Gene medicines: the end of the beginning?

First-generation gene medicines and genetic vaccines represent a promising new class of therapeutics that have the potential to prevent, correct, or modulate genetic or acquired diseases. The rational design of synthetic gene delivery and expression systems continues to be essential to enable the precise temporal and spatial control of transgene expression in vivo. With the tantalizing efficacy results and outstanding safety profile observed with nonviral, plasmid-based product candidates in early clinical trials, a multidisciplinary approach remains critical to further improve the effectiveness, reduce the manufacturing costs, and maintain the safety of gene therapeutics and vaccines for their successful development. This commentary provides an historical perspective on somatic gene therapy and briefly addresses the rate-limiting steps in effective gene transfer and expression. The importance of understanding plasmid pharmacokinetics after administration by conventional routes in animal models and in humans is emphasized. Pharmaceutical scientists have a pivotal role to play in deciphering the key biological parameters to effective gene transfer and designing gene delivery systems that will enable plasmid-based products to become an integral part of the future medical armamentarium.     

The eosinophil as a therapeutic target in asthma: beginning of the end,or end of the beginning?

A major goal in asthma therapy is to reduce or prevent the inflammatory response associated with bronchial hyperresponsiveness, reversible airway obstruction and airway remodelling. However, because of the complex nature of the disease, a single target for such an ideal therapeutic approach remains elusive. To ensure a more rational design of anti-asthma drugs, recent investigations have attempted to elucidate the roles of inflammatory cellular components in asthma. Such studies have shown that eosinophilic infiltration is a prominent feature in the pathophysiology of asthma. Nonetheless, the role of the eosinophil in asthma has been questioned following recent human studies investigating the efficacy of a novel therapeutic strategy targeted at eosinophils.     

Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?

The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.     

Exhaled nitric oxide in asthma in adults: the end is the beginning?

Approximately 20 years after the initial report of the measurement of exhaled nitric oxide (NO) in the exhaled air of humans, numerous publications have evaluated the possible applications of the fraction of exhaled NO (FeNO) in patients with asthma. The aim of the present review is to evaluate the technical issues and confounding factors related to FeNO measurements, as well as the role of FeNO in the diagnosis of asthma, the evaluation of asthmatic patients and the guidance of treatment. Several other issues, including the pursuit for "normal" and best personal values, the prediction of clinically relevant asthma outcomes and the identification of asthma phenotypes and future directions are discussed. FeNO represents the only exhaled biomarker that has reached clinical practice even in primary care settings and this review provides a critical view of the possible applications of this biomarker, both for the basic researcher and the clinician.     

Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy?

Diabetic nephropathy (DN) is a progressive microvascular complication arising from diabetes. Within the kidney, the glomeruli, tubules, vessels and interstitium are disrupted, ultimately impairing renal function and leading to end-stage renal disease (ESRD). Current pharmacological therapies used in individuals with DN do not prevent the inevitable progression to ESRD; therefore, new targets of therapy are urgently required. Studies from animal models indicate that disturbances in mitochondrial homeostasis are central to the pathogenesis of DN. Since renal proximal tubule cells rely on oxidative phosphorylation to provide adequate ATP for tubular reabsorption, an impairment of mitochondrial bioenergetics can result in renal functional decline. Defects at the level of the electron transport chain have long been established in DN, promoting electron leakage and formation of superoxide radicals, mediating microinflammation and contributing to the renal lesion. More recent studies suggest that mitochondrial-associated proteins may be directly involved in the pathogenesis of tubulointerstitial fibrosis and glomerulosclerosis. An accumulation of fragmented mitochondria are found in the renal cortex in both humans and animals with DN, suggesting that in tandem with a shift in dynamics, mitochondrial clearance mechanisms may be impaired. The process of mitophagy is the selective targeting of damaged or dysfunctional mitochondria to autophagosomes for degradation through the autophagy pathway. The current review explores the concept that an impairment in the mitophagy system leads to the accelerated progression of renal pathology. A better understanding of the cellular and molecular events that govern mitophagy and dynamics in DN may lead to improved therapeutic strategies.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Nicotine-replacement therapy in pregnancy-the end of the road?

ABSTRACT:: Smoking in pregnancy is associated with serious perinatal risks, leading to attempts to prevent smoking with the use of nicotine-replacement therapy (NRT). After more than a decade of studies failing to show the effectiveness of NRT for smoking cessation in pregnancy, a recent large, randomized trial has clearly shown that the failure may be caused by >90% dropout rate. Several secondary analyses of randomized trials have shown that NRT is efficacious in decreasing smoking in pregnancy and in optimizing fetal growth among women who take the product. But to be effective in smoking cessation, any drug has to be taken by the patients. Can we overcome the dismal rates of pregnant women's adherence to NRT, so we can save unborn babies from the serious risks associated with their mothers' smoking?     

