Erythropoietin in stroke: quo vadis

Importance of the field: Recombinant erythropoietin (rEPO) failed in a recent clinical study to protect from damages induced by ischemic stroke. The lack of acute treatments in ischemic stroke and the promising outcome in numerous preclinical studies in vivo demands a more critical evaluation of the future use of EPO as an acute treatment.

Areas covered in this review: The current use and administration of rhEPO and its analogs in animal models and the future use of this cytokine in the treatment of ischemic stroke.

What the reader will gain: In this review the potential reasons for the failure of EPO in the clinical trial are analysed and whether the preclinical trials sufficiently evaluated the true potential of recombinant EPO and its analogs is assessed. Alternative methods for administration of EPO to enhance its potential as a neuroprotective drug in ischemic stroke are discussed.

Take home message: Failure in clinical trial does not necessarily indicate the lack of therapeutic potential of EPO. This review encourages further investigation of the true potential of EPO as a candidate drug for the treatment of ischemic stroke by improved preclinical experimental design and utilization of alternative administration methods.     

Erythropoietin and the heart: facts and perspectives

EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio-renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases.     

Rituximab for chronic lymphocytic leukemia

Introduction: Significant advances have been made to understand the mechanisms involved in cardiac cell-based therapies. The early translational application of basic science knowledge has led to several animal and human clinical trials. The initial promising beneficial effect of stem cells on cardiac function restoration has been eclipsed by the inability of animal studies to translate into sustained clinical improvements in human clinical trials.

Areas covered: In this review, the authors cover an updated overview of various stem cell populations used in chronic heart failure. A critical review of clinical trials conducted in advanced heart failure patients is proposed, and finally promising avenues for developments in the field of cardiac cell-based therapies are presented.

Expert opinion: Several questions remain unanswered, and this limits our ability to understand basic mechanisms involved in stem cell therapeutics. Human studies have revealed critical unresolved issues. Further elucidation of the proper timing, mode delivery and prosurvival factors is imperative, if the field is to advance. The limited benefits seen to date are simply not enough if the potential for substantial recovery of nonfunctioning myocardium is to be realized.     

AAV-directed muscular dystrophy gene therapy

Importance of the field: Muscle-directed gene therapy for genetic muscle diseases can be performed by the recombinant adeno-associated viral (rAAV) vector delivery system to achieve long-term therapeutic gene transfer in all affected muscles.

Areas covered in this review: Recent progress in rAAV-vector-mediated muscle-directed gene transfer and associated techniques for the treatment of muscular dystrophies (MD). The review covers literature from the past 2 – 3 years.

What the reader will gain: rAAV-directed muscular dystrophy gene therapy can be achieved by mini-dystrophin replacement and exon-skipping strategies. The additional strategies of enhancing muscle regeneration and reducing inflammation in the muscle micro-environment should be useful to optimize therapeutic efficacy. This review compares the merits and shortcomings of different administration methods, promoters and experimental animals that will guide the choice of the appropriate strategy for clinical trials.

Take home message: Restoration of muscle histopathology and function has been performed using rAAV systemic gene delivery. In addition, the combination of gene replacement and adjuvant therapies in the future may be beneficial with regard to improving muscle regeneration and decreasing myofiber necrosis. The challenges faced by large animal model studies and in human trials arise from gene transfer efficiency and immune response, which may be overcome by optimizing the rAAV vectors utilized and the administration methods.     

Clinical utility of sympathetic blockade in cardiovascular disease management

Introduction: A dysregulated sympathetic nervous system is a major factor in the development and progression of cardiovascular disease; thus, understanding the mechanism and function of the sympathetic nervous system and appropriately regulating sympathetic activity to treat various cardiovascular diseases are crucial.

Areas covered: This review focused on previous studies in managing hypertension, atrial fibrillation, coronary artery disease, heart failure, and perioperative management with sympathetic blockade. We reviewed both pharmacological and non-pharmacological management.

Expert commentary: Chronic sympathetic nervous system activation is related to several cardiovascular diseases mediated by various pathways. Advancement in measuring sympathetic activity makes visualizing noninvasively and evaluating the activation level even in single fibers possible. Evidence suggests that sympathetic blockade still has a role in managing hypertension and controlling the heart rate in atrial fibrillation. For ischemic heart disease, beta-adrenergic receptor antagonists have been considered a milestone drug to control symptoms and prevent long-term adverse effects, although its clinical implication has become less potent in the era of successful revascularization. Owing to pathologic involvement of sympathetic nervous system activation in heart failure progression, sympathetic blockade has proved its value in improving the clinical course of patients with heart failure.     

