AIMS:In heart failure patients, altered myocardial electrical fields linked to oedema may impair left ventricular function. While short-term use of implanted microcurrent generators (C-MIC) has shown promise, long-term effects remain unclear. This study assessed the safety and efficacy of C-MIC use beyond the initial 6 month pilot period. METHODS:Patients from the initial C-MIC pilot study who were alive at 6 months were screened for 2 year follow-up. The primary endpoint included rates of all-cause, cardiac- and device-related mortality, all-cause, cardiac and device related hospitalizations, along with adverse events, device malfunctions and exchanges. Secondary endpoints evaluated device performance via left ventricular ejection fraction (LVEF), 6 min walk distance, New York Heart Association (NYHA) class and SF-36 quality-of-life scores and the need for prolonged therapy. RESULTS:Of the 10 patients enrolled in the initial study, 7 were enrolled in follow-up (mean age 52.4 ± 7.6 years, NYHA Class III and mean LVEF 31.7 ± 3.7%). No device-related adverse events occurred. One non-cardiac, non-device related death was reported at 18 months. Improvement in LVEF of 11.60% [95% confidence interval (CI): 5.64-17.56, P < 0.001] from baseline to 6 months was maintained at 2 years post-C-MIC deactivation, with a sustained increase of 12.56% from baseline (95% CI: 4.67-20.45, P = 0.002). Similarly, the 6 min walk distance improved by 206.35 m at 6 months (95% CI: 161.32-251.39, P < 0.0001) and remained at 191 m above baseline at 2 years (95% CI: 131.83-250.99, P < 0.0001). Improvements in NYHA functional class and SF-36 quality-of-life scores observed at 6 months were also preserved throughout the 2 year follow-up. One patient required C-MIC reactivation. CONCLUSIONS:Long-term use of the C-MIC device appears safe with sustained improvements in NYHA class, LVEF, 6 min walk distance and quality of life, supporting the long-term therapeutic potential of microcurrent therapy.

AIMS:In patients with heart failure, alterations in electrical fields generated within the myocardium have been associated with myocardial oedema which can act as a substrate for left ventricular dysfunction. Safety and efficacy of a direct microcurrent therapy using an implanted generator (C-MIC) remain uncertain. METHODS AND RESULTS:Ambulatory patients with non-ischaemic dilated cardiomyopathy with left ventricular ejection fraction (LVEF) of 25% to 35% and New York Heart Association (NYHA) class III-IV were randomized to C-MIC (device) or control group in addition to guideline-directed medical therapy. The primary endpoint was change in LVEF at 6 months. Pre-specified secondary endpoints included 6-min walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS), and NYHA functional class. Of 70 patients randomized, 65 were included in modified intention-to-treat analysis (C-MIC device: n = 32; control: n = 33). At 6 months, treatment with C-MIC versus control improved LVEF (mean difference: 5.1%; 95% confidence interval [CI] 3.1-7.1%, p < 0.001). The proportions of patients with improvement in at least one NYHA class (risk difference: 68.9%; 95% CI 50.6-87.2, p < 0.001), an increase of ≥5 points in KCCQ-OSS (risk difference: 60.0%; 95% CI 42.3-77.6, p < 0.001), and an increase of ≥30% in 6MWD (risk difference: 38.3%; 95% CI 14.4-62.2) were substantially higher in the device versus control group (p < 0.002). CONCLUSIONS:In patients with non-ischaemic chronic heart failure with reduced ejection fraction, the C-MIC device compared with control improved LVEF, symptoms, functional capacity and quality of life.

Cardiovascular diseases are a significant cause of illness and death worldwide, often resulting in myofibroblast differentiation, pathological remodeling, and fibrosis, characterized by excessive extracellular matrix protein deposition. Treatment options for cardiac fibrosis that can effectively target myofibroblast activation and ECM deposition are limited, necessitating an unmet need for new therapeutic approaches. In recent years, microcurrent therapy has demonstrated promising therapeutic effects, showcasing its translational potential in cardiac care. This study therefore sought to investigate the effects of microcurrent therapy on cardiac myofibroblasts, aiming to unravel its potential as a treatment for cardiac fibrosis and heart failure. The experimental design involved the differentiation of primary rat cardiac fibroblasts into myofibroblasts. Subsequently, these cells were subjected to microcurrent (MC) treatment at 1 and 2 µA/cm2 DC with and without polarity reversal. We then investigated the impact of microcurrent treatment on myofibroblast cell behavior, including protein and gene expression, by performing various assays and analyses comparing them to untreated myofibroblasts and cardiac fibroblasts. The application of microcurrents resulted in distinct transcriptional signatures and improved cellular processes. Gene expression analysis showed alterations in myofibroblast markers, extracellular matrix components, and pro-inflammatory cytokines. These observations show signs of microcurrent-mediated reversal of myofibroblast phenotype, possibly reducing cardiac fibrosis, and providing insights for cardiac tissue repair.