Paediatric clinical pharmacology—at the beginning of a new era

The lack of availability of medicines for children is a large problem. This problem is global. It concerns all children of the world, those in the developing world but also those in the developed world, even in the richest countries. Many generations of paediatricians and other physicians have learned to live with the situation, where more than half of the children are prescribed off-label or unlicensed medicines. However, there is no doubt that medicinal products used to treat the paediatric population should be subjected to ethical research of high quality and be appropriately authorised for use in the paediatric population. Within the last 10 years, the pioneering paediatric initiative in the United States and recent encouraging developments in Europe and at the WHO indicate that change may finally be possible. The developments of the last 2 years have been particularly intensive. It seems that a new era is beginning which will provide unprecedented opportunities but also great challenges for paediatric clinical pharmacologists and other stakeholders working to provide children with the medicines they need.     

COPD: is there light at the end of the tunnel?

No currently available treatments reduce the progression or suppress the inflammation of chronic obstructive pulmonary disease (COPD). However, with a better understanding of the inflammatory and destructive process, several targets have been identified and new treatments are in clinical development. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, including adhesion molecule and chemokine-directed therapy, as well as therapies to inhibit tumour necrosis factor-alpha. Several broad-spectrum anti-inflammatory drugs are also in development, and include inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase and nuclear factor-kappaB. There is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.     

Are we living in the end of the blockbuster drug era?

For the last two decades, we have seen remarkable growth in the pharmaceutical industry. This growth has mainly been due to the approximately 100 new blockbuster drugs, such as Lipitor? (atorvastatin) and Plavix? (clopidogrel). More than half of the revenue of major pharmaceutical companies and above one-third of the total pharmaceutical revenues came from the sales of these blockbuster drugs. Questions concerning the fate of these blockbuster drugs are beginning to surface as they are approaching their patent expiration dates, and as they are expected to face significant competition from generic versions. Branded drugs with more than USD 120 billion in sales (as of 2008) are expected to lose their patent protection in the next 3 to 4 years, while the less expensive generic versions are ready to enter the market. It is plausible that a major paradigm shift in our thinking is needed to stay innovative, competitive and economically feasible in this new era of drug development. A new wave of innovations is expected to boost the blockbuster regime. Herein, we discuss the different threats facing the branded monopoly, as well as some of the hopeful expectations for the blockbuster drug.     

Statins in the 21st century: end of the simple story?

The development of the HMG-CoA reductase inhibitors (the statins) has lead to important advances in the management of cardiovascular disease. There have several landmark mortality and morbidity clinical trials with the statins. The 4S (Scandinavian Simvastatin Survival Study) was the first large-scale randomised cholesterol-lowering trial to show a decrease in mortality. In patients with coronary heart disease and relatively high cholesterol, simvastatin decreased mortality, hospital stays, the risk of undergoing myocardial re-vascularisation, stroke and transient ischaemic attack. The CARE (Cholesterol and Recurrent Events) trial showed that lowering average cholesterol levels after myocardial infarction with pravastatin reduced a composite primary end point of coronary mortality and myocardial infarction, coronary bypass surgery, angioplasty and strokes. The LIPID (Long-term Intervention with Pravastatin in Ischaaemic Disease) study showed that lowering average cholesterol levels after previous myocardial infarction or unstable angina reduced mortality. WOSCOPS (The West of Scotland Coronary Prevention Study) was the first trial to demonstrate the benefit of pravastatin, as primary prevention for cardiovascular disease, in men with high cholesterol levels. AFCAPS/Tex CAPS (The Air Force/Texas Coronary Atherosclerosis Prevention Study) showed that the benefits of lowering cholesterol levels were also evident in healthy men and women who initially had average cholesterol levels. Rather surprisingly the reductions in mortality and morbidity with statins are only associated with small improvements in coronary angiographic findings. A preliminary study indicated than lovastatin prevented restenosis, but larger and better-controlled studies indicate that the statins do not have beneficial effects in restenosis. Effects other than lipid-lowering or as a consequence of their lipid-lowering may contribute to the beneficial effects of statins. These effects include improvement in vascular endothelial function, cardiac remodelling, changes in blood rheology, anti-oxidant, anti-inflammatory and anti-hypertensive actions.     

More light at the end of the tunnel – apixaban in atrial fibrillation

Introduction: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation.

Areas covered: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups.

Expert opinion: Apixaban is much easier for subjects with atrial fibrillation to use than warfarin, as it does not require regular monitoring by a health professional, with dosage adjustment. In addition to replacing warfarin in subjects with atrial fibrillation who are unable or not prepared to use warfarin, apixaban has the potential to replace warfarin more widely in the prevention of thromboembolism in subjects with atrial fibrillation.