N-of-1 strategies can provide high-quality evidence of treatment efficacy at the individual level and optimize evidence-based selection of off-label treatments for patients with rare diseases. Given their design characteristics, n-of-1 strategies are considered to sit at the intersection between medical research and clinical care. Therefore, whether n-of-1 strategies should be governed by research or care regulations remains a debated issue. Here, we delineate differences between medical research and optimized clinical care, and distinguish the regulations which apply to either. We also set standards for responsible optimized clinical n-of-1 strategies with (off-label) treatments for rare diseases. Implementing clinical n-of-1 strategies as defined here could aid in optimized treatment selection for such diseases.

There is currently no universally agreed code of practice for patient engagement (PE), and existing guidelines do not fully cover the scope across medicine development and subsequent life cycle management. This review conceptualises the meaning and summarises the current models of PE. A systematic literature review was conducted and analysed by thematic synthesis. Eight themes were identified as components of how to achieve meaningful PE, and five were identified for where to engage with patients in drug development. This review provides summative guidance for stakeholders intending to introduce PE and establishes a starting point for the development of a universal code of practice.

This report focuses on small non-coding RNA molecules (miRNAs), which have emerged as potential biomarkers with variable diagnostic values and false-positives in different conditions that limit their clinical preference. Current investigations focus on small non-coding RNA molecules (miRNAs), which have emerged as potential biomarkers with variable diagnostic values and false-positives in different conditions that limit their clinical preference. We thoroughly scrutinize the leading pathology of myocardial infarction and contemporary alterations in miRNAs for their specificity, stability and significant prognostic value at the early stage of acute myocardial infarction (AMI). Based on secondary data analysis, we explore common biomarkers and further investigate included miRNA biomarkers for their specificity, stability and area under the curve (AUC) values. We conclude that a group of novel biomarkers, including miRNA-1, miRNA-208a/b and miRNA-499, could help predict the emergence of AMI at an early stage.

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Serine- and arginine-rich splicing factors are pivotal modulators of constitutive splicing and alternative splicing that bind to the cis-acting elements in precursor mRNAs and facilitate the recruitment and assembly of the spliceosome. Meanwhile, SR proteins shuttle between the nucleus and cytoplasm with a broad implication in multiple RNA-metabolizing events. Recent studies have demonstrated the positive correlation of overexpression and/or hyperactivation of SR proteins and development of the tumorous phenotype, indicating the therapeutic potentials of targeting SR proteins. In this review, we highlight key findings concerning the physiological and pathological roles of SR proteins. We have also investigated small molecules and oligonucleotides that effectively modulate the functions of SR proteins, which could benefit future studies of SR proteins.

Cellular localization and deacetylation activity of sirtuin 1 (SIRT1) has a significant role in cancer regulation. The multifactorial role of SIRT1 in autophagy regulates several cancer-associated cellular phenotypes, aiding cellular survival and cell death induction. SIRT1-mediated deacetylation of autophagy-related genes (ATGs) and associated signaling mediators control carcinogenesis. The hyperactivation of bulk autophagy, disrupted lysosomal and mitochondrial biogenesis, and excessive mitophagy are key mechanism for SIRT1-mediated autophagic cell death (ACD). In terms of the SIRT1–ACD nexus, identifying SIRT1-activating small molecules and understanding the possible mechanism triggering ACD could be a potential therapeutic avenue for cancer prevention. In this review, we provide an update on the structural and functional intricacy of SIRT1 and SIRT1-mediated autophagy activation as an alternative cell death modality for cancer prevention.

Efficient intracellular delivery is essential for most therapeutic agents; however, existing delivery vectors face a dilemma between efficiency and toxicity, and always encounter the challenge of endolysosomal trapping. The cell-penetrating poly(disulfide) (CPD) is an effective tool for intracellular delivery, as it is taken up through thiol-mediated cellular uptake, thus avoiding endolysosomal entrapment and ensuring efficient cytosolic availability. Upon cellular uptake, CPD undergoes reductive depolymerization by glutathione inside cells and has minimal cytotoxicity. This review summarizes CPD’s chemical synthesis approaches, cellular uptake mechanism, and recent advances in the intracellular delivery of proteins, antibodies, nucleic acids, and other nanoparticles. Overall, CPD is a promising candidate carrier for efficient intracellular delivery.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no known cure, which has prompted the exploration of novel therapeutic approaches. The clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) tool has generated significant interest for its potential in AD therapeutics by correcting faulty genes. Our report comprehensively reviews emerging applications for CRISPR-Cas9 in developing in vitro and in vivo models for AD research and therapeutics. We further assess its ability to identify and validate genetic markers and potential therapeutic targets for AD. Moreover, we review the current challenges and delivery strategies for the in vivo application of CRISPR-Cas9 in AD therapeutics.

Peptide drugs play an important part in medicine owing to their many therapeutic applications. Of the 80 peptide drugs approved for use in humans, at least five are now off-patent and are consequently being developed as generic alternatives to the originator products. To accelerate access to generic products, the FDA has proposed new regulatory pathways that do not require direct comparisons of generics to originators in clinical trials. The ‘Abbreviated New Drug Application’ (ANDA) pathway recommends that sponsors provide information on any new impurities in the generic drug, compared with the originator product, because the impurities can have potential to elicit unwanted immune responses owing to the introduction of T-cell epitopes. This review describes how peptide drug impurities can elicit unexpected immunogenicity and describes a framework for performing immunogenicity risk assessment of all types of bioactive peptide products. Although this report primarily focuses on generic peptides and their impurities, the approach might also be of interest for developers of novel peptide drugs who are preparing their products for an initial regulatory review.