Current therapies significantly improve survival and clinical endpoints in patients suffering from chronic heart failure with reduced ejection fraction (HFrEF), but most are not sufficient to reverse adverse remodeling and improve myocardial contractility. Herein, we report the first-in-man experience with a novel fully implantable device for cardiac electrical microcurrent (C-MIC) application. A 79-year-old man suffering from HFrEF (dilated cardiomyopathy, NYHA class III, left ventricular ejection fraction 30%) successfully underwent implantation of the C-MIC device through left anterolateral thoracotomy. At 30-day follow-up, no device-related complications were observed, demonstrating feasibility of C-MIC implantation in a patient suffering from HFrEF.

Clinical features of Coronavirus disease 2019 (COVID-19) are caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Acute infection management is a substantial healthcare issue, and the development of long-Covid syndrome (LCS) is extremely challenging for patients and physicians. It is associated with a variety of characteristics as impaired capillary microcirculation, chronic fatigue syndrome (CFS), proinflammatory cytokines, and functional autoantibodies targeting G-protein-coupled receptors (GPCR-AAbs). Here, we present a case report of successful healing of LCS with BC 007 (Berlin Cures, Berlin, Germany), a DNA aptamer drug with a high affinity to GPCR-AAbs that neutralizes these AAbs. A patient with a documented history of glaucoma, recovered from mild COVID-19, but still suffered from CFS, loss of taste, and impaired capillary microcirculation in the macula and peripapillary region. He was positively tested for various targeting GPCR-AAbs. Within 48 h after a single BC 007 treatment, GPCR-AAbs were functionally inactivated and remained inactive during the observation period of 4 weeks. This observation was accompanied by constant improvement of the fatigue symptoms of the patient, taste, and retinal capillary microcirculation. Therefore, the removal of GPCR-AAb might ameliorate the characteristics of the LCD, such as capillary impairment, loss of taste, and CFS.

COVID-19 is a pandemic respiratory disease that is caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anti-SARS-CoV-2 antibodies are essential weapons that a patient with COVID-19 has to combat the disease. When now repurposing a drug, namely an aptamer that interacts with SARS-CoV-2 proteins for COVID-19 treatment (BC 007), which is, however, a neutralizer of pathogenic autoantibodies in its original indication, the possibility of also binding and neutralizing anti-SARS-CoV-2 antibodies must be considered. Here, the highly specific virus-neutralizing antibodies have to be distinguished from the ones that also show cross-reactivity to tissues. The last-mentioned could be the origin of the widely reported SARS-CoV-2-induced autoimmunity, which should also become a target of therapy. We, therefore, used enzyme-linked immunosorbent assay (ELISA) technology to assess the binding of well-characterized publicly accessible anti-SARS-CoV-2 antibodies (CV07-209 and CV07-270) with BC 007. Nuclear magnetic resonance spectroscopy, isothermal calorimetric titration, and circular dichroism spectroscopy were additionally used to test the binding of BC 007 to DNA-binding sequence segments of these antibodies. BC 007 did not bind to the highly specific neutralizing anti-SARS-CoV-2 antibody but did bind to the less specific one. This, however, was a lot less compared to an autoantibody of its original indication (14.2%, range 11.0–21.5%). It was also interesting to see that the less-specific anti-SARS-CoV-2 antibody also showed a high background signal in the ELISA (binding on NeutrAvidin-coated or activated but noncoated plastic plate). These initial experiments suggest that the risk of binding and neutralizing highly specific anti-SARS CoV-2 antibodies by BC 007 should be low.