Prevalence of comorbidities in heart failure patients and those treated with cellular therapeutics

Introduction: Changes in our daily living, particularly in work routines, diet, and physical exercise, have influenced a worldwide crisis for life-threatening comorbidities and the likelihood of cardiovascular disease diagnosis. Cardiovascular regenerative medicine researchers continue to investigate new therapeutic approaches and reexamine completed clinical trials to design more effective future studies. As the frequency of cardiovascular disease diagnosis continues to rise, investigations of how to repair and regenerate the failing myocardium remains an essential mission for human health.

Areas covered: This review first examines the aging process, the rising rate of comorbidities, and the likelihood of developing heart disease. In the ongoing efforts to recapitulate human health needs in clinical trials, a review of clinical trials involving cellular therapeutics for cardiac repair, with a focus on the patient population and patients’ complex medical records, is presented.

Expert opinion: The expert opinion first draws attention to the changing demographics of patients diagnosed with diseases that lead to heart failure and focusing on obesity as a primary driver for increased cardiovascular disease. The opinion focuses on the importance of designing preclinical models and experimentation that better mimic the patient population and clinical situations to evaluate the effectiveness of potential future therapeutic interventions.     

Angiogenic gene therapy for refractory angina

ABSTRACT

Introduction: Stimulation of coronary collateral vessel growth by therapeutic angiogenesis (TA) offers an alternative treatment option for patients with refractory angina. Several TA modalities, including delivery to the heart of angiogenic growth factors (proteins or genes) and cells have been tested in clinical trials in the past two decades, but so far none of them resulted in significant therapeutic efficacy in large scale studies. This review attempts to identify the main obstacles hindering clinical success and recommends measures to overcome them in the future.

Areas covered: After stating the medical need and rational for TA, and listing and briefly discussing past and current TA clinical trials, three main areas of obstacles are described: conceptual questions, technical limitations and clinical design uncertainties. Based on scientific and technical advances and lessons learned in past clinical trials, potential solutions to overcome some of these obstacles are proposed.

Expert opinion: Several success criteria are identified, which apply to any TA approach of choice. It is emphasized, that each of these criteria needs to be met in future clinical trials to have a chance of therapeutic success.     

Recent advances in the use of therapeutic cancer vaccines in genitourinary malignancies

Introduction: Despite a recent increase in US FDA-approved treatments, genitourinary malignancies remain a source of significant morbidity and mortality. One focus of research is the use of therapeutic cancer vaccines in these diseases, and a significant body of clinical trial experience now exists for refining vaccine strategies to enhance antitumor efficacy and develop immune-based combination regimens.

Areas covered: In recent years, clinical data from multiple trials in genitourinary malignancies have enhanced our understanding of the potential for immunotherapy in these cancers. There are also emerging clinical strategies that combine cancer vaccines with chemotherapy, radiation, androgen-deprivation therapy and immune checkpoint inhibitors. This review is based on a search of relevant literature for data presented over the past 5 years from clinical trials of cancer vaccines in prostate, bladder and renal carcinomas.

Expert opinion: In the coming years, clinical trials informed by decades of preclinical data and emerging clinical data will help to define the role of immunotherapy in genitourinary malignancies. Combination strategies that capitalize on the immune properties of standard treatments will bring greater clinical benefits, and immune-based combinations will likely be moved to the neoadjuvant setting, where they may have optimal clinical impact.     

Modification of mesenchymal stem cells for cardiac regeneration

Importance of the field: Mesenchymal stem cells (MSCs) have the greatest potential for use in cell-based therapy of human heart diseases, especially in myocardial infarcts. The therapeutic potential of MSCs in myocardial repair is based on the ability of MSCs to directly differentiate into cardiac tissue and on the paracrine actions of factors released from MSCs. However, the major obstacle in the clinical application of MSC-based therapy is the poor viability of the transplanted cells due to harsh microenvironments like ischemia, inflammation and/or anoikis in the infarcted myocardium. Recently, various approaches have been implemented in an effort to improve the survival of implanted MSCs through ex vivo manipulation of MSCs.

