Review Articles in 2019

Most rare diseases still lack approved treatments. This article analyses the main therapeutic modalities available to researchers interested in translating advances in the scientific understanding of rare diseases into therapies, highlights progress so far and discusses overarching issues in drug development for rare diseases.

Genomic screenings have enabled the discovery of synthetic lethal partners as potential drug targets in cancer. This Review discusses how the genetic concept of synthetic lethality paired with CRISPR-based functional genomic screening can be applied to identify additional synthetic lethal pairs as new and druggable cancer targets.

Cell plasticity has emerged as a mode of targeted therapy evasion in various cancers. This Review discusses the different mechanisms that drive tumour cell plasticity and the potential therapeutic strategies to target them in order to achieve more durable clinical responses.

Precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3′ ends by cleavage and polyadenylation, is frequently altered in tumours. This Review describes small molecules and oligonucleotides that modulate the spliceosome and are now in clinical trials for the treatment of cancer.

Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.

Fibrosis features in numerous chronic diseases, such as non-alcoholic steatohepatitis and heart failure, and no existing therapies can prevent or reverse this abnormal deposition of extracellular matrix, which leads to organ dysfunction. Here, Liu and colleagues describe how this energy-intensive process could be targeted by therapies that interfere with metabolism, including the metabolic implications of drugs directed at transforming growth factor-β and the deposition of extracellular matrix.

Our increased understanding of how regulatory T cells suppress immune responses has led to their use in early-phase clinical trials for inflammatory disorders, with promising results. This Review describes the key advances and prospects in designing and implementing regulatory T cells as multifaceted, adaptable smart therapeutics in autoimmunity and transplantation.

γδT cells display potent cytotoxicity towards a large array of haematological and solid tumours while preserving normal tissues. In this Review, Sebestyen et al. analyse the tumour specificity mechanisms of γδT cells and the challenges and opportunities for the use of such cells and their receptors in cancer immunotherapy.

Defective lysosomal function has been implicated in diseases ranging from rare lysosomal storage disorders to more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. Here, Muller and colleagues provide an overview of the physiological and pathological roles of lysosomes and assess the progress and opportunities for therapeutically targeting lysosomal proteins and processes.

Drug development for treatment of hepatitis B virus infection has trailed behind that for infection with the related hepatitis C virus, but encouraging progress has been made in recent years. Fanning and colleagues review advances in hepatitis B therapies and challenges for their development, including antiviral and immune-boosting strategies that could be part of combination strategies to achieve functional cure.

The pathophysiological complexity of progressive multiple sclerosis (MS) challenges the development of effective treatments, despite the substantial unmet clinical need. In this Review, Faissner, Yong and colleagues highlight the need for therapies that target inflammation, neurodegeneration and remyelination, which will likely be needed in combination. The setbacks encountered so far and future challenges are also discussed.

Cyclic nucleotide phosphodiesterases (PDEs) have roles in numerous biological processes and their dysfunction has been associated with various diseases including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Here, Kelly and colleagues assess the current status of therapeutic PDE inhibitors, and highlight emerging novel strategies to therapeutically target PDE function.

Metabolic reprogramming alters immune cell activation, differentiation and function. Powell and colleagues discuss how to specifically modulate the activity of immune cells by altering their metabolism, suggesting a model of ‘cellular selectivity based on demand’, and highlight the opportunities to therapeutically target immunometabolism in cancer and autoimmune disorders.

The complement system has a pivotal role in immunosurveillance and its dysregulation is involved in a variety of diseases. Here, Lambris and colleagues provide an overview of the pathological roles of the complement system in acute and chronic disorders, assessing recent developments in complement drug discovery, while highlighting the associated opportunities and challenges.

Oncolytic viruses are currently seen as a potential therapeutic option for patients with cancer who do not respond to immune checkpoint inhibitors. This Review discusses the different therapeutic approaches to develop oncolytic viruses, delivery modalities and methods for assessing their biological activity.

Bromodomains are attractive targets from a chemical and structural perspective. The promising therapeutic effects of BET bromodomain inhibitors prompted chemical probe development to understand the potential of new agents targeting bromodomains. This Review discusses the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications.

Bispecific antibodies — a large family of molecules that are designed to recognize two different epitopes or antigens — come in many formats and can have the potential for novel functionalities that are not provided by mixtures of monoclonal antibodies. This article reviews the current bispecific antibody landscape from a mechanistic perspective, including a comprehensive overview of the pipeline.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Research advances have unveiled unexpected disease-associated alterations in human ARSs that have highlighted their potential as therapeutic targets. This Review addresses the emerging biology and therapeutic applications of human ARSs.

Machine learning has been applied to numerous stages in the drug discovery pipeline. Here, Vamathevan and colleagues discuss the most useful techniques and how machine learning can promote data-driven decision making in drug discovery and development. They highlight major hurdles in the field, such as the required data characteristics for applying machine learning, which will need to be solved as machine learning matures.

AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis that is activated by physiological regulators associated with health and longevity. Here, Steinberg and Carling provide an overview of the physiological functions of AMPK and discuss the potential of this enzyme as a therapeutic target across diverse disease areas. Pharmacological activation of AMPK and the associated drug development challenges are assessed.