2013
DOI: 10.1038/gt.2013.63
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Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model

Abstract: Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Ret… Show more

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Cited by 37 publications
(35 citation statements)
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“…Of note, S100A1 protein changes achieved by in vitro and in vivo cDNA delivery felt within the optimal therapeutic range. 38 Hence, our novel mechanistic data obtained in βAR-stimulated failing cardiomyocytes and EHTs strongly support the notion that S100A1 is necessary for diastolic RyR2 function in vivo and inhibits the occurrence of Ca 2+ -triggered lethal fibrillation. As such, the Ca 2+ -dependent inotrope S100A1 combines chronic cardiac performance enhancement with protection against Ca 2+ -triggered arrhythmias.…”
Section: Figure 6 S100a1 Restores Isometric Twitch Tension and Prevensupporting
confidence: 67%
See 1 more Smart Citation
“…Of note, S100A1 protein changes achieved by in vitro and in vivo cDNA delivery felt within the optimal therapeutic range. 38 Hence, our novel mechanistic data obtained in βAR-stimulated failing cardiomyocytes and EHTs strongly support the notion that S100A1 is necessary for diastolic RyR2 function in vivo and inhibits the occurrence of Ca 2+ -triggered lethal fibrillation. As such, the Ca 2+ -dependent inotrope S100A1 combines chronic cardiac performance enhancement with protection against Ca 2+ -triggered arrhythmias.…”
Section: Figure 6 S100a1 Restores Isometric Twitch Tension and Prevensupporting
confidence: 67%
“…Adenovirus and AAV production was performed as described previously. 38 Systemic in vivo adeno-associated virus serotype 9 gene transfer.…”
Section: A Detailed Description Of Materials and Methods Is Availablementioning
confidence: 99%
“…Transcriptional modulators may also have clinically significant toxic off-target effects owing to their ability to regulate the expression of numerous proteins under the control of the same or related transcriptional regulatory assemblies. Although gene therapy has not been used to modulate the expression of S100 family members in patients with cancer, it has been used in preclinical animal models, in which it beneficially upregulates S100A1 expression in heart disease 142 . Other approaches to modulate S100 protein activity include S100A4- and S100P–neutralizing antibodies 93,94,143 , and peptibodies (peptide–Fc fusion proteins) directed against S100A8 and S100A9 (REF.…”
Section: Targeting S100 Proteinsmentioning
confidence: 99%
“…Gene therapy is a new option for treatment of heart failure (HF). Several gene therapies have been developed to improve cardiac performance in HF models by targeting calcium and adrenergic signalling, including the overexpression of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) which regulates calcium movement between the cytoplasm and the sarcoplasmic reticulum (SR), S100A which modifies SR calcium handling, β‐adrenergic receptor kinase (β‐ARKct) which restores β‐adrenergic receptor signalling, small ubiquitin‐related modifier 1 (SUMO‐1) which regulates SERCA2a through post‐transcriptional modification, and an inhibitor of protein phosphatase 1 (I‐1c) which regulates de‐phosphorylation of phospholamban . All of these gene therapies have employed adeno‐associated virus (AAV) vectors to deliver their respective transgene.…”
Section: Introductionmentioning
confidence: 99%