scholarly journals Adeno-associated viral (AAV) vector-mediated therapeutics for diabetic cardiomyopathy – current and future perspectives

2021 ◽  
Vol 135 (11) ◽  
pp. 1369-1387
Author(s):  
Darnel Prakoso ◽  
Mitchel Tate ◽  
Miles J. De Blasio ◽  
Rebecca H. Ritchie
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Diabetic Cardiomyopathy ◽  
Viral Vector ◽  
Therapeutic Potential ◽  
Future Perspectives ◽  
Cardiac Damage ◽  
Pharmacological Agents ◽  
Potential Alternative ◽  
Artery Disease

Abstract Diabetes increases the prevalence of heart failure by 6–8-fold, independent of other comorbidities such as hypertension and coronary artery disease, a phenomenon termed diabetic cardiomyopathy. Several key signalling pathways have been identified that drive the pathological changes associated with diabetes-induced heart failure. This has led to the development of multiple pharmacological agents that are currently available for clinical use. While fairly effective at delaying disease progression, these treatments do not reverse the cardiac damage associated with diabetes. One potential alternative avenue for targeting diabetes-induced heart failure is the use of adeno-associated viral vector (AAV) gene therapy, which has shown great versatility in a multitude of disease settings. AAV gene therapy has the potential to target specific cells or tissues, has a low host immune response and has the possibility to represent a lifelong cure, not possible with current conventional pharmacotherapies. In this review, we will assess the therapeutic potential of AAV gene therapy as a treatment for diabetic cardiomyopathy.

scholarly journals Diabetic cardiomyopathy

2009 ◽  
Vol 116 (10) ◽  
pp. 741-760 ◽  
Author(s):  
Omar Asghar ◽  
Ahmed Al-Sunni ◽  
Kaivan Khavandi ◽  
Ali Khavandi ◽  
Sarah Withers ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diabetic Cardiomyopathy ◽  
Disease Process ◽  
Molecular Targets ◽  
Clinical Trial Data ◽  
Experimental Models ◽  
Trial Data ◽  
Diabetic Patients ◽  
Cardiac Safety ◽  
Artery Disease

Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazoledinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy.

The vulnerable myocardium

2015 ◽  
Vol 35 (01) ◽  
pp. 17-24 ◽  
Author(s):  
C. Bode ◽  
H. Bugger
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Complications ◽  
Artery Disease ◽  
Increased Susceptibility

SummaryCardiovascular disease is the major cause of morbidity and mortality in subjects suffering from diabetes mellitus. While coronary artery disease is the leading cause of cardiac complications in diabetics, it is widely recognized that diabetes increases the risk for the development of heart failure independently of coronary heart disease and hypertension. This increased susceptibility of the diabetic heart to develop structural and functional impairment is termed diabetic cardiomyopathy. The number of different mechanisms proposed to contribute to diabetic cardiomyopathy is steadily increasing and underlines the complexity of this cardiac entity.In this review the mechanisms that account for the increased myocardial vulnerability in diabetic cardiomyopathy are discussed.

Old and New Drugs for Treatment of Advanced Heart Failure

2020 ◽  
Vol 26 (14) ◽  
pp. 1571-1583
Author(s):  
Carmelo Buttá ◽  
Marco Roberto ◽  
Antonino Tuttolomondo ◽  
Rossella Petrantoni ◽  
Giuseppe Miceli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Therapeutic Potential ◽  
Diuretic Therapy ◽  
Advanced Heart Failure ◽  
Therapeutic Options ◽  
New Drugs ◽  
Circulatory Support ◽  
Water Restriction ◽  
Hypertonic Saline Solution ◽  
Pharmacological Agents

