Cardiovascular gene therapy

Gene therapy involves the transfer of therapeutic genes to cells in vivo and is therefore a potentially novel way to treat cardiovascular diseases. Especially good candidate diseases are those arising from inherited mutations in the genetic sequence and which are intransigent to current therapies. An example of an inherited disease is familial hypercholesterolaemia, which arises from a point mutation in the low-density lipoprotein receptor gene and for which effective therapeutics are lacking. Other diseases, like occlusive vascular disease, may be caused by abnormal cellular or tissue responses and may also be good candidates for gene therapy. A number of preclinical efforts have begun to culminate in clinical studies for conditions like hypercholesterolaemia and occlusive vascular disease. Other cardiovascular indications are under investigation, with late stage preclinical studies focusing on restenosis, transplant atherosclerosis and rejection, and a number of lipoprotein abnormalities.     

Therapeutic angiogenesis: protein and gene therapy delivery strategies

Angioplasty and surgical bypass, the primary interventional therapies for the treatment of atherosclerosis, are limited by the development over time of native vessel restenoses and graft occlusions. Furthermore, these therapies are not options for a significant number of individuals in whom the extent of vascular pathology is especially severe or widespread. Angiogenesis, the growth of new vasculature, is a critical biological response to ischemia that provides collateralization, or 'biological revascularization' of vascular obstructions. Therapeutic angiogenesis is a strategy whereby one of several known 'angiogens', mediators that induce angiogenesis, can be administered to augment the native angiogenic processes and enhance the formation of collateral vasculature. This report describes the techniques available for providing therapeutic angiogenesis, including acute and sustained-release techniques to deliver protein angiogens and a number of gene therapy strategies to deliver genes coding for the angiogens.     

Cancer gene therapy targeting angiogenesis： An updated review

INTRODUCTION Angiogenesis is the formation of new blood vessels frompre-existing ones. Many developmental and pathological processes require angiogenesis[1]. As proposed by Folkman in 1971, angiogenesis is required for tumor growth[2]. Angiogenesis consists of several steps: endothelial cell (EC) proliferation, migration, basement membrane degradation, and new lumen organization[3]. This multi-step process is determined by a net balance between pro- and anti- angiogenesis regulators in t…     

Therapeutic angiogenesis for peripheral artery disease: gene therapy

Peripheral artery disease is a highly prevalent disease which is characterised by a high unmet medical need particularly in the more advanced stages of disease. Recent advances in the knowledge of the complex regulation of angiogenesis and arteriogenesis and ways to its induction offer hope for a novel strategy that is based on the generation of such new vessels. This strategy termed "therapeutic angiogenesis" is a concept based on the use of angiogenic factors or stem cells or their combination to promote neovascularisation for the treatment of ischaemic tissues. This article reviews both regulation of angiogenesis and the development of therapeutic strategies based on this knowledge using gene therapy. This includes knowledge from animal experiments as well as from phase I and phase II clinical trials. This information may be particularly important at a time when angiogenesis gene therapy enters the stage of phase III clinical testing hopefully leading to the first time approval of this completely new class of drug in the near future. Following articles of this series will review therapeutic angiogenesis approaches based on cytokine therapy and stem cell therapy.     

Cardiac angiogenesis and gene therapy: a strategy for myocardial revascularization

Angiogenesis, the de novo formation of new vasculature, is a critical response to ischemia that provides neovascularization of ischemic tissues. In therapeutic angiogenesis, an angiogen--a mediator that induces angiogenesis--is delivered to targeted tissues, augmenting the native angiogenic process and enhancing reperfusion of ischemic tissues. Gene transfer is a novel means of providing therapeutic angiogenesis: the cDNA coding for specific angiogens, rather than the proteins themselves, is administered to the tissues in which angiogenesis is desired. This review is focused on therapeutic angiogenesis based on gene transfer strategies for the provision of myocardial revascularization.     

