Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review in 2015

The gasotransmitters nitric oxide, carbon monoxide and hydrogen sulfide are involved in a large number of physiological processes. In this Review, the author explains how, in cancer, each of these gaseous mediators exhibits a biphasic pharmacological character, whereby increasing or decreasing gasotransmitter concentrations in the tumour can exert antitumour effects.

Single-cell analysis tools are rapidly evolving, enabling cellular analyses at the genomic, transcriptomic and proteomic levels. Here, Heath and colleagues provide an overview of recently developed single-cell analysis technologies, discuss their biological applications and highlight their potential uses in drug discovery and development, focusing on the field of oncology.

CNS myeloid cells mediate the local immune response during development, health and brain diseases and are emerging as potential therapeutic targets for the treatment of neurological and psychiatric disorders. Here, Biber and colleagues assess strategies for targeting CNS myeloid cells and consider key issues associated with their clinical translation.

Cells within the microvascular compartment, particularly leukocytes, can affect angiogenesis, inflammation and fibrosis. Kreuger and Phillipson discuss how to target these cells therapeutically, focusing on ways to interfere with intracellular communication and reprogramme leukocytes, which could have applications in the design of drugs and their delivery systems.

Optogenetics has already had a major impact on neuroscience research, particularly in the study of cognitive and emotional processes. Here, Song and Knöpfel discuss emerging applications of optogenetic technologies, focusing on their potential to transform neuroscience drug discovery programmes and to provide novel therapeutic approaches for conditions such as Parkinson disease, mood disorders and epilepsy.

As critical regulators of glucose and lipid metabolism, as well as vitamin D and phosphate homeostasis, the endocrine fibroblast growth factors (FGFs) have therapeutic potential in various chronic human diseases. Here, Moschetta and colleagues discuss the physiological roles of FGF19, FGF21 and FGF23, focusing on recent advances and the associated challenges in their therapeutic exploitation.

Several Phase I trials evaluating systemically administered siRNA-based therapeutics for cancer have recently been completed. Here, Zuckerman and Davis critically assess these studies and discuss key lessons learnt and implications for the future development of siRNA-based therapeutics and clinical trial design.

Dysfunction of voltage-gated calcium channels is associated with a variety of neurological and psychiatric conditions. Several drugs that block these channels are already in clinical use, with new agents currently in development. Here, Zamponi highlights the functions of voltage-gated calcium channels and assesses their potential as therapeutic targets for nervous system disorders.

The complement cascade, a key regulator of innate immunity, is a rich source of potential therapeutic targets for diseases including autoimmune, inflammatory and degenerative disorders. Morgan and Harris discuss the progress made in modulating the complement system and the existing challenges, including dosing, localization of the drug to the target and how to interfere with protein–protein interactions.

Targeted delivery to the lymphatic system has the potential to improve bioavailability, enhance prophylactic and therapeutic vaccination or tolerance induction, and target drug delivery to lymph-resident infection or metastasis. In this Review, Trevaskis, Kaminskas and Porter provide an overview of lymphatic targeting and delivery strategies in drug development, and discuss the clinical applications of these approaches.

Inflammatory conditions such as asthma, atopic dermatitis and chronic sinusitis with nasal polyps are caused by type 2 inflammation. In this Review, Gandhiet al. explore the idea that these conditions can be treated by targeting the common proximal drivers of type 2 inflammation, which include interleukin-4 (IL-4), IL-5 and IL-13, and discuss the supporting clinical evidence as well as candidate drugs in development.

Human pluripotent stem cells are being developed for therapeutic use in numerous conditions that affect different organs. In this Review, Kimbrel and Lanza discuss the history and science behind the approach and provide an overview of the products that are in clinical development or close to clinical development.

The zebrafish, a well-established model organism in basic biomedical research, has also become tractable for numerous applications in drug discovery, from phenotypic screens to testing for toxicity. In this Review, MacRae and Peterson discuss how zebrafish have been used in such applications, advances that could make it an increasingly attractive tool — particularly for phenotypic screening — and the challenges that need to be addressed.

The misfolding and aggregation of specific proteins — a process known as amyloidogenesis — seem to underlie a range of degenerative disorders. Here, Kelly and colleagues discuss the current understanding of the process and pathological role of protein aggregation, focusing on emerging disease-modifying strategies to ameliorate aggregation-associated degenerative disorders.

Fibrosis is a common but often debilitating pathological process involved in diseases of different tissues. Here, Macdonald and colleagues describe the common features and pathophysiological processes that lead to fibrosis of different organs, and present a 'fibrosis toolbox': a collection of small molecules that can be used to further dissect the pathogenesis of tissue fibrosis.

Oncolytic viruses can kill tumour cells through a dual mechanism of action; the direct lysis of cells, and the induction of an immune response. The first oncolytic virus has been approved in China, and another has been recommended for approval in the United States. This Review discusses the biology of oncolytic viruses as well as key oncolytic viruses in clinical development, and investigates the challenges associated with developing oncolytic viruses as a new therapeutic modality for cancer.

Nitric oxide (NO) is now established as a pivotal signalling molecule in the regulation of the cardiovascular system, and it has an important role in protection against cardiovascular disease. Here, Lundberget al. discuss the limitations of existing NO-targeting agents and assess emerging novel approaches to therapeutically modulate NO bioavailability.

Small-molecule drugs have several advantages that are complementary to, and possibly synergistic with, biologic approaches for anticancer immunotherapy. This Review provides an overview of immunological pathways that can best be targeted with small molecules and discusses how these approaches fit into the armamentarium of immunotherapeutic strategies for cancer.

Anticancer immunotherapy through checkpoint blockade enables the patient to mount active antitumour responses and can dramatically improve survival. In this Review, Mahoney, Rennert and Freeman examine targets for next-generation immunomodulators and discuss how these may be integrated in rational combination therapies with existing and upcoming immune-targeted drugs.

Chimeric antigen receptors (CARs) provide a powerful means to augment T cell-based anticancer efficacy, and second-generation CARs have shown remarkable results in clinical trials. Here, the authors discuss the immunopharmacology of the different CAR constructs that are currently in clinical testing.