Reviews & Analysis

CRISPR technology is revolutionizing the development of therapies for genetic disorders. However, the application of CRISPR-based therapeutics is challenged by factors impacting stability, efficiency, delivery and safety. This Review focuses on chemical engineering of CRISPR–Cas systems to address these issues, it assesses next-generation CRISPR–Cas systems, and it highlights CRISPR-based therapies that are approved or in clinical development.

Regulatory T cells keep the immune system in check to maintain homeostasis and restrain inflammation. This Review discusses strategies to harness these cells therapeutically for autoimmunity, transplant tolerance or cancer, for example, by boosting their endogenous function, depleting them or administering them as engineered cell-based therapies.

CD8 T cells and natural killer (NK) cells play a key role in cancer immunosurveillance. However, their anticancer activity is rapidly diminished in the tumour microenvironment, associated with a decline in their metabolic function. This Review provides an overview of metabolic programmes in CD8 T cells and NK cells, discusses the dysfunction that can occur in cancer, and assesses therapeutic strategies to overcome this.

Cancer-preventive vaccines can reduce cancer occurrence by inducing a specific immune response against tumours before they can fully develop. This Review discusses results from pioneering clinical studies and potential approaches to design potent prophylactic cancer vaccines in the future.

Driven by chronic overnutrition and associated with obesity, metabolic dysfunction-associated steatotic liver disease is increasing in prevalence. This Review discusses two main therapeutic approaches: improving the metabolism with incretin mimetics such as semaglutide and directly _targeting the liver with agents such as the recently approved resmetirom.

Lysine acetylation is a post-translational modification on histones and other proteins that is catalysed by acetyltransferases (‘writers’) and mediates interactions with bromodomains and other ‘reader’ domains. This Review summarizes the properties and functions of these writers and readers and discusses efforts to identify small-molecule therapeutics that _target them, some of which are being evaluated in clinical trials.

Recent progress in understanding senescence has spurred interest in the development of approaches that _target senescent cells. This Review assesses the current status of senotherapies, such as senolytics and senomorphics, how these approaches can be combined with cancer therapies, and the challenges and opportunities in moving senotherapies to clinical practice.

Defects in the DNA damage response have been utilized therapeutically for cancer for a decade. This Review analyses the lessons learnt from the development of PARP inhibitors and how these may be applied to new _targets to maximize success. _targeting multiple DNA damage response pathways simultaneously and combinations with other therapies are also discussed.

A very small number of people with rare diseases caused by unique genetic variants have been treated with therapies developed specifically for them, known as N-of-1 therapies. This Review discusses advances and challenges for N-of-1 therapies based on cases in which they have been successfully developed, highlights why the traditional drug development and reimbursement pathway is not fit for purpose in this field, and provides a roadmap for the development of these individualized therapies.

Members of the TNF superfamily (TNFSF) of ligands and their receptors have emerged as promising _targets in the treatment of autoimmune diseases and cancer, with several biologics gaining FDA approval. However, there are still many hurdles to realizing the true potential of _targeting these superfamilies. This Review assesses past and ongoing clinical trials of agents modulating TNFSF ligands or receptors, highlighting ongoing challenges and future opportunities.

Vaccines play a critical role in combating infectious diseases, but their development faces challenges related to suboptimal efficacy, reactogenicity, slow development and high cost. This Review assesses emerging vaccine technologies aiming to address these limitations, focusing on advances in antigen and adjuvant selection and design, and next-generation delivery systems.

Engineered protein therapeutics, including antibodies, are valuable drugs offering major health benefits, but they can elicit unwanted immune responses. This Review identifies key challenges in assessing and mitigating the risk of immunogenicity, particularly the generation of anti-drug antibodies, and suggests pragmatic steps to address them.

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 nerve–cancer 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 — including an increased understanding of receptor biology and signalling, as well as the application of structure-based drug design — 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.