Cardiovascular effects of erythropoietin: anemia and beyond

We did a PubMed and Cochrane Database System review of different studies on the diverse effects of erythropoietin (EPO), focusing mainly on the cardiovascular system. The direct erythropoietic action of EPO is well studied and widely used. Published studies report dramatic improvement in the course of heart failure with EPO treatment. New controlled clinical trials on large and diverse groups of patients are warranted. Antiapoptotic effects of EPO are newly discovered, opening new horizons in both clinical investigation and therapy. The salvage of cardiomyocytes in acute coronary syndromes, limiting the size of myocardial infarction and improving functional recovery, is only one of multiple potential applications of this effect. Derivatives of EPO with selective antiapoptotic properties seem to hold the best prospects for future studies. Heart failure and ischemic heart disease are potential areas where adding EPO to the conventional treatment may be beneficial.     

Therapeutic angiogenesis induced by hepatocyte growth factor: potential gene therapy for ischemic diseases.

Recent progress in molecular biology has led to the development of gene therapy as a new strategy to treat a variety of cardiovascular diseases. Targeted diseases range from single gene deficiency diseases to more complex diseases in adults such as restenosis after angioplasty. One obvious major target in the field of gene therapy is ischemic diseases such as myocardial infarction, angina and peripheral arterial diseases (i.e. ASO (arteriosclerosis obliterans)). In a large proportion of such patients, the anatomical extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. Of importance, there is no optimal medical therapy for severe ischemic hearts and critical ischemic limbs. Therefore, novel therapies are required to treat these patients. Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia and myocardial ischemia. Thus, the strategy for therapeutic angiogenesis using angiogenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. The endothelial cell specificity of VEGF has been considered to be an important advantage for therapeutic angiogenesis, as endothelial cells represent the critical cellular element responsible for new vessel formation. Indeed, human gene therapy for ASO and angina has already begun in the USA, with surprising and beneficial effects. We have focused on hepatocyte growth factor (HGF), which is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis in various types of cells. Recently, HGF is also considered to be a powertul growth tactor for endothelial cells. In this review, we described the potential gene therapy for ischemic diseases using HGF.     

Cardiovascular complications associated with novel angiogenesis inhibitors: Emerging evidence and evolving perspectives

Novel cancer therapies targeting tumor angiogenesis have revolutionized treatment options in a variety of tumors. Specifically, VEGF signaling pathway (VSP) inhibitors have been introduced into clinical practice at a rapid pace over the last decade. It is becoming increasingly clear that VSP inhibitors can cause cardiovascular toxicities including hypertension, thrombosis, and heart failure. This review highlights these toxicities and proposes several strategies in their prevention and treatment. However, we recognize the dearth of data in this area and advocate a multi-disciplinary approach involving cardiologists and oncologists, as well as clinical and translational studies, in understanding and treating VSP-inhibitor associated toxicities.     

Prophylactic adenovirus-mediated human kallistatin gene therapy suppresses rat arthritis by inhibiting angiogenesis and inflammation

