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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.
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.
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.
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.
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.
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.
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
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.
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.
Immunoscore classifies cancers according to their immune infiltration. In this Review, Galon and Bruni provide a panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours.
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.
