The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs with accomplished preclinical and clinical phases, updating our previous drug development pipeline review with new entries and relevant milestones for pre-existing candidates. Three interventional first-in-human clinical trials got underway with distinct drug classes, namely AOC 1001 and DYNE-101 nucleic acid-based therapies, and the small molecule pitolisant, which joins the race toward market authorization with other repurposed drugs, including tideglusib, metformin, or mexiletine, already in clinical evaluation. Furthermore, newly disclosed promising preclinical data for several additional nucleic-acid therapeutic candidates and a CRISPR-based approach, as well as the advent into the pipeline of novel therapeutic programs, increase the plausibility of success in the demanding task of providing valid treatments to patients with DM1.

Alzheimer's disease (AD) is the most common form of dementia, characterized by intracellular neurofibrillary tangles (NFTs) and extracellular β-amyloid (βA) plaques. No disease-modifying therapy is currently available to prevent the progression of, or cure, the disease. Misfolded hyperphosphorylated tau (p-tau) is considered a pivotal point in the pathogenesis of AD and other tauopathies. Compelling evidence suggests that it is a key driver of the accumulation of NFTs and can be directly correlated with the extent of dementia in patients with AD. Therefore, inhibiting tau hyperphosphorylation-induced aggregation could be a viable strategy to discover and develop therapeutics for patients with AD.

The burden of osteoarthritis (OA), one of the major causes of functional disabilities in humans and animals, continues to increase worldwide while no disease-modifying OA drugs (DMOADs) that either slow down or reverse disease progression have been made available. Here, we provide a brief overview of recent advances in: designing new OA drug delivery approaches, focusing on lubrication-based biomaterials and drug delivery systems, such as hydrogels, liposomes, dendrimers, micro- and nanoparticles; using either large (horse) or small (zebrafish) relevant animal models to evaluate new therapeutic strategies; and OA in vitro modeling, focusing on 3D (organoid) models of cartilage regarding the Replace, Reduce and Refine (3R) principle of animal experimentation.

Autism spectrum disorder (ASD) is a heterogenous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. Currently, ASD is diagnosed according to behavior-based criteria that overlook clinical and genomic heterogeneity, thus repeatedly resulting in failed clinical trials. Here, we summarize the scientific evidence pointing to the pressing need to create a precision medicine framework for ASD and other NDDs. We discuss the role of omics and systems biology to characterize more homogeneous disease subtypes with different underlying pathophysiological mechanisms and to determine corresponding tailored treatments. Finally, we provide recent initiatives towards tackling the complexity in NDDs for precision medicine and cost-effective drug discovery.

Central nervous system (CNS) drug discovery suffers from high attrition rates; translational neuroscience approaches aiming to reduce these high rates include the use of brain imaging technologies. However, there is a need to better understand what methods are being used and for what diseases and purposes. Our analysis of the literature found that magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) were the neuroimaging techniques used most often in clinical trials for the most prevalent CNS diseases: Alzheimer's disease (AD), Parkinson's disease (PD), depression, and schizophrenia. Moreover, the number of initiated clinical trials using MRI, PET, and SPECT increased over the period 1981-2021. Such insights indicate that the significant increase in the use of neuroimaging studies could decrease the attrition of novel drug candidates in late clinical development.

Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are hepatic manifestations of systemic metabolic dysfunction, which affect one-quarter of the adult population worldwide as estimated, and exhibit high risk in progressing to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Current drug discovery focuses on modifying homeostasis of lipids, carbohydrates, and cholesterol, as well as inhibiting inflammation and fibrogenesis. Many natural products show promising activities on various molecular targets involving these mechanisms; however, they have not been fully exploited. Since some compounds are components of healthy food, they may be employed in chemoprevention as adjuvants to lifestyle modification, while natural products such as alkaloids and sesquiterpenoids could serve as promising starting points for structural modifications and deserve further development.

The FAIR (findable, accessible, interoperable and reusable) principles are data management and stewardship guidelines aimed at increasing the effective use of scientific research data. Adherence to these principles in managing data assets in pharmaceutical research and development (R&D) offers pharmaceutical companies the potential to maximise the value of such assets, but the endeavour is costly and challenging. We describe the 'FAIR-Decide' framework, which aims to guide decision-making on the retrospective FAIRification of existing datasets by using business analysis techniques to estimate costs and expected benefits. This framework supports decision-making on FAIRification in the pharmaceutical R&D industry and can be integrated into a company's data management strategy.

The successful development of nonviral delivery systems for nucleic acids has been reported extensively over the past number of years. Among them, lipid-based nanoparticles (LNPs) represent the most advanced platform. This review provides an overview of the state-of-the-art in LNP technology, focusing on the delivery of a range of nucleic acids. Recent advances in the development of an efficient and safe lipid-based system are critically analyzed with a particular emphasis on the rationale behind the design of LNPs and on attempts to elucidate the resulting molecular assembly and structure, their interactions with cellular proteins and biodistribution. In addition, manufacturing methods including microfluidics and their potential to influence stability and scale-up are summarized.

