Genetic therapies for cardiovascular diseases

Recent advances in understanding the molecular and cellular basis of cardiovascular diseases, together with the availability of tools for genetic manipulation of the cardiovascular system, offer possibilities for new treatments. Gene therapies have demonstrated potential usefulness for treating complex cardiovascular diseases, such as hypertension, atherosclerosis and myocardial ischemia, in various animal models. Some of these experimental therapies are now undergoing clinical evaluation in patients with cardiovascular disease. However, the successful transition of these therapies into mainstream clinical practice awaits further improvements to vector platforms and delivery tools and the documentation of clinical feasibility, safety and efficacy through multi-center randomized trials.     

脑内移植治疗帕金森病的研究概述

帕金森病(Parkinson’s disease,PD)是一种与年龄有关的神经系统退行性疾病,主要是由于中脑黑质多巴胺能神经元的变性和消失而造成纹状体内多巴胺水平下降。其行为上特征性表现为运动减少,肌肉僵直、震颤。除了运动感觉功能障碍外,病人还可能伴有心理障碍及认知能力的下降。20世纪初,人们开始     

The zebrafish as a tool to identify novel therapies for human cardiovascular disease

Over the past decade, the zebrafish has become an increasingly popular animal model for the study of human cardiovascular disease. Because zebrafish embryos are transparent and their genetic manipulation is straightforward, the zebrafish has been used to recapitulate a number of cardiovascular disease processes ranging from congenital heart defects to arrhythmia to cardiomyopathy. The use of fluorescent reporters has been essential to identify two discrete phases of cardiomyocyte differentiation necessary for normal cardiac development in the zebrafish. These phases are analogous to the differentiation of the two progenitor heart cell populations in mammals, termed the first and second heart fields. The small size of zebrafish embryos has enabled high-throughput chemical screening to identify small-molecule suppressors of fundamental pathways in vasculogenesis, such as the BMP axis, as well as of common vascular defects, such as aortic coarctation. The optical clarity of zebrafish has facilitated studies of valvulogenesis as well as detailed electrophysiological mapping to characterize the early cardiac conduction system. One unique aspect of zebrafish larvae is their ability to oxygenate through diffusion alone, permitting the study of mutations that cause severe cardiomyopathy phenotypes such as silent heart and pickwick^m171, which mimic titin mutations observed in human dilated cardiomyopathy. Above all, the regenerative capacity of zebrafish presents a particularly exciting opportunity to discover new therapies for cardiac injury, including scar formation following myocardial infarction. This Review will summarize the current state of the field and describe future directions to advance our understanding of human cardiovascular disease.KEY WORDS: Cardiovascular, Drug discovery, Zebrafish     

Towards stem cell replacement therapies for Parkinson’s disease

Current therapeutic approaches for Parkinson’s disease (PD) provide symptomatic relief but none of them change the course of disease. There is therefore a clear need for regenerative and cell replacement therapies (CRT). However, CRT faces several important challenges. First, the main symptoms of PD result from the loss of midbrain dopamine (DA) neurons, but other cell types are also affected. Second, transplantation of human ventral midbrain tissue from aborted fetuses has lead to proof of principle that CRT may work, however, it has also pointed out to important patient-, surgery- and cell preparation-related variables, which need to be improved. Third, while some patients have developed dyskinesias and, with time, Lewy bodies in the grafted cells, other patients have experienced remarkable improvement and have been able to stop their medication. Is there a case for PD CRT today? What is the possible contribution of stem cells to CRT? In this review, I will discuss what we learned from clinical trials using fetal tissue grafts, recent progress in the development of human stem cell-derived-DA neurons for CRT, and some of the issues that need to be solved in order to develop stem cells as tools for PD CRT.     

Partial adenosine A1 receptor agonists for cardiovascular therapies

Adenosine, a purine nucleoside, is present in all cells in tightly regulated concentrations. It has many different physiological effects in the whole body and in the heart. Adenosine activates four G protein-coupled receptors A1, A2a, A2b, and A3. Activation of myocardial A1 receptors has been shown to inhibit a variety of myocardial pathologies associated with ischemia and reperfusion injury, including stunning, arrhythmogenesis, coronary and ventricular dysfunction, acute myocardial infarction, apoptosis, and chronic heart failure, implying several options for new cardiovascular therapies for diseases, like angina pectoris, control of cardiac rhythm, ischemic injury during an acute coronary syndrome, or heart failure. However, the main issue of using full A1 receptor agonists in such indications is the broad physiologic spectrum of cardiac and extracardiac effects. Desired A1 receptor-mediated protective and regenerative cardiovascular effects might be counter-regulated by unintended side effects when considering full A1 receptor agonists. These effects can be overcome by partial A1 agonists. Partial A1 agonists can be used to trigger only some of the physiological responses of receptor activation depending on endogenous adenosine levels and on receptor reserve in different tissues. CV-Therapeutics reported the identification of a partial A1 receptor agonist CVT-3619, and recently, another partial A1 receptor agonist VCP28 was published. Both compounds are adenosine derivatives. Adenosine-like A1 receptor agonists often have the drawback of a short half-life and low bioavailability, making them not suitable for chronic oral therapy. We identified the first non-adenosine-like partial A1 receptor agonist(s) with pharmacokinetics optimal for oral once daily treatment and characterized the qualities of the partial character of the A1 receptor agonist(s) in preclinical and clinical studies.

