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

Schimke, Ingolf; Wess, Gerhard; Wallukat, Gerd; Fritscher, Anna; Becker, Niels-Peter; Wenzel, Katrin; MuÌˆller, J.

doi:10.1101/575613

Cited by 3 publications

(5 citation statements)

References 49 publications

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“…DP with DCM show many similarities to human DCM, [16][17][18][19][20] and, most importantly, as for human DCM, DP DCM is closely associated with β1-AAB (prevalence: 67.8%), with an indication for the disease-driving role of β1-AAB. 21 In the present study, we show that i.v. treatment with BC 007 induced no adverse effects, effectively reduced β1-AAB in DP with DCM and resulted in improved long-term outcome of the dogs.…”

Section: Introductionsupporting

confidence: 59%

“…This agrees with our recent study that β1-AAB-positive DP with DCM have a significantly shorter survival time than comparable DP without β1-AAB. 21 Last but not least, the longer survival time because of neutralizing β1-AAB by BC 007 in DP with DCM strongly corresponded to the survival effects published for people with DCM who were treated with immunoadsorption for β1-AAB removal. 45…”

Section: Survivalmentioning

confidence: 56%

“…35 In accordance with this, we have selected DP as a model because of the high prevalence of DCM, 15 with many similarities compared with the related human disease, [16][17][18][19][20] including the indication for β1-AAB as a DCM driver. 21 With DP as the study model, and using the enrolment of client-owned purebred DP attending a veterinary medical institution for routine check-up, disease diagnostics, or follow-up, we were able to design our study in a manner similar to common clinical studies. In addition, the DP of our study came from different breeding populations throughout Europe and therefore have greater genetic diversity, which can better reflect the pathogenic situation in human DCM.…”

Section: Animal Model and Study Designmentioning

confidence: 99%

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

et al. 2020

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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 β1-adrenergic receptor (β1-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 β1-AAB positivity for that the disease-driving role in DP DCM was demonstrated, the safety of BC 007, efficacy for neutralizing β1-AAB, and the DP's outcome were investigated. Methods and results Fourteen client-owned β1-AAB-positive DP with electrocardiographically and echocardiographically indicated DCM were treated with BC 007. For controlling, two groups were created: 14 β1-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 β1-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 β1-AAB, which led to a reduction or stabilization of left ventricular end-systolic volume (ESVI) during β1-AAB free time in 10 of the treated DP. In one DP, where β1-AAB returned after 3 months and ESVI worsened again, a second BC 007 treatment after 9 months again cleared the blood from β1-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 β1-AAB neutralization was safe, resulted in a long-lasting reduction of β1-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.

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Section: Introductionsupporting

confidence: 59%

Section: Survivalmentioning

confidence: 56%

Section: Animal Model and Study Designmentioning

confidence: 99%

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

et al. 2020

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“…The binding of Abs to the first extracellular loop was never observed in patients and dogs with DCM. The Abs against the b-AR in DCM dogs may play a similar important role as in the DCM Doberman dogs and patients with DCM (32,33). In patients with DCM, Abs play a very important role in the pathogenesis of this disease.…”

Section: Discussionmentioning

confidence: 90%

Functional antibodies against G-protein coupled receptors in Beagle dogs infected with two different strains of Trypanosoma cruzi

et al. 2022

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The interaction of the anti-beta1-adrenergic receptor autoantibodies (β1ARAb) and the anti-muscarinic M2 receptor autoantibodies (M2RAb) with cardiac neurotransmitter receptors were identified in human chronic Chagas cardiomyopathy (CCC) related to the ECG and dysautonomia disturbances. Dogs are considered gold model to the study of Trypanosoma cruzi infection due the clinical similarities with CCC. This study aims to evaluate whether anti-β1ARAb, anti-β2ARAb, and anti-muscarinic M2RAb are generated in Beagle dogs infected by T. cruzi using Y and Berenice-78 strains of T. cruzi. Animals were infected with 4.0 x 103 bloodstream trypomastigotes/kg of body weight and, after 25 months of infection, blood sample was collected, and serum stored at -80°C. Dog serum was treated by ammonium sulphate precipitation and the IgG antibodies isolated and added to the beating neonatal rats’ cardiomyocytes. All T. cruzi-infected dogs developed agonistic β1ARAb, β2ARAb, and M2RAb. Animals infected by Berenice strain presented less β2ARAb and M2RAb activities than dogs infected by Y strain of the parasite. In cardiomyocytes culture, the antibodies recognized an epitope on the second extracellular loop of the receptors which were similar to findings in human Chagas disease. There was no detection of antibody against G protein-coupled receptor in serum from uninfected dogs. In conclusion, both Y and Berenice-78 strains of T. cruzi induced dog antibodies, whose targets located in the second extracellular loop of the adrenergic and muscarinic receptors were similar to those observed in individuals with CCC. Therefore, our findings highlight dogs as a promisor model to investigate pathogenic roles of functional Ab against G-protein coupled receptors.

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“…Diese sind bei der idiopathischen DCM des Menschen in bis zu 80% der Fälle nachweisbar und binden hauptsächlich an Beta-1-Rezeptoren des Myokards, aber auch an die myokardialen Proteine Myosin-C und Troponin, und führen so zu einer linksventrikulären systolischen Dysfunktion (BECKER et al, 2017). Bei der DCM des Dobermanns können diese ebenfalls nachgewiesen werden und nehmen mit fortschreitender Erkrankung in ihrer Aktivität deutlich zu (WESS et al, 2019). Eine aktuelle Studie konnte zeigen, dass eine Neutralisierung dieser Autoantikörper durch gegen diese gerichtete einzelsträngige DNA-Nukleotide (Aptamer BC 007) bei Dobermännern möglich ist und sich somit die Überlebenszeit der betroffenen Tiere signifikant verlängert (WERNER et al, 2020).…”

Section: äTiologieunclassified

Vorhofflimmern als prognostischer Faktor bei der dilatativen Kardiomyopathie des Dobermanns im kongestiven Herzversagen

Friederich

Seuß

Wess

2021

Tierärztliche Praxis Ausgabe K: Kleintiere / Heimtiere

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

Abstract: 57Doberman pinschers presented β1-AAB associated autoimmunity similar to that driving the 58 pathogenesis of human DCM. Consequently, DP could remove the lack of animal models 59 available for studying β1-AAB autoimmunity in DCM.

Cited by 3 publications

References 49 publications

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

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

Functional antibodies against G-protein coupled receptors in Beagle dogs infected with two different strains of Trypanosoma cruzi

Vorhofflimmern als prognostischer Faktor bei der dilatativen Kardiomyopathie des Dobermanns im kongestiven Herzversagen

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