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Following the success of the COVID-19 vaccines, mRNA vaccines have now entered development for a wide range of infectious diseases. This Review discusses mRNA vaccine design considerations, delivery strategies and mechanisms of action, assessing mRNA vaccines currently in development for various viruses, bacteria and parasites. The challenges, limitations and opportunities facing next-generation mRNA vaccines are considered.
With ageing global populations, cellular senescence is gaining increasing attention as a therapeutic target. In their Review, Orr and colleagues discuss ongoing research into senescence in the central nervous system, including promising targets and drugs in development that aim to clear senescent cells or modulate their senescence-associated secretory phenotype.
Dysregulated cytokine networks are important in the pathogenesis of neuroinflammation. This Review discusses targeting cytokines and their receptors in non-infectious central nervous system inflammatory diseases such as multiple sclerosis and neurosarcoidosis, as well as in the neurotoxic adverse events that can be triggered by cancer immunotherapy.
Targeting the interactions between neurons, cancer cells and other elements in the tumour microenvironment represents a potential paradigm shift in cancer treatment. This Review article provides an overview of the dynamics of the nerveâcancer cell interplay as well as a discussion of current preclinical and clinical evidence of the benefits of targeting the nervous system in cancer.
Multiple protein isoforms arise from most genes by alternative RNA splicing and other mechanisms, but these isoforms are often neglected in drug discovery. This Review discusses the modes of action of emerging therapeutics that focus on protein isoforms as well as how isoforms can serve as biomarkers and facilitate targeted drug delivery.
The M1 and M4 muscarinic acetylcholine receptors represent promising therapeutic targets for Alzheimer disease and schizophrenia. However, the development of agents targeting these receptors has been limited by their adverse cholinergic effects. Here, Tobin discusses how recent advances in the field â including an increased understanding of receptor biology and signalling, as well as the application of structure-based drug design â are enabling a new generation of muscarinic receptor modulators to enter clinical development.
Epilepsy is a common and debilitating brain disorder for which current antiseizure medications (ASMs) provide inadequate efficacy in around 30% of patients. In their Review, Pavel Klein and colleagues survey the diverse ASM pipeline, including new approaches to target specific epilepsy syndromes, and discuss strategies for disease prevention.
Mutations in genes that encode subunits of the SWI/SNF chromatin remodelling complexes are found in more than 20% of cancers as well as in certain neurodevelopmental disorders. This Review discusses mechanisms by which SWI/SNF mutations lead to disease and the strategies to target SWI/SNF complexes and synthetic lethal targets for therapeutic benefit.
Reactive oxygen species are essential molecules that are generated and eliminated through complex balanced mechanisms. Increased reactive oxygen species levels have a role in tumour development, and targeting reactive oxygen species and their regulatory machineries is a promising therapeutic strategy. This Review discusses recent research developments in the field, their implications for cancer drug discovery, as well as emerging concepts and future perspectives.
In situ cancer vaccines generate tumour-specific T cell responses and hold promise for the treatment of solid tumours. This Review discusses drug delivery technologies such as lipid nanoparticles, hydrogels and scaffolds that are being developed to boost the antitumour immune effects of several types of in situ cancer vaccine.
Advances in understanding of the cause of autoimmune diseases and clinical data from novel therapeutic modalities such as chimeric antigen receptor T cells are providing evidence that it may be possible to re-establish immune homeostasis and, potentially, prolong remission or even cure autoimmune diseases. This article proposes a three-step âsequential immunotherapyâ framework for immune system modulation to help achieve this ambitious goal, and discusses existing drugs and those in development for each of the three steps.
The rise of drug resistance presents a significant challenge in the treatment of infectious diseases. This Review summarizes the status and mechanisms of drug resistance in malaria, human immunodeficiency virus (HIV) infection and tuberculosis, and explores strategies to address resistance that could be incorporated into drug development across these disease areas.
RNA has revolutionized modern medicine, creating great expectations. However, challenges with this class of drugs persist. In this Review, John Androsavich analyses lessons learnt from RNA modalities such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNA), and discusses strategies to develop RNA drug platforms, improving their applicability, efficacy and safety profiles.
Immunogenic cell death (ICD) is crucial for the elicitation of anticancer immune responses by therapy, but the successful development of ICD-inducing treatments is hindered by various obstacles. This Review provides an overview of the core mechanisms of ICD, discusses obstacles to the development of novel ICD modulators and assesses established and innovative therapeutic approaches for ICD induction.
Since the groundbreaking discovery of RNAi more than 25 years ago, several small interfering RNA (siRNA)-based therapies that target the liver have gained approval. This Review discusses principal considerations in siRNA-based drug development, focusing on the medicinal chemistry of siRNA design, the application of informatics, delivery platforms and future directions.
The development of prodrugs â derivatives of active pharmaceutical ingredients (APIs) with little or no biological activity themselves that are converted into the API after administration â can address issues with properties of the API such as poor bioavailability. This article provides a holistic analysis of approved prodrugs and discusses trends in prodrug design, their indications, mechanisms of API release and the chemistry of promoieties added to APIs to form prodrugs.
Bispecific antibodies (bsAbs) can mediate therapeutic effects beyond those of natural monospecific antibodies. This Review provides an overview of recent developments in the field of bsAbs for cancer therapy and an outlook into next-generation bsAbs in earlier stages of development.
Treatments for tuberculosis have markedly improved in recent years, but lung disease caused by nontuberculous mycobacteria (NTM) is on the rise and lacks effective cures. This Review discusses promising small-molecule drug candidates and innovative clinical trial designs and highlights how lessons from tuberculosis therapeutic development can be applied to NTM disease.
Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.
The field of nucleic acid therapeutics is rapidly expanding, with mRNA drug and vaccine candidates now under development for diverse indications. However, various safety concerns are associated with the mRNA platform. This Review discusses key challenges and toxicities identified during the development of mRNA drugs and vaccines, assesses models and tools used to limit toxicity, highlighting knowledge gaps and future directions.