Areas covered in this review: Major obstacles in MSC-based therapy are discussed, along with recent advances for enhancing therapeutic potential of engrafted MSCs from the past decade.

What the reader will gain: This review focuses primarily on ex vivo manipulation of MSCs before transplantation, which includes pretreatment, preconditioning and genetic modification of MSCs, and future directions.

Take home message: Modification of MSCs before transplantation has developed into a promising option for enhancing the beneficial effects of MSC-based therapy for cardiac repair after myocardial infarction.     

Immunotherapy for metastatic prostate cancer: where are we at with sipuleucel-T?

Importance of the field: Prostate cancer is the leading malignancy in North American men and despite improvements in treatments 20 – 30% of patients will relapse. Immunotherapy using activated mononuclear cells is a way to harness the body's adaptive immune response to fight metastatic prostate cancer.

Areas covered in this review: In 2005, at least 10 therapeutic cancer vaccines, designed to confer active, specific immunotherapy against tumor-associated antigens, were in clinical trials. These covered potential fields of immunological strategy to overcome castration-resistant prostate cancer.

What the reader will gain: A literature review was performed using the search terms sipuleucel-T, Provenge and APC8015 or APC-8015, and restricted to English language articles from 2000 to 2010. The immunological design and development of sipuleucel-T are summarized. The efficacy and safety of sipuleucel-T are discussed based on current data from clinical trials. Ongoing clinical trials involving sipuleucel-T are summarized.

Take home message: Efficacy and safety with sipuleucel-T has been demonstrated in Phase I/II trials. The latest data from a Phase III trial shows that sipuleucel-T has met the primary endpoint of survival benefit. Further work is needed to understand the mechanisms behind cancer vaccine failure and elucidate the population for whom this vaccine will be suitable.     

Stem cell therapy for the systemic right ventricle

Introduction: In specific forms of congenital heart defects and pulmonary hypertension, the right ventricle (RV) is exposed to systemic levels of pressure overload. The RV is prone to failure in these patients because of its vulnerability to chronic pressure overload. As patients with a systemic RV reach adulthood, an emerging epidemic of RV failure has become evident. Medical therapies proven for LV failure are ineffective in treating RV failure.

Areas covered: In this review, the pathophysiology of the failing RV under pressure overload is discussed, with specific emphasis on the pivotal roles of angiogenesis and oxidative stress. Studies investigating the ability of stem cell therapy to improve angiogenesis and mitigate oxidative stress in the setting of pressure overload are then reviewed. Finally, clinical trials utilizing stem cell therapy to prevent RV failure under pressure overload in congenital heart disease will be discussed.

Expert commentary: Although considerable hurdles remain before their mainstream clinical implementation, stem cell therapy possesses revolutionary potential in the treatment of patients with failing systemic RVs who currently have very limited long-term treatment options. Rigorous clinical trials of stem cell therapy for RV failure that target well-defined mechanisms will ensure success adoption of this therapeutic strategy.     

Targeting B cells with biologics in systemic lupus erythematosus

Importance of the field: The use of biologics as immune modulators in several autoimmune diseases has provided new tools to the physician's therapeutic armamentiarium and has led to improved patients' outcomes and quality of life. By producing autoantibodies, B cells in systemic lupus erythematosus (SLE) are key players in the pathogenesis of the disease and in its clinical manifestations. Therefore, biologics that target B cells in SLE aim at reducing the activity of these cells for the induction of remissions and/or amelioration of disease activity, reduction of organ involvement, and limitation of the complications and side effects caused by immunosuppressive therapies.

Areas covered in this review: This review describes the past and current clinical trials with B-cell-targeted biologics in SLE, to provide a historical perspective and the state-of-the-art on the topic.

What the reader will gain: We review how the disappointment in the field from promising agents has been instrumental in providing valuable lessons leading to an improved design of new trials that are now giving encouraging results.

Take home message: In systemic lupus erythematosus (SLE), the use of B-cell-based biologics in clinical trials has shown both disappointment and promise.     

Gene therapy for ischemic heart disease

Introduction: Coronary artery disease (CAD) is still the leading cause of death in industrialized nations. Even though revascularization strategies such as percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) as well as drug therapy have significantly reduced mortality, about 30% of patients will develop chronic heart failure over time. Ischemic heart disease and heart failure are characterized by an adverse remodeling of the heart, featuring cardiomyocyte hypertrophy, increased fibrosis and capillary rarification.

