Review Articles

  • Review Article |

    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.

    • Soufiane Boumahdi
    •  & Frederic J. de Sauvage
  • Review Article |

    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.

    • Joana Desterro
    • , Pedro Bak-Gordon
    •  & Maria Carmo-Fonseca
  • Review Article |

    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.

    • Claire Vanpouille-Box
    • , Jules A. Hoffmann
    •  & Lorenzo Galluzzi
  • Review Article |

    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.

    • Xiao Zhao
    • , Jennifer Yin Yee Kwan
    • , Kenneth Yip
    • , Peter P. Liu
    •  & Fei-Fei Liu
  • Review Article |

    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.

    • Leonardo M. R. Ferreira
    • , Yannick D. Muller
    • , Jeffrey A. Bluestone
    •  & Qizhi Tang
  • Review Article |

    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.

    • Zsolt Sebestyen
    • , Immo Prinz
    • , Julie Déchanet-Merville
    • , Bruno Silva-Santos
    •  & Jurgen Kuball
  • Review Article |

    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.

    • Srinivasa Reddy Bonam
    • , Fengjuan Wang
    •  & Sylviane Muller
  • Review Article |

    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.

    • Gregory C. Fanning
    • , Fabien Zoulim
    • , Jinlin Hou
    •  & Antonio Bertoletti
  • Review Article |

    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.

    • Simon Faissner
    • , Jason R. Plemel
    • , Ralf Gold
    •  & V. Wee Yong
  • Review Article |

    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.

    • George S. Baillie
    • , Gonzalo S. Tejeda
    •  & Michy P. Kelly
  • Review Article |

    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.

    • Chirag H. Patel
    • , Robert D. Leone
    • , Maureen R. Horton
    •  & Jonathan D. Powell
  • Review Article |

    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.

    • Dimitrios C. Mastellos
    • , Daniel Ricklin
    •  & John D. Lambris
  • Review Article |

    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.

    • Kevin Harrington
    • , Daniel J. Freeman
    • , Beth Kelly
    • , James Harper
    •  & Jean-Charles Soria
  • Review Article |

    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.

    • Andrea G. Cochran
    • , Andrew R. Conery
    •  & Robert J. Sims III
  • Review Article |

    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.

    • Aran F. Labrijn
    • , Maarten L. Janmaat
    • , Janice M. Reichert
    •  & Paul W. H. I. Parren
  • Review Article |

    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.

    • Nam Hoon Kwon
    • , Paul L. Fox
    •  & Sunghoon Kim
  • Review Article |

    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.

    • Jessica Vamathevan
    • , Dominic Clark
    • , Paul Czodrowski
    • , Ian Dunham
    • , Edgardo Ferran
    • , George Lee
    • , Bin Li
    • , Anant Madabhushi
    • , Parantu Shah
    • , Michaela Spitzer
    •  & Shanrong Zhao
  • Review Article |

    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.

    • Gregory R. Steinberg
    •  & David Carling
  • Review Article |

    Advances in the design of vectors based on retroviruses, such as lentiviruses and gammaretroviruses, have led to improvements in the safety and stability of gene therapies directed at haematopoietic stem and progenitor cells. In this Review, Cavazzana and colleagues discuss the results from recent clinical trials of retroviral vectors for the treatment of genetic disorders, including severe combined immunodeficiencies and β-haemoglobinopathies (β-thalassaemia and sickle cell disease). They highlight the progress made and the remaining challenges in applying gene therapies more broadly.

    • Marina Cavazzana
    • , Frederic D. Bushman
    • , Annarita Miccio
    • , Isabelle André-Schmutz
    •  & Emmanuelle Six
  • Review Article |

    Pseudokinases are key components of cellular networks, often acting as scaffolds. Many catalytically active kinases also signal through noncatalytic mechanisms in addition to their enzymatic roles. Kung and Jura discuss strategies to target pseudokinases therapeutically, as well as the progress made so far and lessons learned from inhibitors of active kinases.

