The First Aptamer-Apheresis Column Specifically for Clearing Blood of β1-Receptor Autoantibodies

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp e present here for the first time in vitro and animal experiments demonstrating aptamer-based clearing from blood of pathogenic autoantibodies targeting the second extracellular loop of the β1-receptor using apheresis technology.We recently published the selection and identification of a novel ssDNA aptamer that targets autoantibodies directed against the second extracellular loop of the adrenergic β1-receptor (β1-AABs). 1 As recently summarized, 2,3 autoantibodies directed against the first or second extracellular loop of the adrenergic β1-receptor (ie, β1-AABs) have been found in patients with cardiomyopathies, with evidence that mainly β1-AABs directed at the second loop are related to disease pathogenesis. 4 Up to 80% of patients with dilated cardiomyopathy (DCM) are positive for either first-or second-loop β1-AABs; approximately one-half of the patients present with first-loop β1-AABs, the other half with second-loop β1-AABs. As demonstrated in a Bolivian cohort, nearly 100% of patients with Chagas' cardiomyopathy are positive for second-loop β1-AABs. 5 A first indication exists that exclusively second-loop β1-AABs were found also in patients with peripartum cardiomyopathy. 6 Consequently, technologies have been developed to clear β1-AABs from the blood of β1-AAB-positive DCM patients via immunoapheresis. In addition, β1-AAB immunoapheresis has been suggested for the treatment of Chagas' patients. Background: Application of immunoapheresis to eliminate pathogenic autoantibodies targeting the second extracellular loop of the β1-receptor (β1-AABs) is currently investigated in patients with cardiomyopathy. Aptamers (single short DNA or RNA strands) are a new class of molecules that bind to a specific target molecule. This property qualifies aptamers for potential use in the apheresis technique. We recently identified an aptamer that specifically binds to β1-AABs, so in the present study we tested whether this aptamer could be used as a binder to prepare an apheresis column suitable for clearing β1-AABs from rat's blood.

Novel Retro-Inverso Peptide Inhibitor Reverses Angiotensin Receptor Autoantibody–Induced Hypertension in the Rabbit

“…These include elimination of cardiomyopathic autoantibodies by immunoadsorption 19, 20 and use of specific peptides or oligonucleotides as autoantibody scavengers. 21-23 Orthosteric receptor antagonists are questionable since they also block the normal ligand and thereby impair the normal physiological responses. Small peptide inhibitors as therapeutic agents have several advantages over other small molecules, including high specificity and low levels of toxicity and immunogenicity.…”

Autoantibodies and Cardiovascular Dysfunction: Cause or Consequence?

“…These findings are consistent with the hypothesis that heightened adrenergic drive associated with β 1 AR-AAb generation in DCM can lead to adverse cardiac consequences. Besides anti-adrenergic therapy, studies are currently ongoing to determine if an aptamer for neutralizing β 1 AR-AAbs may curtail disease progression and perhaps even facilitate recovery [31]. …”

Targeting anti‐beta‐1‐adrenergic receptor antibodies for dilated cardiomyopathy

“…Aptamers are small nucleotide sequences engineered to be high affinity ligands for numerous biological targets, including autoantibodies . Following identification of a neutralizing oligonucleotide aptamer that specifically targets anti‐β 1 AR Abs, there has been subsequent development of apheresis columns that remove anti‐β 1 AR Abs with high specificity in animal models of hypertension . To date, no studies have tested the efficacy of aptamer apheresis in humans, but one would expect optimistic results that could clarify the role of anti‐β 1 AR Abs in DCM.…”