a potential therapeutic strategy in hypertension 165 . Clinical challenges of aptamers-based strategies to be addressed include duration of action and rapid degradation rates, excretion by renal filtration, interaction with nonspecific targets, and automation for mass production 159 .…”

Analytica Conference 2014, München 02. April 2014

“…In einem zweiten Konzept werden Aptamere zur in vivo Neutralisation von GPCR-AAK eingesetzt. Für ein spezifisch beta1-AAK bindendes Aptamer als auch für ein Aptamer, das alle in Tabelle 1 aufgeführten GPCR-AAK bindet, wurde die neutralisierende Wirkung auf die jeweiligen GPCR-AAK im Zellsystem und im Tierversuch nachgewiesen [15][16][17]. Verglichen mit Peptiden oder Aptameren mit Spezifität für jeweils nur einen GPCR-AAK könnte das Aptamer, das parallel verschiedenste GPCR-AAK neutralisiert, ein deutlich umfangreicheres Indikationsgebiet finden, insbesondere auch für Patienten von Vorteil sein, deren Erkrankung von mehreren GPCR-AAK determiniert ist (z.B.…”