    • Jennifer E. Kung
    •  & Natalia Jura
  • Review Article |

    The recent approval of the first RNA interference (RNAi)-based therapy has generated considerable excitement in the field. Here, Rossi and colleagues discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, assess the current clinical pipeline and highlight future opportunities and challenges for RNAi-based therapeutics.

    • Ryan L. Setten
    • , John J. Rossi
    •  & Si-ping Han
  • Review Article |

    Imbalances in the kynurenine pathway (KP) of tryptophan metabolism are associated with CNS disorders, infectious diseases, autoimmune diseases and cancer, highlighting KP enzymes as potential therapeutic targets. Here, Platten and colleagues provide an overview of the physiological and pathophysiological roles of tryptophan metabolism, focusing on the clinical potential and challenges associated with targeting this pathway.

    • Michael Platten
    • , Ellen A. A. Nollen
    • , Ute F. Röhrig
    • , Francesca Fallarino
    •  & Christiane A. Opitz
  • Review Article |

    Ion channels are attractive therapeutic targets for a wide range of diseases, but achieving sufficient selectivity with small-molecule drugs can be challenging. In this Review, Wulff and colleagues discuss strategies to selectively modulate ion channel function using biologics — namely, antibodies and venom-derived peptides — highlighting opportunities, hurdles and future directions for the field.

    • Heike Wulff
    • , Palle Christophersen
    • , Paul Colussi
    • , K. George Chandy
    •  & Vladimir Yarov-Yarovoy
  • Review Article |

    Adeno-associated virus (AAV) vectors represent the leading platform for therapeutic gene delivery, with two recombinant AAV gene therapy products having gained regulatory approval in Europe or the United States. Here, Gao and colleagues discuss the fundamentals of AAV and vectorology, focusing on current therapeutic strategies, clinical progress and ongoing challenges.

    • Dan Wang
    • , Phillip W. L. Tai
    •  & Guangping Gao
  • Review Article |

    Interferons are key players in effective host immunological responses to malignant cells. This Review discusses new interferon-directed therapeutic opportunities — ranging from cyclic dinucleotides to genome methylation inhibitors, including combinations with other emerging therapeutic interventions — in cancer treatment.

    • Ernest C. Borden
  • Review Article |

    Understanding the genetic and phenotypic architecture of health and disease is vital to the identification of novel therapeutic targets and therapies. Here, Nadeau and Auwerx review the fundamentals of genotype–phenotype relations in mouse models and discuss how the integration of human and mouse genetic research remains essential to understanding disease pathogenesis, identifying potential therapeutic targets and developing new therapies

    • Joseph H. Nadeau
    •  & Johan Auwerx
  • Review Article |

    The rapid progress in cancer immuno therapy has highlighted the need for new delivery technologies. In this article, Langer, Mitchell and colleagues discuss how recent developments in drug delivery could enable new cancer immunotherapies and improve on existing ones, and examine the current delivery obstacles.

    • Rachel S. Riley
    • , Carl H. June
    • , Robert Langer
    •  & Michael J. Mitchell
  • Review Article |

    The transcription factor NRF2 and its repressor KEAP1 have been implicated in the development and progression of chronic diseases. Here, Dinkova-Kostova and colleagues provide an overview of the physiological and pathological roles of NRF2, present emerging pharmacological modulators of the NRF2–KEAP1 axis and highlight associated drug development challenges.

    • Antonio Cuadrado
    • , Ana I. Rojo
    • , Geoffrey Wells
    • , John D. Hayes
    • , Sharon P. Cousin
    • , William L. Rumsey
    • , Otis C. Attucks
    • , Stephen Franklin
    • , Anna-Liisa Levonen
    • , Thomas W. Kensler
    •  & Albena T. Dinkova-Kostova
  • Review Article |

    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.

    • Iriny Ekladious
    • , Yolonda L. Colson
    •  & Mark W. Grinstaff
  • Review Article |

    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.

    • Marilyn J. Telen
    • , Punam Malik
    •  & Gregory M. Vercellotti
  • Review Article |

    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.

