Introducing Genes to the Heart

Hajjar, Roger J.; Ishikawa, Kiyotake

doi:10.1161/circresaha.116.310039

Cited by 27 publications

(18 citation statements)

References 15 publications

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“…Several strategies are proposed to increase transgene efficacy (28); the practical ones are: 1) using a different vector with a better cardiac tropism; 2) increasing the dose; and 3) modifying the vector delivery method. In the current study, we addressed the first 2 strategies to improve the transduction efficacy from that of CUPID.…”

Section: Discussionmentioning

confidence: 99%

Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Watanabe

Ishikawa

Fish

et al. 2017

Journal of the American College of Cardiology

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BACKGROUND Increased protein phosphatase-1 (PP1) in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting PP1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. OBJECTIVES We sought to determine the therapeutic efficacy of a re-engineered adeno-associated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy. METHODS Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation (MR). One month after MR induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naïve pigs received different doses of BNP116.I-1c for safety evaluation. RESULTS At 1 month after MR induction, pigs developed HF as evidenced by increased left ventricular (LV) end-diastolic pressure and LV volume indexes. Treatment with BNP116.I-1c resulted in improved LV ejection fraction (−5.9 ± 4.2% vs. 5.5 ± 4.0%; p < 0.001) and adjusted dP/dt maximum (−3.39 ± 2.44 s-1 vs. 1.30 ± 2.39s-1; p = 0.007). Moreover, BNP116.I-1c-treated pigs also exhibited a significant increase in left atrial (LA) ejection fraction at 2 months after gene delivery (−4.3 ± 3.1% vs. 7.5 ± 3.1%; p = 0.02). In vitro I-1c gene transfer in isolated LA myocytes from both pigs and rats exhibited increased calcium transient amplitude, consistent with its positive impact on LA contraction. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs. CONCLUSIONS Intracoronary delivery of BNP116.I-1c was safe and improved contractility of the left ventricle and atrium in a large animal model of nonischemic HF.

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Section: Discussionmentioning

confidence: 99%

Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Watanabe

Ishikawa

Fish

et al. 2017

Journal of the American College of Cardiology

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“…The safety of Adeno-Associated Vectors (AAV) in patients with heart failure has expanded their use in various cardiovascular diseases. 5 The early trials with AAV vectors have revealed that higher doses and improved delivery are critical for efficacious gene delivery in patients. 5 …”

Section: Human Psc and Cardiovascular Cell Therapy Sessionmentioning

confidence: 99%

“…5 The early trials with AAV vectors have revealed that higher doses and improved delivery are critical for efficacious gene delivery in patients. 5 …”

Section: Human Psc and Cardiovascular Cell Therapy Sessionmentioning

confidence: 99%

Meeting Report for the 2017 National Institutes of Health National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium

Zhu

Zhang

2017

Circulation Research

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“…Heart failure affects approximately 26 million people worldwide and is characterised by insufficient cardiac function, poor coronary microvascular reactivity, and maladaptive cardiomyocyte hypertrophy. Despite significant therapeutic advances, none of the current treatment strategies provides long‐term benefit since the disease is associated with a 5‐year mortality of almost 50% . Given also that current standard‐of‐care treatments, such as β‐blockers or diuretics, are generally administered indefinitely, can cause serious side effects, and do not fully mitigate heart failure‐related morbidity and mortality, alternative, disease‐modulating solutions are still required.…”

Section: Introductionmentioning

confidence: 99%

Repurposing an anti‐cancer agent for the treatment of hypertrophic heart disease

Dukinfield

Maniati

Reynolds

et al. 2019

The Journal of Pathology

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Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics is a major contributor to heart failure advancement. Thus, dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present evidence for the potential to repurpose a former anti-cancer Arg-Gly-Asp (RGD)-mimetic pentapeptide, cilengitide, here used at low doses. Cilengitide targets v3 integrin and this protein is upregulated in human dilated and ischaemic cardiomyopathies. Treatment of mice after abdominal aortic constriction (AAC) surgery with low-dose cilengitide (ldCil) enhances coronary angiogenesis and directly affects cardiomyocyte hypertrophy with an associated reduction in disease severity. At a molecular level, ldCil treatment has a direct effect on cardiac endothelial cell transcriptomic profiles, with a significant enhancement of pro-angiogenic signalling pathways, corroborating the enhanced angiogenic phenotype after ldCil treatment. Moreover, ldCil treatment of Angiotensin II-stimulated AngII-stimulated cardiomyocytes significantly restores transcriptomic profiles similar to those found in normal human heart. The significance of this finding is enhanced by transcriptional similarities between AngII-treated cardiomyocytes and failing human hearts. Taken together, our data provide evidence supporting a possible new strategy for improved heart failure treatment using low-dose RGD-mimetics with relevance to human disease.

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Introducing Genes to the Heart

Cited by 27 publications

References 15 publications

Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Meeting Report for the 2017 National Institutes of Health National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium

Repurposing an anti‐cancer agent for the treatment of hypertrophic heart disease

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