AbstractAimsMost devices for treating ambulatory Class II and III heart failure are linked to electrical pulses. However, a steady electric potential gradient is also necessary for appropriate myocardial performance and may be disturbed by structural heart diseases. We investigated whether chronic application of electrical microcurrent to the heart is feasible and safe and improves cardiac performance. The results of this study should provide guidance for the design of a two‐arm, randomized, controlled Phase II trial.Methods and resultsThis single‐arm, non‐randomized pilot study involved 10 patients (9 men; mean age, 62 ± 12 years) at two sites with 6 month follow‐up. All patients had New York Heart Association (NYHA) Class III heart failure and non‐ischaemic dilated cardiomyopathy, with left ventricular ejection fraction (LVEF) <35%. A device was surgically placed to deliver a constant microcurrent to the heart. The following tests were performed at baseline, at hospital discharge, and at six time points during follow‐up: determination of LVEF and left ventricular end‐diastolic/end‐systolic diameter by echocardiography; the 6 min walk test; and assessment of NYHA classification and quality of life (36‐Item Short‐Form Health Survey questionnaire). Microcurrent application was feasible and safe; no device‐related or treatment‐related adverse events occurred. During follow‐up, rapid and significant signal of efficacy (P < 0.005) was present with improvements in LVEF, left ventricular end‐diastolic diameter, left ventricular end‐systolic diameter, and distance walked. For eight patients, NYHA classification improved from Class III to Class I (for seven, as early as 14 days post‐operatively); for one, to Class II; and for one, to Class II/III. 36‐Item Short‐Form Health Survey questionnaire scores also improved highly significantly.ConclusionsChronic application of microcurrent to the heart is feasible and safe and leads to a rapid and lasting improvement in heart function and a near normalization of heart size within days. The NYHA classification and quality of life improve just as rapidly.

The Aptamer BC 007 was developed for the neutralization of autoantibodies against G-protein coupled receptors (GPCR-AAB) such as anti-β1-adrenoceptor autoantibodies (β1-AAB), which are strongly present in patients with idiopathic dilated cardiomyopathy (DCM) (prevalence 80 %), whereby β1-AAB are

Background: For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called "functional autoantibodies" bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods: Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56-78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48-82 years, median 64) with urinary stone disorders (controls). Results: Of the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007. Conclusions: We hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer.

BC 007 is a substance with a novel and innovative mode of action for the first-time causal treatment of chronic heart failure, associated with the occurrence of autoantibodies against the β1-adrenoceptor, and other diseases of mostly the heart and vascular system, being accompanied by the occurrence of functionally active agonistic autoantibodies against G-protein-coupled receptors (fGPCR-AAb). The proposed mechanism of action of BC 007 is the neutralisation of these pathogenic autoantibodies which stimulate the respective receptor. To evaluate the safety, tolerability, pharmacokinetics and mode of action of BC 007, single intravenous infusions of increasing concentration were given to healthy young males and healthy elderly autoantibody-negative and autoantibody-positive participants of both sexes. This study was subdivided into three parts. Part A was a single-centre, randomised, double-blind, placebo-controlled safety and tolerability study including healthy young male autoantibody-negative Whites (N = 23) and Asians (N = 1), testing doses of 15, 50 and 150 mg BC 007 (Cohorts 1–3) and elderly male and female Whites (N = 8), testing a dose of 150 mg BC 007 (Cohort 4), randomly assigned in a 3:1 ratio to BC 007 or placebo. Open-label Part B included fGPCR-AAb-positive subjects (50 and 150 mg BC 007, Cohorts 1 and 2, respectively). Open-label Part C included fGPCR-AAb-positive subjects for testing doses of 300, 450, 750, 1350 mg and 1900 mg BC 007. Lower doses were either given as an infusion or divided into a bolus plus infusion up to a dose of 300 mg followed by a constant bolus of 150 mg up to a dose of 750 mg, while at doses of 1350 mg and 1900 mg it was a slow infusion with a constant infusion rate. Infusion times increased with increasing dose from 20 min (15, 50 or 150 mg) to 40 min (300, 450 or 750 mg), 75 min (1350 mg) and 105 min (1900 mg). The mean observed BC 007 area under the concentration–time curve (AUC0–24) increased with increasing dose in a dose proportional manner (slope estimate of 1.039). No serious adverse events were observed. Drug-related adverse events were predominantly the expected mild-to-moderate increase in bleeding time (aPTT), beginning with a dose of 50 mg, which paralleled the infusion and returned to normal shortly after infusion. fGPCR-AAb neutralisation efficiency increased with increasing dose and was achieved for all subjects in the last cohort. BC 007 is demonstrated to be safe and well tolerated. BC 007 neutralised fGPCR-AAb, showing a trend for a dose-response relationship in elderly healthy but fGPCR-AAb-positive subjects. NCT02955420.

