Review Articles in 2013

It has been 25 years since the hepatitis C virus (HCV) was discovered. Now, pipelines are bristling with exciting new direct-acting antiviral drugs, many of which are in late-stage clinical trials. In this Review, Manns and von Hahn examine the future of anti-HCV therapy, the prospect of all-oral interferon-free treatment regimens, and discuss the key challenges faced by clinicians and drug developers.

Current treatments for chronic obstructive pulmonary disease (COPD) do not reduce disease progression or suppress chronic inflammation. This Review highlights new therapeutic targets that have been discovered through a better understanding of the underlying inflammation in COPD and provides an update on the development of anti-inflammatory drugs for this disorder.

Nucleoside analogues have been in clinical use for many years, but there are ongoing efforts to improve patient response rates and reduce side effects. Here, the authors highlight recent progress in the development of new nucleoside and nucleotide analogues for the treatment of cancer and viral diseases.

Although originally believed to be non-functional, key roles for non-coding RNA (ncRNA) transcripts in the regulation of gene expression have now been revealed. Here, Wahlestedt provides an overview of the various subtypes of ncRNA, focusing on the emerging regulatory roles of long non-coding RNAs (lncRNAs) and their links to disease. The potential of targeting the natural antisense transcript subclass of lncRNAs using antisense oligonucleotides known as antagoNATs, to therapeutically upregulate gene expression, is assessed.

Dysfunctional mitochondria are implicated in rare, inherited mitochondrial diseases as well as a variety of common age-related disorders. Here, Auwerx and colleagues provide an overview of diseases that affect mitochondria, highlight strategies for therapeutically intervening in mitochondrial pathways and discuss screening strategies for drug identification.

Re-establishing effective platforms for antibiotic discovery is crucial for combating the growing threats from antibiotic resistance. Here, Lewis discusses the lessons learned from the golden era of antibiotic discovery and reasons for the failure of previous platforms, and proposes strategies to create new platforms or revitalize old ones, including harnessing untapped sources of natural products as well as developing species-selective and prodrug antibiotics.

Tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide and there is an urgent need for novel therapies and treatment regimens of shorter duration. Here, Zumla, Nahid and Cole discuss current concepts and recent advances in TB drug discovery, development and clinical trial evaluation, and provide an update of new agents and approaches currently being investigated.

Owing to their specificity, immunomodulatory biologics generally have better safety profiles than small-molecule drugs. However, adverse effects such as an increased risk of infections or cytokine release syndrome are of concern. Here, Park and colleagues discuss the current strategies used to predict and mitigate these adverse effects and consider how they can be used to inform the development of safer immunomodulatory biologics.

Adenosine signalling has a functional role in many diseases and has long been a target for drug development. However, only one adenosine receptor-specific agent has so far gained approval. Here, Fredholm and colleagues provide an overview of the physiological and pathological functions of adenosine and consider the challenges in the development of compounds targeting adenosine receptors.

Animal models are vital tools in the development of therapies for orphan diseases, given the small populations of patients available to evaluate the therapies. Here, Sepodes and colleagues from the European Medicines Agency's Committee for Orphan Medicinal Products harness their experience to provide an overview of the animal models used to support regulatory applications for metabolic, neuromuscular and ophthalmological rare diseases.

In recent years it has become apparent that the tumour microenvironment has a large effect on tumour cell signalling, proliferation, survival and, importantly, responses to drugs. Here, Mitsiades and colleagues discuss how these considerations can inform anticancer drug discovery and provide an overview of advances in preclinical models that allow better assessment of the impact of the tumour microenvironment on therapeutic efficacy.

The B cell receptor (BCR) activates numerous survival and proliferation pathways, and can signal in an antigen-dependent or antigen-independent (tonic) fashion. Here, Young and Staudt discuss the signalling cascades involved, examine recent evidence for a role of BCR signalling in different subtypes of B cell lymphomas and provide an overview of pipeline candidates that target components of the BCR signalling cascade.

Immunomodulatory biologics targeting cell surface signalling proteins on immune cells allow immune responses to be driven in desired directions — enhancing these in infection or cancer, or dampening them in autoimmune diseases or transplantation. In this Review, Chen and colleagues discuss immunomodulatory signalling pathways that provide targets for immunomodulation, and the current state of drug development in the field.

The clinical success of inhibitors of tumour necrosis factor (TNF) in the treatment of autoimmune diseases has generated interest in the therapeutic potential of targeting other members of the TNF superfamily (TNFSF) of cytokines and their receptors. Here, Croft and colleagues review the current developmental status of biologics targeting these molecules in a range of disorders, highlighting key challenges and emerging therapeutic targets.

The accumulation of eosinophils in blood and tissue is associated with several inflammatory and infectious diseases. Here, the authors describe recent advances in the development of first-generation eosinophil-targeted therapies and highlight innovative new strategies — such as inhibiting eosinophil activation — that are aimed at targeting eosinophils.