Read the April issue

Including articles on targeted protein degradation, polymer–drug conjugates, therapeutic modulation of the NRF2–KEAP1 axis and integrating human and mouse genetics in target validation.

Latest Reviews

  • 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
  • Perspective |

    Cells in the innate immune system can display adaptive characteristics that lead to increased responsiveness to secondary stimulation by pathogens. This innate immune memory has been termed ‘trained immunity’. Here, Mulder and colleagues describe the mechanisms responsible for the induction of trained immunity and propose strategies to regulate it as a potential treatment of immune-related diseases.

    • Willem J. M. Mulder
    • , Jordi Ochando
    • , Leo A. B. Joosten
    • , Zahi A. Fayad
    •  & Mihai G. Netea
  • 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

News & Comment

  • Comment |

    It is increasingly important that regulatory agencies catalyse the translation of scientific and technological innovation into improved patient-centred health care. Here, we highlight the strategic goals of the European Medicines Agency to advance regulatory science and optimize the opportunities arising in areas such as cell and gene therapies, big data and artificial intelligence.

    • Philip A. Hines
    • , Richard H. Guy
    • , Anthony J. Humphreys
    •  & Marisa Papaluca-Amati
  • Comment |

    One aspect of the ongoing debate about drug pricing is the added therapeutic benefit of new drugs compared with existing — and potentially cheaper — therapies. Here, we discuss the merits and pitfalls of proposals that are being discussed with regard to the role of regulatory agencies in establishing added therapeutic benefit.

    • Hans-Georg Eichler
    • , Harald Enzmann
    •  & Guido Rasi

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