Areas covered: Beside an assessment of current vector systems, this review focuses on potential target genes affecting angiogenesis/arteriogenesis and contractility. The potential of micro RNA (miRNA) modulation for the de-repression of survival and pro-angiogenic genes is discussed. Since gene therapy of the target region is preferable to avoid systemic contamination, application routes are discussed.

Expert opinion: miRNAs are a promising new development for successful gene therapy, especially for acute myocardial infarction since their miRNA antagonists are easy to apply and appear to be selectively absorbed by the ischemic myocardial tissue. Rapid uptake and prolonged presence of known antimirs and antagomirs support this notion. For ischemic heart disease the most promising gene therapeutic approach seems to be the regional intravenous application of suitable AAV vectors and vascular growth factors, providing the full scope of angiogenesis, vessel maturation and collateral growth optionally combined with genes enhancing contractility.     

ETC-216 for coronary artery disease

Introduction: Increasing attention has focused on the role of high-density lipoprotein function as a target for cardiprotection. Apolipoprotein A-I_Milano (AIM) involves a single amino-acid mutation of the major wild-type protein carried on high-density lipoprotein (HDL) particles. Early evidence of beneficial activities of AIM has stimulated support in its development as a potential therapy to reduce cardiovascular risk.

Areas covered: The importance of HDL as a target and early data supporting the beneficial effects of AIM are reviewed. All clinical studies of AIM found in PubMed are reviewed.

Expert opinion: ETC-216 represents a lipid-deplete form of HDL containing recombinant AIM. While early evidence suggests that administration of ETC-216 promotes rapid regression of coronary atherosclerosis, bringing this compound to clinical practice will require further trials that evaluate its impact on cardiovascular events.     

Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target

Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR-/- rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.     

Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer.

Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed.

Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.     

Autologous haemopoietic stem cell transplantation for autoimmune diseases

Introduction: Autoimmune diseases are signified by complex errors of immune-regulation, and the development of autoreactive T and B cells targeting self-antigens, which eventually can lead to permanent organ damage. Despite novel therapeutic protocols, the disease course is chronic, debilitating and in some instances the outcome is lethal. Previously, stem cell transplantation has been reported to be beneficial in autoimmune animal models, as well as in autoimmune diseases related to hematological abnormalities, which opened potential new avenues in the treatment of human autoimmune diseases.

Areas covered: In this review, the authors describe the compound cellular regulatory effects of autologous hemopoietic stem cell transplantation (ASCT) and also clinical observations, related to the therapy in a variety of organ-specific and systemic autoimmune diseases.

Expert opinion: ASCT has a broad effect on the re-populated immune system, complex regulatory potentials and long term beneficial effect via down-regulating immune-reactivity, yet its widespread use in autoimmune diseases is limited, mostly due to the serious side-effects of the conditioning treatments. However, in certain autoimmune diseases with severe debilitating, or even life-threatening course, including systemic lupus erythematosus, systemic sclerosis or multiple sclerosis, ASCT can be a reasonable choice when conventional therapy has failed.     

Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return?

Introduction: Two humanized monoclonal antibodies, bapineuzumab and solanezumab, directed against the N terminus and mid-region of β-amyloid (Aβ), respectively, were recently tested in large, long-term Phase III trials in patients with mild-to-moderate Alzheimer’s disease (AD).

Areas covered: This review discusses current clinical data on solanezumab, bapineuzumab and their failure in Phase III trials to show significant clinical benefits, as well as other monoclonal antibodies under investigation for AD.

Expert opinion: Solanezumab showed some beneficial cognitive effects in mildly affected AD patients and this subgroup of AD patients is currently being tested in another Phase III trial to this subgroup of AD patients to confirm previous encouraging observations. Two other monoclonal antibodies, gantenerumab, which preferentially binds to fibrillar Aβ, and crenezumab, which preferentially binds to soluble, oligomeric and fibrillar Aβ deposits, are being tested in secondary prevention trials in presymptomatic subjects with autosomal dominant AD mutations. Solanezumab is also being tested in a prevention study in asymptomatic older subjects, who have positive positron emission tomography scans for brain amyloid deposits. These ongoing secondary prevention trials will tell us if Aβ really plays a crucial role in the pathophysiology of AD.