     

Partial adenosine A1 receptor agonists for cardiovascular therapies

Extracellular purines and pyrimidines have emerged as key regulators of a wide range of physiological and pathophysiological cellular processes acting through P1 and P2 cell surface receptors. Increasing evidence suggests that purinergic receptors can interact with and/or modulate the activity of other classes of receptors and ion channels. This review will focus on the interactions of purinergic receptors with other GPCRs, ion channels, receptor tyrosine kinases, and steroid hormone receptors. Also, the signal transduction pathways regulated by these complexes and their new functional properties are discussed.     

Splice modulating therapies for human disease

Dysregulation of splicing and alternative splicing underlies many genetic and acquired diseases. We present an overview of recent strategies and successes in modulating splicing therapeutically in clinical and preclinical contexts. Effective approaches include restoring open reading frames, influencing alternative splicing, and inducing exon inclusion to generate beneficial proteins and remove deleterious ones.     

Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease

The broad repertoire of secreted trophic and immunomodulatory cytokines produced by mesenchymal stem cells (MSCs), generally referred to as the MSC secretome, has considerable potential for the treatment of cardiovascular disease. However, harnessing this MSC secretome for meaningful therapeutic outcomes is challenging due to the limited control of cytokine production following their transplantation. This review outlines the current understanding of the MSC secretome as a therapeutic for treatment of ischemic heart disease. We discuss ongoing investigative directions aimed at improving cellular activity and characterizing the secretome and its regulation in greater detail. Finally, we provide insights on and perspectives for future development of the MSC secretome as a therapeutic tool.     

Established and emerging therapies for Huntington's disease

Huntington's disease is a genetic, neurodegenerative disorder causing cell dysfunction prior to cell death. Mechanisms that underlie the pathological changes continue to be elucidated, which in turn increases the number of potential therapeutic targets which have the ability to reverse or prevent further cell damage. As well as cell protection strategies, cell replacement techniques have been developed with the aim of replacing dead cells and restoring functional circuits. This review describes therapies used in clinical practice, therapies that have shown promise in experimental models either at the genetic or molecular level, and therapies that are subject to human clinical trials. It is likely that any successful therapy in clinical practice will involve a number of different approaches aimed at different targets in order to achieve both cell protection and cell replacement.     

Imaging stem cell implant for cellular-based therapies

Stem cell-based cellular therapy represents a promising outlook for regenerative medicine. Imaging techniques provide a means for noninvasive, repeated, and quantitative tracking of stem cell implant or transplant. From initial deposition to the survival, migration and differentiation of the transplant/implanted stem cells, imaging allows monitoring of the infused cells in the same live object over time. The current review briefly summarizes and compares existing imaging methods for cell labeling and imaging in animal models. Several studies performed by our group using different imaging techniques are described, with further discussion on the issues with these current imaging approaches and potential directions for future development in stem cell imaging.     

Therapeutic angiogenesis for cardiovascular disease

The identification of angiogenic growth factors, such as vascular endothelial growth factor and fibroblast growth factor, has fueled interest in using such factors to induce therapeutic angiogenesis. The results of numerous animal studies and clinical trials have offered promise for new treatment strategies for various ischemic diseases. Increased understanding of the cellular and molecular biology of vessel growth has, however, prompted investigators and clinicians alike to reconsider the complexity of therapeutic angiogenesis. The realization that formation of a stable vessel is a complex, multistep process may provide useful insights into the design of the next generation of angiogenesis therapy.     

Apoptosis: a potential target for discovering novel therapies for cardiovascular diseases.

The realization that apoptosis is genetically programmed raises the exciting prospect that modulating apoptosis may provide novel approaches for treatment of cardiovascular diseases in which apoptosis has been demonstrated. Low molecular weight inhibitors of caspases and mitogen-activated protein kinases have been evaluated, with promising results in a variety of cardiovascular apoptotic models.     

B cell targeted therapies

Although the precise pathogenesis of rheumatoid arthritis (RA) remains unclear, many cell populations, including monocytes, macrophages, endothelial cells, fibroblasts and B cells, participate in the inflammatory process. Ongoing research continues to evaluate the critical roles played by B cells in sustaining the chronic inflammatory process of RA. These findings have contributed to the development of targeted therapies that deplete B cells, such as rituximab, as well as inhibitors of B lymphocyte stimulation, such as belimumab. In a phase I trial, belimumab treatment significantly reduced CD20+ levels in patients with systemic lupus erythematosus. Phase I and phase II trials of rituximab found that rituximab plus methotrexate achieved significantly better American College of Rheumatology 50% responses for patients with RA than those patients receiving monotherapy with methotrexate. These clinical trial data present promising evidence for B cell targeted therapies as future therapeutic options for RA.     

Large animal models for cardiac stem cell therapies

Cardiovascular disease is the leading cause of death in developed countries and is one of the leading causes of disease burden in developing countries. Therapies have markedly increased survival in several categories of patients, nonetheless mortality still remains high. For this reason high hopes are associated with recent developments in stem cell biology and regenerative medicine that promise to replace damaged or lost cardiac muscle with healthy tissue, and thus to dramatically improve the quality of life and survival in patients with various cardiomyopathies.Much of our insight into the molecular and cellular basis of cardiovascular biology comes from small animal models, particularly mice. However, significant differences exist with regard to several cardiac characteristics when mice are compared with humans. For this reason, large animal models like dog, sheep and pig have a well established role in cardiac research. A distinct characteristic of cardiac stem cells is that they can either be endogenous or derive from outside the heart itself; they can originate as the natural course of their differentiation programme (e.g., embryonic stem cells) or can be the result of specific inductive conditions (e.g., mesenchymal stem cells). In this review we will summarize the current knowledge on the kind of heart-related stem cells currently available in large animal species and their relevance to human studies as pre-clinical models.