    • Aaron C. Anselmo
    • , Yatin Gokarn
    •  & Samir Mitragotri
  • Review Article |

    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.

    • Sung-Joon Lee
    • , Inge Depoortere
    •  & Hanns Hatt
  • Review Article |

    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.

    • Xueman Chen
    •  & Erwei Song
  • Review Article |

    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.

    • Ichio Shimada
    • , Takumi Ueda
    • , Yutaka Kofuku
    • , Matthew T. Eddy
    •  & Kurt Wüthrich
  • Review Article |

    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.

    • Michael P. Murphy
    •  & Richard C. Hartley
  • Review Article |

    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.

    • Luca Cassetta
    •  & Jeffrey W. Pollard
  • Review Article |

    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.

    • Dale W. Laird
    •  & Paul D. Lampe
  • Review Article |

    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.

    • Amir Sharabi
    • , Maria G. Tsokos
    • , Ying Ding
    • , Thomas R. Malek
    • , David Klatzmann
    •  & George C. Tsokos
  • Review Article |

    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.

    • Sudeep Pushpakom
    • , Francesco Iorio
    • , Patrick A. Eyers
    • , K. Jane Escott
    • , Shirley Hopper
    • , Andrew Wells
    • , Andrew Doig
    • , Tim Guilliams
    • , Joanna Latimer
    • , Christine McNamee
    • , Alan Norris
    • , Philippe Sanseau
    • , David Cavalla
    •  & Munir Pirmohamed
  • Review Article |

    Existing dopaminergic-based therapies for Parkinson disease (PD) are limited by side effects and lack of long-term efficacy. Here, Charvin et 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.

    • Delphine Charvin
    • , Rossella Medori
    • , Robert A. Hauser
    •  & Olivier Rascol
  • Review Article |

    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.

    • Adrian P. Campbell
    •  & Alan V. Smrcka
  • Review Article |

    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.

    • Nicholas S. Caron
    • , E. Ray Dorsey
    •  & Michael R. Hayden
  • Review Article |

    In this Review, Pastor et 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.

    • Fernando Pastor
    • , Pedro Berraondo
    • , Iñaki Etxeberria
    • , Josh Frederick
    • , Ugur Sahin
    • , Eli Gilboa
    •  & Ignacio Melero
  • Review Article |

    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.

    • Barry Boland
    • , Wai Haung Yu
    • , Olga Corti
    • , Bertrand Mollereau
    • , Alexandre Henriques
    • , Erwan Bezard
    • , Greg M. Pastores
    • , David C. Rubinsztein
    • , Ralph A. Nixon
    • , Michael R. Duchen
    • , Giovanna R. Mallucci
    • , Guido Kroemer
    • , Beth Levine
    • , Eeva-Liisa Eskelinen
    • , Fanny Mochel
    • , Michael Spedding
    • , Caroline Louis
    • , Olivier R. Martin
    •  & Mark J. Millan
  • Review Article |

    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.

    • Benjamin E. Deverman
    • , Bernard M. Ravina
    • , Krystof S. Bankiewicz
    • , Steven M. Paul
    •  & Dinah W. Y. Sah
  • Review Article |

    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.

    • Matthew S. J. Mangan
    • , Edward J. Olhava
    • , William R. Roush
    • , H. Martin Seidel
    • , Gary D. Glick
    •  & Eicke Latz
  • Review Article |

    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.

    • Patrick A. Mayes
    • , Kenneth W. Hance
    •  & Axel Hoos
  • Review Article |

    New therapies in development for haemophilia — including gene therapies, proteins with extended half-lives and inhibitors of natural anticoagulants — look poised to change the management of this disease. In this Review, Peters and Harris discuss recent progress, including the hurdles that still need to be overcome in order to translate these advances into routine clinical use.

    • Rob Peters
    •  & Tim Harris
  • Review Article |

    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.

    • Jean-Paul Renaud
    • , Ashwin Chari
    • , Claudio Ciferri
    • , Wen-ti Liu
    • , Hervé-William Rémigy
    • , Holger Stark
    •  & Christian Wiesmann