Expert Opinion on Therapeutic Targets最新文献

Introduction: Crohn's disease (CD) is a chronic inflammatory bowel disease affecting the entire gastrointestinal tract with a progressive and relapsing course. Achieving mucosal healing has emerged as a critical therapeutic goal, as it is associated with sustained clinical remission, reduced hospitalizations, and fewer surgery rates. Therefore, targeting mucosal healing is essential for long-term control in CD.

Areas covered: This review evaluates the efficacy of novel biologic therapies and small molecules in inducing mucosal healing, specifically targeting pathways like IL-12/23, IL-23, α4β7 integrins, Janus kinase 1 (JAK1), and sphingosine-1-phosphate receptor (S1PR) in adults (≥18 years) with moderate-to-severe CD. The rationale for selecting these specific pathways is their central role in modulating key inflammatory processes implicated in CD pathogenesis. We compare these therapies with placebo for both induction and maintenance of remission, based on a PubMed literature review for published articles and ClinicalTrials.gov for ongoing trials.

Expert opinion: Upadacitinib and anti-IL23p19 agents (risankizumab, guselkumab and mirikizumab) are promising advanced non-TNF-targeting therapies for inducing endoscopic remission and mucosal healing but further studies are needed to integrate mucosal healing into a broader definition of endoscopic response, with a unified and precise definition.

Introduction: Heart failure (HF) is a complex and heterogeneous syndrome resulting from any diastolic or systolic dysfunction of the cardiac muscle. In addition to comorbid conditions, pressure overload, and myocardial ischemia are associated with cardiac remodeling which manifests as extracellular matrix (ECM) perturbations, impaired cellular responses, and subsequent ventricular dysfunction.

Areas covered: The current review discusses the main aspects of the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway (cGMP-PKG) pathway modulators and highlights the promising outcomes of its novel pharmacological boosters.

Expert opinion: Among several signaling pathways involved in the pathogenesis of pressure overload, ischemia and HF with preserved ejection fraction (HFpEF) is cGMP-PKG pathway. This pathway plays a pivotal role in the regulation of cardiac contractility, and modulation of cGMP-PKG signaling, contributing to the development of the diseases. Ventricular cardiomyocytes of HF patients and animal models are known to exhibit reduced cGMP levels and disturbed cGMP signaling including hypophosphorylation of PKG downstream targets. However, restoration of cGMP-PKG signaling improves cardiomyocyte function and promotes cardioprotective effects.

Introduction: Human kallikrein-related peptidases (KLKs) represent a subgroup of 15 serine endopeptidases involved in various physiological processes and pathologies, including cancer.

Areas covered: This review aims to provide a comprehensive overview of the KLK family, highlighting their genomic structure, expression profiles and substrate specificity. We explore the role of KLKs in tumorigenesis, emphasizing their potential as biomarkers and therapeutic targets in cancer treatment. The dysregulated activity of KLKs has been linked to various malignancies, making them promising candidates for cancer diagnostics and therapy.

Expert opinion: : Recent advancements in understanding the mechanistic pathways of KLK-related tumorigenesis offer new prospects for developing targeted cancer treatments. Expert opinion suggests that while significant progress has been made, further research is necessary to fully exploit KLKs' potential in clinical applications.

Introduction: Globally, ~850 million people are affected by different kidney diseases. The pathogenesis of kidney diseases is intricate, where autophagy is crucial for maintaining kidney homeostasis. Iteliminates damaged organelles, thus reducing renal lesions and allowing tissue regeneration. Therefore, targeting various autophagy proteins, e.g. Unc-51-like autophagy-activating kinase 1 (ULK1), is emerging as potential therapeutic strategy against kidney disease.

Areas covered: This review provides insights into the role of ULK1 as a therapeutic target in kidney diseases. Additionally, we have discussed the recent evidence based on pre-clinical studies for possible novel therapies modulating ULK1-mediated autophagy in kidney diseases.