Constant electrical microcurrent (EM) applied to the myocardial tissue effects multiple components of the cardiomyocytes, the extracellular matrix and the intracellular signal transduction. After a series of preclinical trials, we investigated in a human pilot study whether the application of EM

Corona virus disease 2019 (COVID-19) is a respiratory disease caused by a new coronavirus (SARS-CoV-2) which causes significant morbidity and mortality. The emergence of this novel and highly pathogenic SARS-CoV-2 and its rapid international spread poses a serious global public health emergency. To date 32,174,627 cases, of which 962,613 (2.99%) have died, have been reported (https://www.who.int/westernpacific/health-topics/coronavirus, accessed 23 Sep 2020). The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020. There are still not many SARS-CoV-2-specific and effective treatments or vaccines available. A second round of infection is obviously unavoidable. Aptamers had already been at the centre of interest in the fight against viruses before now. The selection and development of a new aptamer is, however, a time-consuming process. We therefore checked whether a clinically developed aptamer, BC 007, which is currently in phase 2 of clinical testing for a different indication, would also be able to efficiently bind DNA-susceptible peptide structures from SARS-CoV-2-spreading crucial proteins, such as the receptor binding domain (RBD) of the spike protein and the RNA dependent RNA polymerase of SARS-CoV-2 (re-purposing). Indeed, several such sequence-sections have been identified. In particular for two of these sequences, BC 007 showed specific binding in a therapy-relevant concentration range, as shown in Nuclear magnetic resonance (NMR)- and Circular dicroism (CD)-spectroscopy and isothermal titration calorimetry (ITC). The excellent clinical toxicity and tolerability profile of this substance opens up an opportunity for rapid clinical testing of its COVID-19 effectiveness.

In the 1970s, autoantibodies directed against G-protein-coupled receptors (GPCR, GPCR-AAB) were discovered. After receptor binding, GPCR-AAB trigger uncontrolled receptor mediated signal cascades, thus producing pathologies. Diseases associated with such functionally active autoantibody type (functional autoantibodies) can be called "functional autoantibody diseases". Here we focus exclusively on GPCR-AAB directed against the GPCR's extracellular loops. The GPCR's role in the pathogenesis and progression is accepted in idiopathic dilated cardiomyopathy and is increasingly considered in diseases such as Chagas' cardiomyopathy, peripartum cardiomyopathy, hypertension, diabetes mellitus and scleroderma and even dementia, complex regional pain syndrome and postural orthostatic tachycardia syndrome. We briefly summarize the mechanistic background of GPCR-AAB induced pathologies, mainly focused on autoantibodies targeting the β1-adrenergic and muscarinic 2 receptors, due to their importance for cardiomyopathies. Furthermore, treatment strategies for "functional autoantibody diseases", such as for GPCR-AAB removal (therapeutic plasma exchange, immunoadsorption) and in vivo GPCR-AAB attack (intravenous IgG treatment, B-cell depletion, GPCR-AAB in vivo binding and neutralization) are critically reflected with respect to their patient benefits focused on but not exclusive to patients with dilated cardiomyopathy.

Given the growing burden of systolic heart failure (HF), there is an immense need for novel treatment strategies, which aim at myocardial recovery. Direct application of an electrical microcurrent to the myocardium triggers reverse remodeling and modifies myocardial inflammation. The aim of the

Since there is no clear evidence in the literature to show how non-modified single-stranded DNA (ssDNA) drugs are metabolized in humans, we assessed the metabolism of BC 007, an ssDNA therapeutic, under development as a neutralizer of autoantibodies against G-protein-coupled receptors. In-vitro, investigating its stability in monkey plasma and serum, a successive 3′-exonuclease degradation resulting in several n–x degradation products has been previously reported. Here, we investigated the metabolism of BC 007 in humans after intravenous application to autoantibody-positive healthy subjects, in line with Phase I safety testing. 1H-NMR was applied for n–x degradation product search and beta-aminoisobutyric acid (bAIBA) measurement in urine; ultra-performance liquid chromatography–mass spectrometry was also used for the latter. Colorimetric assays were used for quantification of uric acid in serum and urine. Fast degradation prohibited the detection of the intermediate n–x degradation products in urine using 1H-NMR. Instead, NMR revealed a further downstream degradation product, bAIBA, which was also detected in serum shortly after initial application. The purine degradation product, uric acid, confirmed this finding of fast metabolism. Fast and full degradation of BC 007, shown by nucleic bases degradation products, is one of the first reports about the fate of a ssDNA product in humans.