Background: Advanced heart failure (HF) is a progressive disease with high mortality and limited medical therapeutic options. Long-term mechanical circulatory support and heart transplantation remain goldstandard treatments for these patients; however, access to these therapies is limited by the advanced age and multiple comorbidities of affected patients, as well as by the limited number of organs available. Methods: Traditional and new drugs available for the treatment of advanced HF have been researched. Results: To date, the cornerstone for the treatment of patients with advanced HF remains water restriction, intravenous loop diuretic therapy and inotropic support. However, many patients with advanced HF experience loop diuretics resistance and alternative therapeutic strategies to overcome this problem have been developed, including sequential nephron blockade or use of the hypertonic saline solution in combination with high-doses of furosemide. As classic inotropes augment myocardial oxygen consumption, new promising drugs have been introduced, including levosimendan, istaroxime and omecamtiv mecarbil. However, pharmacological agents still remain mainly short-term or palliative options in patients with acute decompensation or excluded from mechanical therapy. Conclusions: Traditional drugs, especially when administered in combination, and new medicaments represent important therapeutic options in advanced HF. However, their impact on prognosis remains unclear. Large trials are necessary to clarify their therapeutic potential and prognostic role in these fragile patients.

Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction

2021 ◽  
Vol 13 (600) ◽  
pp. eabd6892
Author(s):  
Shijie Liu ◽  
Ke Li ◽  
Leonardo Wagner Florencio ◽  
Li Tang ◽  
Todd R. Heallen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Gene Therapy ◽  
Viral Vector ◽  
Left Ventricular ◽  
Border Zone ◽  
High Dose ◽  
Cell Renewal ◽  
Hippo Signaling ◽  
Lung Pathology

Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav–short hairpin RNA (shRNA) or a control AAV9 viral vector carrying green fluorescent protein (GFP) directly into border zone cardiomyocytes via catheter-mediated subendocardial injection. Three months after injection, pig hearts treated with a high dose of AAV9-Sav-shRNA exhibited a 14.3% improvement in ejection fraction (a measure of left ventricular systolic function), evidence of cardiomyocyte division, and reduced scar sizes compared to pigs receiving AAV9-GFP. AAV9-Sav-shRNA–treated pig hearts also displayed increased capillary density and reduced cardiomyocyte ploidy. AAV9-Sav-shRNA gene therapy was well tolerated and did not induce mortality. In addition, liver and lung pathology revealed no tumor formation. Local delivery of AAV9-Sav-shRNA gene therapy to border zone cardiomyocytes in pig hearts after myocardial infarction resulted in tissue renewal and improved function and may have utility in treating heart failure.

scholarly journals Gene Therapy: A Potential Approach for Cancer Pain

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Chalonda R. Handy ◽  
Christina Krudy ◽  
Nicholas Boulis
Keyword(s):  
Gene Therapy ◽  
Cancer Pain ◽  
Cancer Patients ◽  
Viral Vector ◽  
Sensory Neuropathy ◽  
Pharmacological Agents ◽  
Clinical Investigations ◽  
Pain Models ◽  
Prevalence Of Pain ◽  
Target Effects

Chronic pain is experienced by as many as of cancer patients at some point during the disease. This pain can be directly cancer related or arise from a sensory neuropathy related to chemotherapy. Major pharmacological agents used to treat cancer pain often lack anatomical specificity and can have off-target effects that create new sources of suffering. These concerns establish a need for improved cancer pain management. Gene therapy is emerging as an exciting prospect. This paper discusses the potential for viral vector-based treatment of cancer pain. It describes studies involving vector delivery of transgenes to laboratory pain models to modulate the nociceptive cascade. It also discusses clinical investigations aimed at regulating pain in cancer patients. Considering the prevalence of pain among cancer patients and the growing potential of gene therapy, these studies could set the stage for a new class of medicines that selectively disrupt nociceptive signaling with limited off-target effects.

scholarly journals Therapeutic Potential of Senolytics in Cardiovascular Disease

2020 ◽  
Author(s):  
Emily Dookun ◽  
João F. Passos ◽  
Helen M. Arthur ◽  
Gavin D. Richardson
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Cardiovascular Health ◽  
Therapeutic Potential ◽  
Senescent Cell ◽  
Apoptosis Induction ◽  
Secretory Phenotype ◽  
Artery Disease

Abstract Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the leading cause of death in 40% of individuals over 65 years old. Ageing is associated with both an increased prevalence of cardiovascular disease including heart failure, coronary artery disease, and myocardial infarction. Furthermore, ageing is associated with a poorer prognosis to these diseases. Genetic models allowing the elimination of senescent cells revealed that an accumulation of senescence contributes to the pathophysiology of cardiovascular ageing and promotes the progression of cardiovascular disease through the expression of a proinflammatory and profibrotic senescence-associated secretory phenotype. These studies have resulted in an effort to identify pharmacological therapeutics that enable the specific elimination of senescent cells through apoptosis induction. These senescent cell apoptosis-inducing compounds are termed senolytics and their potential to ameliorate age-associated cardiovascular disease is the focus of this review.

