Aptamer Therapy for Heart Failure?

Port, J. David; Bristow, Michael R.

doi:10.1161/circresaha.111.255661

Cited by 9 publications

(5 citation statements)

References 35 publications

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“…Accordingly, anti‐β 1 AR‐ab titres of GST–β 1 AR‐immunized animals never increased in response to once‐monthly repeated i.v injections of β 1 AR‐analogous cyclic peptides, among them COR‐1, for an observation period of up to 1 year . Considering all these results, we therefore do not believe that treatment with COR‐1 or other tested β 1 AR‐EC II‐homologous cyclic peptides could induce an immune response by itself, similarly to what is expected for a proposed alternative therapeutic approach with anti‐β 1 AR‐ab‐directed aptamers ,…”

Section: Discussionmentioning

confidence: 77%

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β₁‐adrenergic receptor antibody neutralization and of immune parameters

Münch

Boivin‐Jahns

Holthoff

et al. 2012

European J of Heart Fail

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AimsA novel concept for the treatment of heart failure is the neutralization of antibodies against the b 1 -adrenergic receptor (anti-b 1 AR-ab). In a rat model of autoimmune cardiomyopathy, the cyclic peptide COR-1 (given i.v. once monthly) neutralized anti-b 1 AR-abs and prevented anti-b 1 AR-ab-induced myocardial damage, and completely reverted cardiac dysfunction over 3-6 months. Methods and resultsA clinical phase I trial was designed as a single-blinded, placebo-controlled study. Fifty human volunteers received COR-1 or matching placebo as a single i.v. administration with ascending doses (10 -240 mg). Primary endpoints were safety and tolerability, while the pharmacokinetic profile of COR-1 was assessed as a secondary endpoint. All five investigated dose groups were well tolerated; no drug-related side effects occurred. Pharmacokinetics revealed a favourable profile with an almost complete plasma clearance within 60 min after administration. Pharmacodynamic investigation showed dose-dependent efficacy with almost complete scavenging of pathological antib 1 AR-abs ex vivo at the two highest doses. No anti-COR-1 autoantibodies occurred. No other effects on the immune system (such as an increase of crucial cytokines) were observed up to 43 days after drug administration, nor upon incubation of anti-b 1 AR-ab-positive patient blood samples with COR-1 ex vivo. ConclusionsCOR-1 was shown to be safe after i.v. administration in vivo; no relevant side effects occurred. Efficacy was estimated from ex vivo investigation of the potency to neutralize specific anti-b 1 -AR-abs.

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Section: Discussionmentioning

confidence: 77%

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β₁‐adrenergic receptor antibody neutralization and of immune parameters

Münch

Boivin‐Jahns

Holthoff

et al. 2012

European J of Heart Fail

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“…In a further move, new high specificity ligands called ‘aptamers’ have been developed that bind to and theoretically neutralize anti‐β 1 AR‐Abs. 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 .…”

Section: Therapeutic Options In the Pipelinementioning

confidence: 99%

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

Patel

Hernandez

2013

European J of Heart Fail

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Anti-beta-1-adrenergic receptor antibodies (anti-b 1 AR Abs) have long been implicated in the pathogenesis of dilated cardiomyopathy (DCM). It is believed that these autoantibodies bind to and constitutively stimulate the b 1 AR to promote pathological cardiac remodelling and b 1 AR desensitization and downregulation. The prevalence of anti-b 1 AR Abs in patients with DCM ranges from 26% to 60%, and the presence of these autoantibodies correlates with a poor prognosis. Several small studies have shown improvements in functional status, haemodynamics, and biomarkers of heart failure upon removal or neutralization of these antibodies from the sera of affected patients. Traditionally, removal of anti-b 1 AR Abs required immunoadsorption therapy with apheresis columns directed against human immunoglobulins (Igs) and subsequent i.v. Ig infusion, thereby essentially performing a plasma exchange transfusion. However, recent advances have allowed the development of small peptides and nucleotide sequences that specifically target and neutralize anti-b 1 AR Abs, providing a hopeful avenue for future drug development to treat DCM. Herein, we briefly review the clinical literature of therapy directed against anti-b 1 AR Abs and highlight the opportunity for further research and development in this area.--

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“…11 Our previously selected aptamer using the Monolex technology 12 bound β1-AABs isolated from patients with DCM, Chagas' cardiomyopathy, or peripartum cardiomyopathy and neutralized their pathogenic functions, which we demonstrated in vitro by reducing β1-AAB-induced chronotropy and apoptosis. 1 However, as recently discussed, 13 the relationship between the selected aptamer and β1-AABs must be consolidated in vivo using animal models.…”

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confidence: 99%

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

Wallukat

Haberland

Berg

et al. 2012

Circ J

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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.

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Aptamer Therapy for Heart Failure?

Cited by 9 publications

References 35 publications

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β₁‐adrenergic receptor antibody neutralization and of immune parameters

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β₁‐adrenergic receptor antibody neutralization and of immune parameters

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

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

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Aptamer Therapy for Heart Failure?

Cited by 9 publications

References 35 publications

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β1‐adrenergic receptor antibody neutralization and of immune parameters

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β1‐adrenergic receptor antibody neutralization and of immune parameters

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

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

Contact Info

Product

Resources

About

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β₁‐adrenergic receptor antibody neutralization and of immune parameters

Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β₁‐adrenergic receptor antibody neutralization and of immune parameters