Adverse drug events (ADEs) are responsible for a significant number of hospital admissions and fatalities. Machine learning models have been developed to assess individual patient risk of having an ADE. In this article, we have reviewed studies addressing the prediction of ADEs in observational health data with machine learning. The field of individualised ADE prediction is rapidly emerging through the increasing availability of additional data modalities (e.g., genetic data, screening data, wearables data) and advanced deep learning models such as transformers. Consequently, personalised adverse drug event predictions are becoming more feasible and tangible.

Abstract not available

Recently, there has been a change in the types of drug target entering early drug discovery portfolios. A significant increase in the number of challenging targets or which would have historically been classed as intractable has been observed. Such targets often have shallow or non-existent ligand-binding sites, can have disordered structures or domains or can be involved in protein–protein or protein–DNA interactions. The nature of the screens required to identify useful hits has, by necessity, also changed. The range of drug modalities explored has also increased and the chemistry required to design and optimise these molecules has adapted. In this review, we discuss this changing landscape and provide insights into the future requirements for small-molecule hit and lead generation.

Uncoupling protein 1 (UCP1) has been discovered as a possible target for obesity treatment because of its widespread distribution in the inner mitochondrial membrane of brown adipose tissue (BAT) and high energy expenditure capabilities to burn calories as heat. UCP1 is dormant and does not produce heat without activation as it is inhibited by purine nucleotides. However, activation of UCP1 via either direct interaction with the UCP1 protein, an increase in the expression of UCP1 genes or the physiological production of fatty acids can lead to a rise in the thermogenesis phenomenon. Hence, activation of UCP1 through small molecules of synthetic and natural origin can be considered as a promising strategy to mitigate obesity.

The European Medicines Agency (EMA) and FDA have policy goals of strengthening benefit–risk (B–R) capabilities; but how this has been translating into regulatory practice is unclear. A systematic review of oncology drug approvals between 2015 and 2020 was conducted with approvals identified through review of FDA and EMA annual reports, with extraction of information on submission, clinical program and B–R assessment from publicly available review documents. Data were extracted from 236 reviews (EMA: 66 new submissions, 100 label extensions; FDA: 70 new submissions). The standard of evidence for B–R assessments seems to have diversified over time; yet, despite policy targets to extend their use, these assessments rarely include patient experience or real-world data.Teaser: Harmonization of evidentiary needs across agencies, including the use of real-world and patient-experience data, can accelerate approval timelines and enable quicker patient access to oncology drugs.

The quality of biopharmaceuticals is carefully monitored by manufacturers and regulators to ensure safety and efficacy throughout the entire product life cycle. Quality defects can lead to post-approval regulatory actions (RAs) to inform healthcare professionals (HCPs). The present study identified quality-related RAs for biopharmaceuticals approved in the European Union and United States between 1995 and 2019. Quality-related RAs were issued due to various quality defects and required different actions by HCPs. The quality defects were not identified due to a negative impact on efficacy and/or safety, which is reassuring. The findings reflect the capability of the stringent regulatory system and quality control to capture and counter various quality defects before the affected product and batches can harm patients.

The novel coronavirus crisis caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was a global pandemic. Although various therapeutic approaches were developed over the past 2 years, novel strategies with more efficient applicability are required to target new variants. Aptamers are single-stranded (ss)RNA or DNA oligonucleotides capable of folding into unique 3D structures with robust binding affinity to a wide variety of targets following structural recognition. Aptamer-based theranostics have proven excellent capability for diagnosing and treating various viral infections. Herein, we review the current status and future perspective of the potential of aptamers as COVID-19 therapies.

Targeted protein degraders (TPDs), which act through the ubiquitin proteasome system (UPS), are one of the newest small-molecule drug modalities. Since the initiation of the first clinical trial in 2019, investigating the use of ARV-110 in patients with cancer, the field has rapidly expanded. Recently, some theoretical absorption, distribution, metabolism, and excretion (ADME) and safety challenges have been posed for the modality. Using these theoretical concerns as a framework, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) Protein Degrader Working Group (WG) conducted two surveys to benchmark current preclinical practices for TPDs. Conceptually, the safety assessment of TPDs is the same as for standard small molecules; however, the techniques used, assay conditions/study endpoints, and timing of assessments might need to be modified to address differences in mode of action of the class.

The DNA Damage and Response (DDR) pathway ensures accurate information transfer from one generation to the next. Alterations in DDR functions have been connected to cancer predisposition, progression, and response to therapy. DNA double-strand break (DSB) is one of the most detrimental DNA defects, causing major chromosomal abnormalities such as translocations and deletions. ATR and ATM kinases recognize this damage and activate proteins involved in cell cycle checkpoint, DNA repair, and apoptosis. Cancer cells have a high DSB burden, and therefore rely on DSB repair for survival. Therefore, targeting DSB repair can sensitize cancer cells to DNA-damaging agents. This review focuses on ATM and ATR, their roles in DNA damage and repair pathways, challenges in targeting them, and inhibitors that are in current clinical trials.

Glypicans (GPCs) are generally involved in cellular signaling, growth and proliferation. Previous studies reported their roles in cancer proliferation. GPC1 is a co-receptor for a variety of growth-related ligands, thereby stimulating the tumor microenvironment by promoting angiogenesis and epithelial–mesenchymal transition (EMT). This work reviews GPC1-biomarker-assisted drug discovery by the application of nanostructured materials, creating nanotheragnostics for targeted delivery and application in liquid biopsies. The review includes details of GPC1 as a potential biomarker in cancer progression as well as a potential candidate for nano-mediated drug discovery.