80 percent of patients with non-ischemic heart failure (HF) and reduced ejection fraction have autoantibodies against β1-adrenoceptos (β1-AAB), which cause and/or sustain HF. The removal of β1-AAB by immunoadsorption (IA) leads to an improvement of cardiac function and significantly reduced

Possible unwanted folding of biopharmaceuticals during manufacturing and storage has resulted in analysis schemes compared to small molecules that include bioanalytical characterization besides chemical characterization. Whether bioanalytical characterization is required for nucleotide-based drugs, may be decided on a case-by-case basis. Nucleotide-based pharmaceuticals, if chemically synthesized, occupy an intermediate position between small-molecule drugs and biologics. Here, we tested whether a physicochemical characterization of a nucleotide-based drug substance, BC 007, was adequate, using circular dichroism (CD) spectroscopy. Nuclear magnetic resonance confirmed CD data in one experimental setup. BC 007 forms a quadruplex structure under specific external conditions, which was characterized for its stability and structural appearance also after denaturation using CD and nuclear magnetic resonance. The amount of the free energy (Delta G(0)) involved in quadruplex formation of BC 007 was estimated at +8.7 kJ/mol when dissolved in water and +1.4 kJ/mol in 154 mM NaCl, indicating structural instability under these conditions. However, dissolution of the substance in 5 mM of KCl reduced the Delta G(0) to -5.6 kJ/mol due to the stabilizing effect of cations. These results show that positive DG0 of quadruplex structure formation in water and aqueous NaCl prevents BC 007 from preforming stable 3-dimensional structures, which could potentially affect drug function. (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

Background: 80 percent of patients with non-ischemic heart failure (HF) and reduced ejection fraction have autoantibodies against β1- adrenoceptors (β1-AAB), which cause and/or sustain HF. The removal of β1-AAB by immunoadsorption (IA) leads to an improvement of cardiac function and significantly reduced mortality. With the aptamer BC 007, a new drug is under study that neutralizes autoantibodies against G-Protein-coupled receptors (GP-AAB) including β1-AAB. Aptamers are often referred to as chemical antibodies and offer a number of advantages over e.g. peptides and biologics when used for treatment. Based on in vitro studies followed by animal testing, BC 007 was recently step-by-step transferred to humans. We present here a Phase I study investigated the safety, tolerability, and pharmacological effect of BC 007.Methods: In a randomized, double blind, placebo controlled single ascending dose study, 3 cohorts of 8 male healthy subjects each (age 18 - 45 yrs) were dosed with 15, 50 and 150 mg of BC 007 by i. v. infusion over 20 min. Additional 8 elderly healthy subjects of both sexes (55 - 70 yrs) received 150 mg BC007 or placebo. Subsequently, in an open labelled study part with 5 cohorts of 6 elderly volunteers each (55 - 75 yrs), who showed evidence for GP-AAB dosages of 50, 150, 300, 450, and 750 mg were tested. Infusion duration was 20 min in the 50 and 150 mg and 40 min in the 300, 450 and 750 mg cohort. Subjects safety was carefully monitored during the study (ECG, blood pressure, lab, injection site reactions, VS, physical examination, adverse events). 12 blood samples were taken from before the infusion began until 24 h thereafter for clinical chemistry, hematological and pharmacokinetic analysis. Urine was collected.Results: BC 007 was extremely well tolerated and without clinically relevant adverse events. GP-AAB neutralization has been seen 24 h after BC 007 infusion in 1 of 6 individuals in the 150 mg cohort, in 2/6 in the 300 and 400 mg and 5/6 in the 750 mg cohort. A slightly elevated aPTT (max 49 s) was observed in 5 subjects of the 300, 450, and 750 mg cohort which quickly normalized after end of infusion. AUC increased by rising dosage from 21 to 556 μg*min/mL, Cmax increased from 1610 to 15832 ng/mL. The half-life was short at appr 4 min.Conclusion: BC 007 is a powerful new drug for the neutralization of β1-AAB with a favorable side-effect profile which will be tested as the first causative acting drug for patients with β1-AAB induced heart failure. Derived from IA data, a huge number of patients with HF will profit from this new drug.