Review Articles in 2018

The conjugation of therapeutic agents to polymer carriers, such as polyethylene glycol (PEG), can control drug delivery, enhance solubilization, increase efficacy and improve pharmacokinetics. Here, Grinstaff, Colson and Ekladious discuss recent advances in the preclinical and clinical development of different classes of polymer–drug conjugates and highlight current challenges and future directions.

Although the molecular basis for sickle cell disease (SCD) has been known for decades, progress in developing therapies that ameliorate the complex systemic manifestations of SCD has been slow. This article reviews recent advances that are providing the basis for therapies that could improve outcomes by targeting different aspects of SCD pathophysiology and highlights the opportunity for combination strategies. The potential for curative gene therapy is also discussed.

The requirement for delivery by injection is currently a limitation for the use of biologic drugs such as antibodies. In this Review, Mitragotri and colleagues discuss advances made in non-invasive drug delivery for biologics, including the transdermal, oral and inhalation routes, highlighting which routes are the most promising and the additional challenges to bringing these systems to the clinic.

Olfactory and taste receptors are ectopically expressed in multiple extra-nasal and extra-oral tissues, exhibiting potential functions in a diverse range of biological processes. Here, Lee et al. discuss the physiological roles of these ectopic olfactory and taste receptors, assessing their emerging therapeutic and diagnostic potential in conditions including asthma, wound healing, obesity and cancer.

Cancer-associated fibroblasts (CAFs) are often the most abundant cell type in the tumour microenvironment. Here, Song and colleagues discuss how to target or harness these cells for cancer therapy. They highlight the progress made to date and the remaining challenges in bringing CAF-targeted therapies to the clinic.

Determination of the crystal structures of more than 50 human G protein-coupled receptors (GPCRs) during the past decade has provided a platform for structure-based drug design for this key target class, which is being augmented with cryo-electron microscopy (cryo-EM) structures and nuclear magnetic resonance (NMR) spectroscopy studies of dynamic features. This Review describes the application of NMR techniques to GPCRs and projects where crystal and/or cryo-EM structures have been complemented with NMR studies and discusses the impact of this integrative approach on GPCR biology and drug discovery.

Mitochondrial dysfunction contributes to many common disorders, and therapeutic strategies aimed at restoring mitochondrial function are now emerging, with a small number of agents now in clinical trials. Here, Murphy and Hartley assess therapeutic approaches and challenges in targeting mitochondria and highlight examples of promising indications.

Tumour-associated macrophages (TAMs) promote cancer initiation and malignant progression. This Review evaluates current strategies to target TAMs, exploring their toxicity and compensatory mechanisms, and proposes novel strategies in light of new findings regarding macrophage biology and their mechanism of action.

The connexin family of channel-forming proteins is critical for cellular communication, being involved in both health and disease. Here, Laird and Lampe assess the potential of connexins as therapeutic targets in acquired and inherited diseases, as well as wound repair, highlighting agents currently in development and the associated clinical challenges.

Regulatory T cells are important in controlling immune reactions and thus are implicated in autoimmune diseases, transplantation and cancer. In this Review, Tsokos and colleagues discuss how these cells can be harnessed or manipulated for therapeutic use and describe the progress that has been made as well as impending challenges.

Drug repurposing — a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication — has the potential for greater success rates and reduced costs compared with developing entirely new drugs. Pirmohamed and colleagues present approaches used for drug repurposing, discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed.

Existing dopaminergic-based therapies for Parkinson disease (PD) are limited by side effects and lack of long-term efficacy. Here, Charvinet al. discuss the challenges facing the development of novel treatments for PD, assess emerging disease-modifying non-dopaminergic therapeutic strategies and highlight novel therapies aimed at managing symptoms of the disease.

Identifying ligands of G protein-coupled receptors (GPCRs) that elicit biased downstream signalling is an established strategy for separating the desired and unwanted effects of these receptors. Campbell and Smrcka describe how inhibiting the downstream G proteins themselves could also be used to bias GPCR signalling, as well as block pathways shared by multiple GPCRs involved in complex diseases, and discuss how the currently available G protein ligands could be optimized to generate therapeutic leads.

New therapies, including RNA-based and gene therapies, are poised to change the therapeutic landscape for Huntington disease. In this article, Hayden and colleagues review the progress that has been made in the past 25 years in developing therapies for this disease and highlight the pitfalls and potential of future treatments.

In this Review, Pastoret al. provide an overview of RNA-based agents used in cancer immunotherapy — ranging from RNA vaccines encoding cancer neoantigens to interference RNAs and protein-binding RNA aptamers — providing insights into this emerging field.

Neurodegenerative disorders of ageing such as Alzheimer disease, Parkinson disease and Huntington disease are characterized by the presence of neurotoxic misfolded and aggregated proteins. One reason underlying the accumulation of these proteins is insufficient clearance by intracellular and extracellular pathways such as the autophagic–lysosomal network and the glymph system. This article reviews the potential for therapeutically enhancing the clearance of neurotoxic proteins to curtail the onset and slow the progression of neurodegenerative disorders of ageing.

The potential of adeno-associated viral (AAV)-mediated gene therapy for neurological disorders is rapidly emerging. Evidence of clinical efficacy and safety, as well as durable transgene expression, has now been reported in several central nervous system disorders. Here, Sah and colleagues discuss key considerations in the design and development of therapeutic AAV vectors, highlighting promising therapeutic targets and recent clinical trials.

The inflammasome is a key integration point for innate immunity. As such, targeting this signalling hub has the potential to be useful in numerous autoimmune and metabolic disorders. In this article, Latz and colleagues discuss the progress that has been made towards targeting the inflammasome, highlighting the therapeutic potential of some of these compounds as well as caveats for their use.

Co-stimulatory receptors mediate the anticancer immune response. This Review discusses the current efforts in targeting co-stimulatory receptors with agonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.

Recent technological advances with cryo-electron microscopy (cryo-EM) — a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies — have raised hopes that it might soon become an important tool for drug discovery, particularly for 'intractable' targets that are still not accessible to analysis by X-ray crystallography. This article describes these advances and critically assesses their relevance for drug discovery.