Gene and Cell Therapy for Heart Disease

Abstract

SummaryHeart disease is the most common cause of morbidity and mortality in Western society and the incidence is projected to increase significantly over the next few decades as our population ages. Heart failure occurs when the heart is unable to pump blood at a rate to commensurate with tissue metabolic requirements and represents the end stage of a variety of pathological conditions. Causes of heart failure include ischemia, hypertension, coronary artery disease, and idiopathic dilated cardiomyopathy. Hypertension and ischemia both cause infarction with loss of function and a consequent contractile deficit that promotes ventricular remodeling. Remodeling results in dramatic alterations in the size, shape, and composition of the walls and chambers of the heart and can have both positive and negative effects on function. In 30-40% of patients with heart failure, left ventricular systolic function is relatively unaffected while diastolic dysfunction predominates. Recent progress in our understanding of the molecular and cellular bases of heart disease has provided new therapeutic targets and led to novel approaches including the delivery of proteins, genes, and cells to replace defective or deficient components and restore function to the diseased heart. This review focuses on three such strategies that are currently under development: (a) gene transfer to modulate contractility, (b) therapeutic angiogenesis for the treatment of ischemia, and (c) embryonic and adult stem cell transfer to replace damaged myocardium. of all forms of heart disease. Impairment of left ventricular diastolic function often occurs before systolic dysfunction particularly in dilated cardiomyopathy and ischemic heart disease (1) and there is debate over which elements of the contractile system should be targeted. At the molecular level the cause of defective muscle contractility can be broadly attributed to abnormal sarcoplasmic reticulum (SR) calcium handling and alterations in myofilament calcium sensitivity, both of which are under β-adrenergic control. In this section of this review we focus on the evidence that implicates abnormal intracellular calcium handling and altered β-adrenergic receptor signaling in heart failure and the molecular approaches that are being pursued to correct them. Molecular Regulation of Muscle ContractionMuscle contraction and relaxation occurs through a series of coordinated steps. Electrical excitation across the sarcolemma leads to the opening of voltage-gated (L-type) Ca 2+ channels. Entry of a small amount of Ca 2+ into the cell triggers the release of larger stores of Ca 2+ from the sarcoplasmic reticulum (SR) through the Ca 2+ release channels known as ryanodine receptors (RyR). The rise in the intracellular Ca 2+ concentration ([Ca 2+ ]i) initiates contraction by binding to the myofilament protein troponin C. Conformational changes within the troponin complex disrupt the high-affinity binding sites on tropomyosin, resulting in acto-myosin cross-bridge formation and muscle contraction. Maximum force-...

On how Rac controls hematopoietic stem cell activity

“…A goal of PB stem cell transplant (PBSCT) for hemato‐oncological diseases is to optimize the number of HSCs to ensure low levels of the morbidity and mortality that is associated with rescue in the myeloablative setting 5,10 . In addition, PBSCs are ideal targets for cell and gene therapies 13 . The administration of G‐CSF is currently the major method for mobilization of HSC/P for clinical usage.…”

“…5,10 In addition, PBSCs are ideal targets for cell and gene therapies. 13 The administration of G-CSF is currently the major method for mobilization of HSC/P for clinical usage. However, over 40% of patients who have undergone intensive chemotherapy, and between 10 and 20% of all patients and normal individuals, fail to mobilize sufficient numbers of HSC/P for successful PBSCT.…”

Lack of JunD Promotes Pressure Overload–Induced Apoptosis, Hypertrophic Growth, and Angiogenesis in the Heart

“…4 For instance, therapeutic enhancement of angiogenesis has been shown to improve cardiac function. 5 One of the earliest responses of the heart to stress (eg, acute infarction, ischemic preconditioning, pressure overload, or neurohumoral stimulation) is the reexpression of silenced activator protein 1 (AP-1) transcription factors and the formation of AP-1 transcriptional complexes. 6 -11 In this respect, AP-1 transcription factors have been implicated in cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis.…”

Transplantation of Stem Cells to the Heart:

“…The strategies are based upon several sources of cells: (1) human embryonic stem cells; (2) autologous and heterologous mesenchymal stem cells; and (3) implants of xenografts, more differentiated autologous cells, or unfractionated mononuclear bone marrow cells 5 . The human embryonic stem cell strategy offers hope because it provides a source of undifferentiated pluripotent cells that may be minimally immunogenic in a nonautologous background.…”