AAV6. ARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model

Raake, Philip; Ksienzyk, Jan; Reinkober, Julia; Barthelmes, Jens; Schinkel, Stefanie; Pleger, Sven T.; Mier, Walter; Haberkorn, Uwe; Koch, Walter J.; Katus, Hugo A.; Most, Patrick; Müller, Oliver

doi:10.1093/eurheartj/ehr447

Cited by 136 publications

(115 citation statements)

References 24 publications

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“…This approach has been primarily done with the bARKct as a peptide inhibitor of GRK2. [42][43][44][45][46][47][48] A recent report has also shown similar effects with a small molecular inhibitor of GRK2 that, interestingly, appears to act as the bARKct in targeting G bg binding. 45 The bARKct was designed by us in the 1990s for targeted inhibition of the GRK2-Gbg interaction.…”

Section: Myocardial Grk2 As a Hf Gene Therapy Targetmentioning

confidence: 66%

“…We have recently completed a study in a preclinical large animal model (farm pigs) aimed at investigating whether GRK2 inhibition with the bARKct represents a feasible therapeutic approach for HF. 46 In this study, taking advantage of our established ischemic cardiomyopathy pig model, 52 we found that AAV6-bARKct delivery via retrograde coronary venous perfusion could improve left ventricular dysfunction, and this therapeutic effect was accompanied by normalization of neurohormonal signaling and repression of adverse cardiac remodeling and fetal gene expression. 46 This study is important as the pig HF model more closely reflects human pathophysiology and is thus a prerequisite for planning clinical testing (Figure 3).…”

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 74%

“…Furthermore, in studies with bARKct in rat and pig models of HF, 40,46 chronic bARKct expression in failing myocardium resulted in lower circulating catecholamine levels, showing that when bARs are normalized there is feedback to the SNS to lower its stimulation. This is also a property of b-blockers.…”

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 98%

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Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

et al. 2012

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Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of b-adrenergic receptor antagonism.

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Section: Myocardial Grk2 As a Hf Gene Therapy Targetmentioning

confidence: 66%

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 74%

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 98%

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Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

et al. 2012

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“…Results [33] show that targeted deletion and lowering of cardiac myocyte GRK-2 activity by β-ARKct gene therapy leads to a novel protective and inotropic phenotype, which prevents post-ischemic HF and rescues a phenotype of established HF. The same authors reported that the inhibition of GRK-2 by β-ARKct had a beneficial effect, not only on the hemodynamic parameters of heart function, but also on normalization of the catecholaminergic neurohormonal axis [33].…”

Section: G Protein Related Kinases -General Overviewmentioning

confidence: 95%

“…The genetic manipulations at different levels of β-AR signaling demonstrate that the right point of intervention is important to the function of the heart and suggest that it is more desirable to circumvent β-AR desensitization than to simply facilitate β-AR activation [33]. Results [33] show that targeted deletion and lowering of cardiac myocyte GRK-2 activity by β-ARKct gene therapy leads to a novel protective and inotropic phenotype, which prevents post-ischemic HF and rescues a phenotype of established HF. The same authors reported that the inhibition of GRK-2 by β-ARKct had a beneficial effect, not only on the hemodynamic parameters of heart function, but also on normalization of the catecholaminergic neurohormonal axis [33].…”

Section: G Protein Related Kinases -General Overviewmentioning

confidence: 99%

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

Bojić¹,

Sudar-Milovanović²,

Mikhailidis³

et al. 2012

aoms

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A b s t r a c tIn coronary artery disease the G protein related kinases (GRKs) play a role in desensitization of β-adrenoreceptors (AR) after coronary occlusion. Targeted deletion and lowering of cardiac myocyte GRK-2 decreases the risk of postischemic heart failure (HF). Studies carried out in humans confirm the role of GRK-2 as a marker for the progression of HF after myocardial infarction (MI). The level of GRK-2 could be an indicator of β-AR blocker efficacy in patients with acute coronary syndrome. Elevated levels of GRK-2 are an early ubiquitous consequence of myocardial injury. In hypertension an increased level of GRK-2 was reported in both animal models and human studies. The role of GRKs in vagally mediated disorders such as vasovagal syncope and atrial fibrillation remains controversial. The role of GRKs in the pathogenesis of neurocardiological diseases provides an insight into the molecular pathogenesis process, opens potential therapeutic options and suggests new directions for scientific research.K Ke ey y w wo or rd ds s: : autonomic, sympathetic, vagal, molecular signaling pathway. Neurocardiovascular pathophysiology: sympathetic versus vagally mediated disordersNeural control of the cardiovascular (CV) system is an integral part of CV physiology and consequently a part of CV pathological mechanisms. Two fundamental parts of the autonomic nervous system -the sympathetic and parasympathetic (vagal) components -play a role in the development and initiation of the pathological process. The classification of neurocardiological disorders by Goldstein [1] is as follows: 1) Sympathetic disorders -diseases in which activation of the catecholamine system worsens an independent pathological state (coronary artery disease, arrhythmias as long QT syndrome, sudden death, heart failure (HF)) as well as diseases in which abnormal catecholaminergic function is etiologic (sympathetic neurocirculatory failure, hypertension, cardiac necrosis and cardiomyopathy), and 2) Vagally mediated disorders -both neurally mediated syncope (vasovagal syncope, carotid sinus hypersensitivity) and vagally mediated atrial fibrillation. Neural regulation of the CV system can be studied by using different techniques [2][3][4][5][6][7][8]. G protein related kinases (GRKs) exist in 7 isoforms -GRK 1-7. They are serine-threonine protein kinases that are C Co or rr re es sp po on nd di in ng g a au ut th ho or r: :

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Gene Therapy in Heart Failure

Hayward¹,

Patel²,

Welch³

et al. 2017

Encyclopedia of Life Sciences

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Heart failure is a chronic condition leading to debilitating symptoms and reduced life expectancy. Several pharmacological therapies which improve symptoms and mortality have been developed over the past 30 years. These therapies are, however, limited in terms of both efficacy and side‐effect profile. Gene therapy represents a fundamental change in the way treatments are developed with the potential to directly target and correct individual molecular abnormalities. These therapies have the potential to offer long‐term beneficial effects from a single treatment and, with direct targeting, less off‐target effects. As with any new therapy, a number of challenges must be overcome before gene therapy can be considered a realistic option to patients with heart failure. Key Concepts Gene therapy could allow direct targeting of molecular abnormalities in patients with heart failure. Preclinical data suggests that in animal models of heart failure, SERCA2a gene therapy significantly improves haemodynamic parameters, reduces arrhythmia risk and corrects molecular abnormalities. Initial clinical data in a small number of patients suggested that SERCA2a gene therapy was beneficial to patients with advanced heart failure. However, a recent study in a larger number of patients was disappointingly neutral. A number of molecular abnormalities exist in the failing myocytes, each of which could represent a potential target to treat heart failure. Gene therapy requires a large financial commitment from pharmaceutical companies and cost is a major limitation to the development of gene therapy products.

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AAV6. ARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model

Abstract: These data--showing sustained amelioration of cardiac function in a post-MI pig HF model--demonstrate the therapeutic potential of βARKct gene therapy for HF.

Cited by 136 publications

References 24 publications

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

Gene Therapy in Heart Failure

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