Gene Therapy in Heart Failure

Hayward, Carl; Patel, Hitesh; Lyon, Alexander R.

doi:10.1253/circj.cj-14-1053

Cited by 15 publications

(3 citation statements)

References 53 publications

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“…Serca2 expression as well as protein abundance is significantly altered in the diseased or aged sinus node (Tellez et al, 2011 ; Benoist et al, 2014 ). It has been long established that SERCA2a expression and activity is decreased in human heart failure of most etiologies and SERCA2a is a promising target for gene therapy in heart failure (Unverferth et al, 1988 ; Mercadier et al, 1990 ; Hasenfuss et al, 1994 ; Bers et al, 2003 ; Hayward et al, 2014 ). However, it has not been clear whether Serca2 loss is a basis for or a result of sinus node disease and heart failure.…”

Section: Clinical Perspectives and Future Applicationsmentioning

confidence: 99%

Ca2+-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance

et al. 2016

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Background: The sarcoplasmic reticulum Ca2+-ATPase (SERCA2) pump is an important component of the Ca2+-clock pacemaker mechanism that provides robustness and flexibility to sinus node pacemaking. We have developed transgenic mice with reduced cardiac SERCA2 abundance (Serca2 KO) as a model for investigating SERCA2's role in sinus node pacemaking.Methods and Results: In Serca2 KO mice, ventricular SERCA2a protein content measured by Western blotting was 75% (P < 0.05) lower than that in control mice (Serca2 FF) tissue. Immunofluorescent labeling of SERCA2a in ventricular, atrial, sinus node periphery and center tissue sections revealed 46, 45, 55, and 34% (all P < 0.05 vs. Serca2 FF) lower labeling, respectively and a mosaic pattern of expression. With telemetric ECG surveillance, we observed no difference in basal heart rate, but the PR-interval was prolonged in Serca2 KO mice: 49 ± 1 vs. 40 ± 1 ms (P < 0.001) in Serca2 FF. During exercise, heart rate in Serca2 KO mice was elevated to 667 ± 22 bpm, considerably less than 780 ± 17 bpm (P < 0.01) in Serca2 FF. In isolated sinus node preparations, 2 mM Cs+ caused bradycardia that was equally pronounced in Serca2 KO and Serca2 FF (32 ± 4% vs. 29 ± 5%), indicating no change in the pacemaker current, If. Disabling the Ca2+-clock with 2 μM ryanodine induced bradycardia that was less pronounced in Serca2 KO preparations (9 ± 1% vs. 20 ± 3% in Serca2 FF; P < 0.05), suggesting a disrupted Ca2+-clock. Mathematical modeling was used to dissect the effects of membrane- and Ca2+-clock components on Serca2 KO mouse heart rate and sinus node action potential. Computer modeling predicted a slowing of heart rate with SERCA2 downregulation and the heart rate slowing was pronounced at >70% reduction in SERCA2 activity.Conclusions: Serca2 KO mice show a disrupted Ca2+-clock-dependent pacemaker mechanism contributing to impaired sinus node and atrioventricular node function.

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Section: Clinical Perspectives and Future Applicationsmentioning

confidence: 99%

Ca2+-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance

et al. 2016

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“…[4] Approaches to restore abnormal Ca2 + homeostatic imbalance have been developed for decades, among which SERCA2a gene therapy is one of the hot spots of research, and cardiac function in heart failure patients can be improved by SERCA2a gene therapy. [5] However, the main studies of SERCA2a are the expression in myocardial tissue and its activity on heart failure and the feasibility of gene therapy, and there are few studies on SERCA2a expression in serum heart failure patients and whether it responds to the severity of heart failure patients consistent with the expression level in myocardial tissue. Our search revealed reports that SERCA2a serum levels may be associated with the occurrence of primary graft dysfunction and rejection after heart transplantation, [6,7] so, is the concentration of SERCA2a serum levels also associated with the outcome of distant events in heart failure patients?…”

Section: Introductionmentioning

confidence: 99%

Serum SERCA2a levels in heart failure patients are associated with adverse events after discharge

Chen,

Wu,

et al. 2024

Medicine

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Calcium homeostasis imbalance is one of the important pathological mechanisms in heart failure. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), a calcium ATPase on the sarcoplasmic reticulum in cardiac myocytes, is a myocardial systolic-diastolic Ca2 + homeostasis regulating enzyme that is not only involved in cardiac diastole but also indirectly affects cardiac myocyte contraction. SERCA2a expression was found to be decreased in myocardial tissue in heart failure, however, there are few reports on serum SERCA2a expression in patients with heart failure, and this study was designed to investigate whether serum SERCA2a levels are associated with the occurrence of adverse events after discharge in patients hospitalized with heart failure. Patients with heart failure hospitalized in the cardiovascular department of the Second Affiliated Hospital of Guangdong Medical University, China, from July 2018 to July 2019 were included in this study, and serum SERCA2a concentrations were measured; each enrolled patient was followed up by telephone after 6 months (6 ± 1 months) for general post-discharge patient status. The correlation between serum SERCA2a levels and the occurrence of adverse events (death or readmission due to heart failure) after hospital discharge was assessed using multiple analysis and trend analysis. Seventy-one patients with heart failure were finally included in this study, of whom 38 (53.5%) were men and 33 (46.5%) were women (All were postmenopausal women). Multiple analysis revealed no correlation between serum SERCA2a levels and the occurrence of adverse events in the total study population and in male patients, but serum SERCA2a levels were associated with the occurrence of adverse outcome events after hospital discharge in female patients (OR = 1.02, P = .047). Further analysis using a trend analysis yielded a 4.0% increase in the risk of adverse outcomes after hospital discharge for each unit increase in SERCA2a in female patients (OR = 1.04; P = .02), while no significant difference was seen in men. This study suggests that serum SERCA2a levels at admission are associated with the occurrence of post-discharge adverse events in postmenopausal female patients hospitalized with heart failure.

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“… 1 The first approved AAV-based gene therapy in the Western world is alipogene tiparvovec for the treatment of lipoprotein deficiency, which shows that this approach can be successfully and safely applied to monogenic diseases. 2 Additionally, AAV vectors for the treatment of more complex diseases such as heart failure have seen some success in clinical trials, 3 , 4 and many advances are made using these vectors as cancer therapeutics. 5 …”

Section: Introductionmentioning

confidence: 99%

Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model

Crommentuijn

Kantar

Noske

et al. 2016

Molecular Therapy - Oncolytics

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Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver), with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors.

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Gene Therapy in Heart Failure

Cited by 15 publications

References 53 publications

Ca2+-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance

Ca2+-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance

Serum SERCA2a levels in heart failure patients are associated with adverse events after discharge

Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model

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