Diabetic cardiomyopathy: mechanisms, diagnosis and treatment

2004 ◽  
Vol 107 (6) ◽  
pp. 539-557 ◽  
Author(s):  
Sajad A. HAYAT ◽  
Billal PATEL ◽  
Rajdeep S. KHATTAR ◽  
Rayaz A. MALIK
Keyword(s):  
Heart Failure ◽  
Diabetic Cardiomyopathy ◽  
Experimental Studies ◽  
Disease Process ◽  
Diagnostic Methods ◽  
Diabetic Patients ◽  
Developing Heart ◽  
Increased Risk ◽  
Distinct Disease ◽  
Artery Disease

Independent of the severity of coronary artery disease, diabetic patients have an increased risk of developing heart failure. This clinical entity has been considered to be a distinct disease process referred to as ‘diabetic cardiomyopathy’. Experimental studies suggest that extensive metabolic perturbations may underlie both functional and structural alterations of the diabetic myocardium. Translational studies are, however, limited and only partly explain why diabetic patients are at increased risk of cardiomyopathy and heart failure. Although a range of diagnostic methods may help to characterize alterations in cardiac function in general, none are specific for the alterations in diabetes. Treatment paradigms are very much limited to interpretation and translation from the results of interventions in non-diabetic patients with heart failure. This suggests that there is an urgent need to conduct pathogenetic, diagnostic and therapeutic studies specifically in diabetic patients with cardiomyopathy to better understand the factors which initiate and progress diabetic cardiomyopathy and to develop more effective treatments.

scholarly journals Pathophysiology, Clinical Characteristics of Diabetic Cardiomyopathy: Therapeutic Potential of Natural Polyphenols

2020 ◽  
Vol 7 ◽  
Author(s):  
Neha Atale ◽  
Dhananjay Yadav ◽  
Vibha Rani ◽  
Jun-O Jin
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Therapeutic Potential ◽  
Diabetic Patients ◽  
Future Perspectives ◽  
Local Inflammation ◽  
Natural Polyphenols ◽  
Culture Models ◽  
Metabolic Activities ◽  
Cell Culture Models ◽  
Potential Use

Diabetic cardiomyopathy (DCM) is an outcome of disturbances in metabolic activities through oxidative stress, local inflammation, and fibrosis, as well as a prime cause of fatality worldwide. Cardiovascular disorders in diabetic individuals have become a challenge in diagnosis and formulation of treatment prototype. It is necessary to have a better understanding of cellular pathophysiology that reveal the therapeutic targets and prevent the progression of cardiovascular diseases due to hyperglycemia. Critical changes in levels of collagen and integrin have been observed in the extracellular matrix of heart, which was responsible for cardiac remodeling in diabetic patients. This review explored the understanding of the mechanisms of how the phytochemicals provide cardioprotection under diabetes along with the caveats and provide future perspectives on these agents as prototypes for the development of drugs for managing DCM. Thus, here we summarized the effect of various plant extracts and natural polyphenols tested in preclinical and cell culture models of diabetic cardiomyopathy. Further, the potential use of selected polyphenols that improved the therapeutic efficacy against diabetic cardiomyopathy is also illustrated.

scholarly journals Intravenous Gene Therapy With PIM-1 Via a Cardiotropic Viral Vector Halts the Progression of Diabetic Cardiomyopathy Through Promotion of Prosurvival Signaling

2011 ◽  
Vol 108 (10) ◽  
pp. 1238-1251 ◽  
Author(s):  
Rajesh Katare ◽  
Andrea Caporali ◽  
Lorena Zentilin ◽  
Elisa Avolio ◽  
Graciela Sala-Newby ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Diabetic Cardiomyopathy ◽  
Viral Vector
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