Caseinolytic protease P with its AAA1 chaperone, known as Mycobacterium tuberculosis (Mtb)ClpP1P2 proteolytic machinery, maintains protein homeostasis in Mtb cells and is essential for bacterial survival. It is regarded as an important biological target with the potential to address the increasingly serious issue of multidrug-resistant (MDR) TB. Over the past 10 years, many MtbClpP1P2-targeted modulators have been identified and characterized, some of which have shown potent anti-TB activity. In this review, we describe current understanding of the substrates, structure and function of MtbClpP1P2, classify the modulators of this important protein machine into several categories based on their binding subunits or pockets, and discuss their binding details; Such information provides insights for use in candidate drug research and development of TB treatments by targeting MtbClpP1P2 proteolytic machinery.

In recent decades, advances in chemical synthesis and delivery systems have accelerated the development of therapeutic nucleic acids, several of which have been approved by the Us Food and Drug Administration (FDA). Oral nucleic acid delivery is preferred because of its simplicity and patient compliance, but it still presents distinct challenges. The negative charge, hydrophilicity, and large molecular weight of nucleic acids combined with in vivo gastrointestinal (GI) barriers (e.g., acidic pH, enzymes, mucus, and intestinal epithelial cells) severely hinder their delivery efficacy. Recently, various nanoparticles (NPs), ranging from polymeric to lipid-based (L)NPs and extracellular vesicles (EVs), have been extensively explored to address these obstacles. In this review, we describe the physiological barriers in the GI tract and summarize recent advances in NP-based oral nucleic acid therapeutics.

Neurodegenerative mechanisms affect the brain through a variety of processes that are reflected as changes in brain structure and physiology. Although some biomarkers for these changes are well established, others are at different stages of development for use in clinical trials. One of the most challenging biomarkers to harmonize for clinical trials is cerebral blood flow (CBF). There are several magnetic resonance imaging (MRI) methods for quantifying CBF without the use of contrast agents, in particular arterial spin labeling (ASL) perfusion MRI, which has been increasingly applied in clinical trials. In this review, we present ASL MRI techniques, including strategies for implementation across multiple imaging centers, levels of confidence in assessing disease progression and treatment effects, and details of image analysis.

The FDA modernisation Act 2.0 marks a game-changing legislation enabling drug registration without the absolute requirement for the use of animals in safety toxicology assessment. We discuss landmark developments in the legislation under which the FDA operates and consider the implications of this most recent chapter in the evolution of the drug regulation pathway, focussing on new opportunities to embed microphysiological systems.

Epigenetics targets are the newest branches for building a novel platform of drugs for preventive and regenerative skin health care. Epigenetic regions [vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), transforming growth factor beta (TGFβ), DNA methyltransferases (DNMTs), histone deacetylase 1/2 (HDAC1/2), and miRNA) are innovative druggable targets. As we discuss here, a series of epigenetic-based small molecules are undergoing both clinical and preclinical trials for skin regeneration. Epigenetic writers, eraser targets, and epigenetic readers will become the key therapeutic windows for skin regenerative in the near future.

Tautomerism is an important phenomenon exhibited by many drugs. As we discuss in this review, identifying the different tautomers of drugs and exploring their importance in the mechanisms of drug action are integral components of current drug discovery. Nuclear magnetic resonance (NMR), infrared (IR), ultraviolet (UV), Raman, and terahertz spectroscopic techniques, as well as X-ray diffraction, are useful for exploring drug tautomerism. Quantum chemical methods, in association with pharmacoinformatics tools, are being used to evaluate tautomeric preferences in terms of energy effects. Desmotropy (i.e., tautomeric polymorphism) of the drugs is particularly important in drug delivery studies.

Bacterial infections constitute a major challenge of clinical medicine, particularly in specialties such as dermatology and dental medicine. Antiseptics and antibiotics are the main adjunctive therapies to anti-infective procedures in these specialties. However, antibacterial photodynamic therapy (PDT) has been introduced as a novel and promising alternative to conventional antibacterial approaches. PDT relies on the formation of reactive oxygen species (ROS) by a photosensitizer (PS) after activation by a specific light source. Nanotechnology was later introduced to enhance the antibacterial efficacy of PS during PDT. In this review, we describe the different nanoparticles (NPs) used in PDT and their properties. Recent in vivo data of NPs in antibacterial PDT in dermatology and dental medicine and their safety concerns are also reviewed.

Antimicrobial resistance (AMR) is a silent pandemic with the third highest global mortality. The antibiotic development pipeline is scarce even though AMR has escalated uncontrollably. Artificial intelligence (AI) is a revolutionary approach, accelerating drug discovery because of its fast pace, cost efficiency, lower labor requirements, and fewer chances of failure. AI has been used to discover several beta-lactamase inhibitors and antibiotic alternatives from antimicrobial peptides (AMPs), nonribosomal peptides, bacteriocins, and marine natural products. The significant recent increase in the use of AI platforms by pharmaceutical companies could result in the discovery of efficient antibiotic alternatives with lower chances of resistance generation.

Mycobacterial infections, including multidrug and extreme drug-resistant (MDR and XDR) infections, are a severe challenge and create a virtual antibiotic-deficient era. Bacterial transcription is an established antimicrobial drug target. In mycobacteria, efficient transcription termination relies on the ATP-dependent RNA helicase factor Rho. Rho factor is essential for Mycobacterium tuberculosis (Mtb) survival, and is a valid antibacterial drug target with no homolog in eukaryotes. Rho maintains genomic stability and virulence and prevents pervasive transcription in Mtb. In this review, we provide an overview of the essentiality of Rho in Mtb, which makes it an attractive drug target for inhibitor discovery.