Reviews & Analysis

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  • Evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown in the past decade. Nedergaard and colleagues overview the evidence for the glymphatic system and its role in disease, and discuss opportunities to harness the glymphatic system therapeutically; for example, by improving the effectiveness of intrathecally delivered drugs.

    • Terhi J. Lohela
    • Tuomas O. Lilius
    • Maiken Nedergaard
  • The potential of therapeutically targeting RNA structures with small molecules is being increasingly recognized. Here, Disney and colleagues review strategies to identify, validate and optimize small-molecule RNA binders. Examples of existing RNA-targeted small molecules, as well as challenges and future directions in the field, are discussed.

    • Jessica L. Childs-Disney
    • Xueyi Yang
    • Matthew D. Disney
    Review Article
  • Antibody function is dependent on avidity — the accumulated strength of multiple affinity interactions between the antibody, antigen, cell surface receptors and other antibodies. In this Review, Oostindie et al. discuss the role of avidity in eliciting antibody functional responses and review the current engineering strategies for manipulating avidity interactions in antibody-based therapies.

    • Simone C. Oostindie
    • Greg A. Lazar
    • Paul W. H. I. Parren
    Review Article
  • Monoclonal antibodies (mAbs) are appealing as potential therapeutics and prophylactics for viral infections. This Review describes advances in antibody discovery and engineering that have led to the development of mAbs that target viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus and Ebola virus, and also considers the implications for vaccine development.

    • Giuseppe Pantaleo
    • Bruno Correia
    • Laurent Perez
    Review Article
  • Multiple sclerosis (MS) is an immune-mediated neurological disorder featuring central nervous system demyelination. Increasing understanding of the complex pathophysiology of this disease has led to considerable expansion of the MS therapeutic toolbox over the past 20 years, but substantial limitations remain. In this Review, Sven Meuth and colleagues highlight promising non-classical targets for MS that could provide fruitful avenues for future therapies.

    • Laura Bierhansl
    • Hans-Peter Hartung
    • Sven G. Meuth
    Review Article
  • Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infections. Here, Mehrotra and Ravichandran discuss the mechanisms of efferocytosis and the role of this physiological process in disease, and assess strategies and agents for therapeutic intervention.

    • Parul Mehrotra
    • Kodi S. Ravichandran
    Review Article
  • The widespread clinical translation and commercialization of cell-based therapies are hampered by challenges related to cell source, viability, potency, safety and scalability. Here, Veiseh and colleagues overview progress in the development of cell-based therapeutics and discuss how biological engineering approaches — including genome editing, synthetic biology and the use of biomaterials — are beginning to address key challenges in the field.

    • Caleb J. Bashor
    • Isaac B. Hilton
    • Omid Veiseh
    Review Article
  • Phenotypic drug discovery has re-emerged over the past decade as an approach to systematically pursue drug discovery based on therapeutic effects in realistic disease models. This article discusses recent successes with this approach, and considers ongoing challenges and strategies to address them.

    • Fabien Vincent
    • Arsenio Nueda
    • Mark Mercola
  • System-wide methods to monitor protein activity are still underused in drug discovery. This Review discusses the potential of proteomics and chemoproteomics approaches for target identification, validation and identification of safety hazards.

    • Felix Meissner
    • Jennifer Geddes-McAlister
    • Marcus Bantscheff
    Review Article
  • Psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have emerging therapeutic potential for neuropsychiatric diseases such as depression and anxiety. In this Perspective, McClure-Begley and Roth discuss the promises and pitfalls of psychedelic pharmacology, including complex activity profiles beyond canonical 5-HT2A receptor activation that continue to be elucidated. They consider progress and challenges for clinical studies, as well as prospects for parsing the therapeutic from psychedelic effects of this class of compounds to develop ‘cleaner’ drugs.

    • Tristan D. McClure-Begley
    • Bryan L. Roth
  • Natural products derived from bacteria are an important source of potential new drug compounds, such as antibiotics and anticancer agents, but how to efficiently mine this resource remains a challenge. In their Review, Hemmerling and Piel discuss newly developed computational tools and strategies to access biosynthetic novelty in bacterial genomes. They consider the opportunities and challenges associated with different bacterial sources, including cultivated, ecology-based and previously untapped bacterial ‘dark matter’.

    • Franziska Hemmerling
    • Jörn Piel
    Review Article
  • Immune checkpoint inhibitors (ICIs) have dramatically improved the treatment of many tumours, but only a subset of patients respond when ICIs are used as standalone immunotherapeutic interventions. Here, Galluzzi and colleagues discuss the potential of harnessing clinical agents that target oncogene and non-oncogene addiction to enhance ICI sensitivity by converting immunologically ‘cold’ tumours into ‘hot’ lesions.

    • Giulia Petroni
    • Aitziber Buqué
    • Lorenzo Galluzzi
    Review Article
  • The past decade has witnessed rapid growth in the field of extracellular vesicle (EV) research, and the potential of harnessing EVs in the treatment and diagnosis of diseases is now well recognized. Here, Cheng and Hill provide an overview of the physiological and pathological roles of EVs, discuss how they could be therapeutically exploited and consider the associated challenges.

    • Lesley Cheng
    • Andrew F. Hill
    Review Article
  • Advances in oligonucleotide design and delivery platforms have enabled the recent approval of several oligonucleotide-based therapies. Here, Goga and Stoffel discuss applications of RNA-silencing oligonucleotide therapeutics in metabolic diseases, recent developments in the field, ongoing challenges and possible future directions.

    • Algera Goga
    • Markus Stoffel
    Review Article
  • Many drugs that target amyloid-β in Alzheimer disease have failed in clinical trials. Karran and De Strooper analyse clinical trial data for these drugs in the light of drug properties that could affect their clinical performance. They propose that amyloid plaque would need to be reduced to a low level to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe such a benefit.

    • Eric Karran
    • Bart De Strooper
  • In this Review, Quintana and colleagues discuss astrocytes, a type of glial cell that could be manipulated to treat neurological conditions. Potential astrocyte targets, and the progess made towards developing astrocyte-directed therapies, are highlighted, along with their potential pitfalls. They also propose a novel nomenclature for astrocyte subsets.

    • Hong-Gyun Lee
    • Michael A. Wheeler
    • Francisco J. Quintana
    Review Article
  • Mutations in cancer cells can generate tumour-specific neoepitopes, which are attractive targets for anticancer vaccines. This Review discusses the mechanisms of neoantigen T cell recognition and computational approaches to predict which neoantigens might confer proficient antitumour immunity in a given clinical context.

    • Franziska Lang
    • Barbara Schrörs
    • Ugur Sahin
    Review Article
  • Targeted protein degradation with proteolysis-targeting chimeras (PROTACs) has the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. This article summarizes the first two decades of PROTAC discovery and discusses key areas for the future of this therapeutic modality, including establishing the target classes for which it is most suitable and extending its application beyond oncology.

    • Miklós Békés
    • David R. Langley
    • Craig M. Crews
    Review Article