Excitable cells — including neurons, muscle cells and cardiac myocytes — are unique in expressing high densities of voltage-gated sodium (NaV) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of ‘the’ sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (NaV1.1–NaV1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these NaV subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.
The immune-related adverse events associated with chimeric antigen receptor (CAR)-T cell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-T cell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on–off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloid cell-intrinsic druggable targets and cellular engineering strategies to develop safer CAR-T cells.
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