Millions of people worldwide suffer from sarcopenia, a clinically recognized syndrome that is defined as the age-related loss of skeletal muscle mass and strength. Sarcopenia reduces mobility, leads to falls and fractures, and increases the risk of death, posing an ever-increasing health-care and economic burden to society. There are currently no approved therapies for the syndrome, partly owing to its multifactorial aetiology, highlighting the need for therapies with pleiotropic beneficial effects on muscle function. Increased understanding of the cellular, metabolic and molecular mechanisms that drive muscle wasting with ageing is informing pharmacological interventions to increase muscle strength by promoting mitochondrial function (NAD+-related molecules, urolithin A), restoring impaired autophagy (mTORC1 inhibitors), promoting anabolic signalling (myostatin inhibitors), acting as selective androgen receptor modulators, maintaining vascularization (VEGF, apelin), reducing inflammageing (inhibitors of cytokine signalling), and restoring innervation, anabolism and regeneration (inhibitors of the gerozyme 15-PGDH). The recent surge in clinical trials combining weight loss-inducing GLP1RA therapies with drugs that preserve muscle tissue suggests that treatments that promote both healthspan and lifespan, or 'healthy ageing', are on the horizon.
Edith Heard, CEO of the Francis Crick Institute, discusses the need to break down biomedical boundaries.
Prominent members of the solute carrier (SLC) superfamily of membrane transporters are established targets of central nervous system (CNS) drugs, including the blockbuster neurotransmitter reuptake inhibitors. Numerous other SLC transporters exhibit dysregulated expression in the CNS relative to other tissues, many of which have been genetically or functionally linked to neurological disorders and may therefore represent tractable therapeutic targets. As key regulators of metabolite and ion fluxes, SLCs shape developmental programmes and cellular states associated with epilepsy, neurodegeneration and autism spectrum disorders. Recent advances in assigning biochemical and cellular functions to previously uncharacterized SLCs, together with emerging chemical strategies to increase or decrease transporter abundance, are expanding the therapeutic landscape and positioning SLC biology at the forefront of next-generation CNS drug discovery.
As Takeda’s oveporexton (Orzeyful) becomes a first-in-class treatment for narcolepsy type 1, industry eyes broader indications for orexin receptor agonists.
Artificial intelligence (AI) in drug discovery has attracted increasing interest over the past decade. It is now time for a critical review of progress in the field: where did we advance - and where are we yet to see impact - when it comes to what matters in drug discovery, which is to deliver safer and more efficacious medicines to patients faster? Although a wide variety of AI methods have been developed, applied and benchmarked, evidence of their clinically relevant impact is, so far, disappointingly limited. In this Perspective we discuss potential reasons, including an insufficient focus on clinical translation during model development, difficulties with applying AI algorithms on conditional life science data, and insufficient problem definitions and the resulting underspecification of computational models for real-world use cases. 'Technology push' compared with 'science pull' is also likely to be an underlying factor, as well as the substantial time required to operationalize technical capabilities into systems that are sufficiently scaled and accessible for users. We provide recommendations for the development of AI in drug discovery with the aim of increasing its translational relevance. For example, benchmarking studies of AI tools in drug discovery need to move on from model validation and instead focus on their ability to improve decision making.
