Reviews & Analysis

Although neurotrophins could provide benefit in neurological diseases, their therapeutic application is limited by poor pharmacological properties and undesirable pleiotropic actions. Here, Longo and Massa highlight recent progress in the targeting of individual neurotrophin receptors using small-molecule ligands in an effort to overcome these limitations.

More than half of all patients with cancer receive radiation therapy, but normal tissue tolerance to radiation often limits the ability to cure tumours with radiation therapy. Here, Moding, Kastan and Kirsch discuss current approaches and possible future directions for combining radiation therapy with targeted therapies to enhance the probability of tumour cure.

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.

There is substantial debate over the best approach for developing transformative drugs and how this might be supported. To help inform this debate by improving the understanding of the characteristics of transformative drug innovation, the authors surveyed a US-based group of ∼180 expert physicians in 15 medical specialities, who identified the drugs that they considered to be the most transformative in their fields over the past 25 years, as well as key factors affecting their opinions.

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.

Rapid advances in next-generation sequencing (NGS) are facilitating deeper insights into the molecular classifications of cancer and the mechanisms of resistance development, thereby paving the way for a new era of personalized medicine. In this Perspective, Simon and Roychowdhury explore how genomic information can be used in the design of clinical trials for molecularly targeted anticancer drugs as well as for the development of new biomarkers.

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.

Extracellular vesicles have emerged as important mediators of intercellular communication, and they are now implicated in numerous biological and pathological processes. Here, Wood and colleagues focus on the role of extracellular vesicles in diseases including cancer, HIV and neurodegenerative disorders, and consider how extracellular vesicles might be targeted or directly exploited for therapeutic intervention.

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.

The therapeutic outcome of a drug or procedure is influenced by the placebo response in both drug development and clinical practice. Enck and colleagues examine how the placebo response can be utilized in these settings to ensure that the most desirable outcome is attained.

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.

Pharmacogenetics is an increasingly important tool for drug development, which has been reflected in recent guidelines from regulatory agencies on the application of pharmacogenetics in studies of investigational drugs. In this article, authors from Europe, the United States and Japan overview the guidelines from the regulatory agencies in each region and discuss the common themes and differences.