Expert opinion: ULK1 is one of the critical regulators of autophagy. Moreover, ULK1 works differently for different types of kidney disease. Considering its significant role in kidney disease pathogenesis, it could be a potential target to tackle kidney diseases. However, the dynamic molecular understanding of ULK1 in the context of various kidney diseases is still in its infancy and should be investigated further.

Introduction: The global rise in ulcerative colitis (UC) incidence highlights the urgent need for enhanced diagnostic and therapeutic strategies. Recent advances in genome-wide association studies (GWAS) have identified genetic loci associated with UC, providing insights into the disease's molecular mechanisms, including immune modulation, mucosal defense, and epithelial barrier function. Despite these findings, many GWAS signals are located in non-coding regions and are linked to low risk, suggesting that protein-coding genes alone do not fully explain UC's pathophysiology. Emerging research emphasizes the potential of microRNAs (miRNAs) as biomarkers and therapeutic targets due to their crucial role in UC. This review explores the current understanding of miRNAs in UC, including their mechanisms of action and their potential as both biomarkers and therapeutic targets. The present review provides the latest update on their potential as a biomarker and therapeutic target.

Areas covered: This review synthesizes an extensive literature search on miRNAs in UC, focusing on their roles in the mucosal barrier, innate and adaptive immunity, and their potential applications as biomarkers and therapeutic modalities.

Expert opinion: While miRNAs present promising opportunities as biomarkers and novel therapeutic agents in UC, challenges in validation, specificity, delivery, and clinical application need to be addressed through rigorous, large-scale studies.

Introduction: Glypican-3 (GPC3) is a cell membrane-anchored heparan sulfate proteoglycan that has recently garnered attention as a cancer antigen owing to its high expression in numerous cancers, particularly hepatocellular carcinoma (HCC), and to limited expression in adult normal tissue.

Areas covered: Here, we propose the potential of GPC3 as a cancer antigen based on our experience with the GPC3 peptide vaccine against HCC, having developed a vaccine that progressed from preclinical studies to first-in-human clinical trials. In this review, we present a summary of the current status and future prospects of immunotherapies targeting GPC3 by focusing on clinical trials; peptide vaccines, mRNA vaccines, antibody therapy, and chimeric antigen receptor/T-cell receptor - T-cell therapy and discuss additional strategies for effectively eliminating HCC through immunotherapy.

Expert opinion: GPC3 is an ideal cancer antigen for HCC immunotherapy. In resectable HCC, immunotherapies that leverage physiological immune surveillance, immune checkpoint inhibitors, and GPC3-target cancer vaccines appear promising in preventing recurrence and could be considered as a prophylactic adjuvant therapy. However, in advanced HCC, clinical trials have not demonstrated sufficient anti-tumor efficacy, in contrast with preclinical studies. Reverse translation, bedside-to-bench research, is crucial to identify the factors that have hindered GPC3 target immunotherapies.

Introduction: The growing prevalence and lack of effective pain therapies for knee osteoarthritis (KOA) results in a substantial unmet need for novel analgesic therapies. The transient receptor potential vanilloid 1 (TRPV1) receptor is expressed in subsets of nociceptive sensory neurons and has major roles in pain transmission and regulation. In the structures of the knee joint, nociceptors are present in abundance.

Areas covered: TRPV1-expressing nociceptors in the knee represent a rational target to modulate activity at the origin of the pain pathway in KOA and may avoid systemic side effects seen with currently available analgesics. TRPV1 antagonists can induce analgesia, but hyperthermia and thermal hypesthesia side effects have limited their utility. Clinical development of TRPV1 agonists for pain management has progressed further than that of TRPV1 antagonists. Capsaicin and resiniferatoxin have provided proof-of-concept for the modulation of TRPV1 activity in KOA.

Expert opinion: Intra-articular administration of TRPV1 agonists enables direct delivery to target nerve terminals in the knee, offering a potentially transformative approach for the management of pain associated with KOA. Here, we explore the advances in understanding innervation of the knee joint in KOA, the role of TRPV1-expressing neurons and progress in developing TRPV1 modulators for KOA.