OBJECTIVE: Kallistatin has been shown to be an angiogenesis inhibitor. In this study, we investigated whether adenovirus-mediated kallistatin gene delivery has a prophylactic effect in a rat arthritis model. METHODS: Adenovirus containing the human kallistatin gene (AdHKBP) was injected intraarticularly into ankle joints before the onset of arthritis in a rat model. The effect of kallistatin gene transfer on endothelial cell proliferation in joint extracts was assayed. The response to kallistatin treatment was determined according to clinical parameters, including ankle circumference, articular index, and radiographic scores. Hematoxylin and eosin staining was performed in order to score joint tissues and count neutrophil numbers. In addition, small vessels were quantified by identification of von Willebrand factor-positive endothelial cells. The inflammatory responses were determined by measuring tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) levels in ankle homogenates. RESULTS: The expression of recombinant human kallistatin in rat ankle joints after gene transfer was identified by immunohistochemical analysis and Western blotting. Significant reductions in the ankle circumference, articular index, and radiographic score were observed in AdHKBP-treated rats compared with control rats treated with the adenoviral plasmid carrying green fluorescent protein. Kallistatin gene transfer also significantly ameliorated the histologic scores in ankle joints and reduced vessel density and neutrophil numbers. The inhibitory effect of kallistatin on the accumulation of inflammatory cells in ankle joints was accompanied by reduced TNFalpha and IL-1beta levels in joint homogenates. Furthermore, an in vitro experiment showed that the proliferation of endothelial cells was markedly inhibited by the addition of AdHKBP-treated joint extract to the culture media, supporting a role of kallistatin in inhibiting angiogenesis. CONCLUSION: This study demonstrates that kallistatin gene therapy has a prophylactic effect in inhibiting arthritis in the rat ankle. Kallistatin inhibits arthritis through its antiangiogenesis and antiinflammation activities. These results implicate potential therapeutic applications for suppression of arthritis by kallistatin gene therapy.     

New approaches of B-cell-directed therapy: beyond rituximab

PURPOSE OF REVIEW: This study reviews therapeutic approaches of direct and indirect B-cell targeting in autoimmune diseases and their impact on protective immunity. RECENT FINDINGS: Beyond recent clinical experiences with rituximab as B-cell-depleting agent, other biologicals targeting CD20, such as ocrelizumab, ofatumumab, hA20, and TRU-015 mainly deplete B cells and are under clinical investigation in different entities. Moreover, anti-CD22 targeting as another approach that has been studied in clinical trials showed a modest depletion, but inhibition of B-cell activation. More indirect innovative B-cell-affecting therapies comprise blockade of cytokines, such as B-cell-activating factor (BAFF/BLyS), APRIL, and their receptors as well as blockade of costimulation. Although decreases of immunoglobulin levels were seen, so far no major increases in infections were reported. SUMMARY: The value of certain B-cell-depletion therapies as well as other therapies modulating B-cell functions needs to be further delineated, especially in the therapeutic regimen of rheumatoid arthritis, specific collagen vascular diseases and vasculitis. Long-term observations of protective immunity are also needed to further evaluate the rate of infections.     

Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease

We aim to determine the efficacy and safety of gene and cell angiogenic therapies in the treatment of peripheral arterial disease (PAD) and evaluate them for the first time by a meta-analysis. We include in the formal meta-analysis only the randomized placebo-controlled phase 2 studies with any angiogenic gene or cell therapy modality to treat patients with PAD (intermittent claudication, ulcer or critical ischemia) identified by electronic search in MEDLINE and EMBASE databases (1980 to date). Altogether, 543 patients are analyzed from six randomized, controlled trials that are comparable with regard to patient selection, study design, and endpoints. We perform the meta-analysis regarding clinical improvement (improvement of peak walk time, relief in rest pain, ulcer healing or limb salvage) and rate of adverse events. At the end of treatment, therapeutic angiogenesis shows a significantly clinical improvement as compared to placebo in patients with PAD (odds ratio [OR] = 1.437; 95% confidence interval [CI] = 1.03?2.00; P = 0.033). The response rate (improvement of peak walk time) of the pooled groups according to clinical severity does not significantly differ for gene therapy as compared with placebo in the treatment of claudicating patients (OR = 1.304; 95% CI = 0.90?1.89; P = 0.16). Otherwise, we find significant efficacy of the treatment in critical ischemia (OR = 2.20; 95% CI = 1.01?4.79; P = 0.046). The adverse events rates show a slightly significantly higher risk of potential nonserious adverse events (edema, hypotension, proteinuria) in the treated group (OR = 1.81; 95% CI = 1.01?3.38; P = 0.045). We find no differences in mortality from any cause, malignancy, or retinopathy. The patients with PAD, and particularly those with critical ischemia, improve their symptoms when treated with angiogenic gene and cell therapy with acceptable tolerability.