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Journal of Thrombosis and Haemostasis :... Apr 2023Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric... (Review)
Review
Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric complications. APS is a paradigmatic thromboinflammatory disease. Thromboinflammation is a pathophysiological mechanism coupling inflammation and thrombosis, which contributes to the pathophysiology of cardiovascular disease. APS can serve as a model to unravel mechanisms of thromboinflammation and the relationship between innate immune cells and thrombosis. Monocytes are activated by aPL into a proinflammatory and procoagulant phenotype, producing proinflammatory cytokines such as tumor necrosis factor α, interleukin 6, as well as tissue factor. Important cellular signaling pathways involved are the NF-κB-pathway, mammalian target of rapamycin (mTOR) signaling, and the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome. All of these may serve as future therapeutic targets. Neutrophils produce neutrophil extracellular traps in response to aPL, and this leads to thrombosis. Thrombosis in APS also stems from increased interaction of neutrophils with endothelial cells through P-selectin glycoprotein ligand-1. NETosis can be targeted not only with several experimental therapeutics, such as DNase, but also through the redirection of current therapies such as defibrotide and the antiplatelet agent dipyridamole. Activation of platelets by aPL leads to a procoagulant phenotype. Platelet-leukocyte interactions are increased, possibly mediated by increased levels of soluble P-selectin and soluble CD40-ligand. Platelet-directed future treatment options involve the inhibition of several platelet receptors activated by aPL, as well as mTOR inhibition. This review discusses mechanisms underlying thromboinflammation in APS that present targetable therapeutic options, some of which may be generalizable to other thromboinflammatory diseases.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Thromboinflammation; Endothelial Cells; Inflammation; Thrombosis; TOR Serine-Threonine Kinases
PubMed: 36696191
DOI: 10.1016/j.jtha.2022.12.002 -
Signal Transduction and Targeted Therapy May 2023Since the proposal of Paul Ehrlich's magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody,... (Review)
Review
Since the proposal of Paul Ehrlich's magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody, antitoxin to targeted drug delivery that emerged in the past decades, more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone is characterized by a complex remodeling and homeostatic regulation mechanism, which makes drug therapy for skeletal diseases more challenging than other tissues. Bone-targeted therapy has been considered a promising therapeutic approach for handling such drawbacks. With the deepening understanding of bone biology, improvements in some established bone-targeted drugs and novel therapeutic targets for drugs and deliveries have emerged on the horizon. In this review, we provide a panoramic summary of recent advances in therapeutic strategies based on bone targeting. We highlight targeting strategies based on bone structure and remodeling biology. For bone-targeted therapeutic agents, in addition to improvements of the classic denosumab, romosozumab, and PTH1R ligands, potential regulation of the remodeling process targeting other key membrane expressions, cellular crosstalk, and gene expression, of all bone cells has been exploited. For bone-targeted drug delivery, different delivery strategies targeting bone matrix, bone marrow, and specific bone cells are summarized with a comparison between different targeting ligands. Ultimately, this review will summarize recent advances in the clinical translation of bone-targeted therapies and provide a perspective on the challenges for the application of bone-targeted therapy in the clinic and future trends in this area.
Topics: Humans; Ligands; Bone Diseases; Antineoplastic Agents; Drug Delivery Systems; Signal Transduction
PubMed: 37198232
DOI: 10.1038/s41392-023-01467-8 -
Human Gene Therapy Sep 2020Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory, they can... (Review)
Review
Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory, they can silence or edit any gene by encoding CRISPR nucleases, or alternatively, produce any missing protein. Yet not all mRNA therapies are equally likely to succeed. Over the past several years, an increasing number of clinical trials with siRNA- and antisense oligonucleotide-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by nonviral systems. First, scientists have come to understand that some genes make better targets for RNA therapies than others. Second, scientists have learned that the type and position of chemical modifications made to an RNA drug can alter its therapeutic window, toxicity, and bioavailability. Third, scientists have found that safe and targeted drug delivery vehicles are required to ferry mRNA therapies into diseased cells. In this study, we apply these learnings to cystic fibrosis (CF). We also describe lessons learned from a subset of CF gene therapies that have already been tested in patients. Finally, we highlight the scientific advances that are still required for nonviral mRNA- or CRISPR-based drugs to treat CF successfully in patients.
Topics: CRISPR-Cas Systems; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Editing; Genetic Therapy; Humans; RNA, Messenger
PubMed: 32799680
DOI: 10.1089/hum.2020.137 -
International Journal of Cancer Mar 2022Wnt signaling plays an essential role in the initiation and progression of various types of cancer. Besides, the Wnt pathway components have been established as reliable... (Review)
Review
Wnt signaling plays an essential role in the initiation and progression of various types of cancer. Besides, the Wnt pathway components have been established as reliable biomarkers and potential targets for cancer therapy. Wnt signaling is categorized into canonical and noncanonical pathways. The canonical pathway is involved in cell survival, proliferation, differentiation and migration, while the noncanonical pathway regulates cell polarity and migration. Apart from its biological role in development and homeostasis, the Wnt pathway has been implicated in several pathological disorders, including cancer. As a result, inhibiting this pathway has been a focus of cancer research with multiple targetable candidates in development. In this review, our focus will be to summarize information about ongoing and completed clinical trials targeting various Wnt pathway components, along with describing current and emerging Wnt targeted therapies. In addition, we will discuss potential opportunities and associated challenges of inhibiting Wnt signaling for cancer therapy.
Topics: Acyltransferases; Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Membrane Proteins; Neoplasms; Tankyrases; Wnt Signaling Pathway; beta Catenin
PubMed: 34536299
DOI: 10.1002/ijc.33811 -
Trends in Pharmacological Sciences May 2023Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are... (Review)
Review
Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation.
Topics: Humans; Proteolysis; Neoplasms; Drug Delivery Systems; Proteolysis Targeting Chimera
PubMed: 37059054
DOI: 10.1016/j.tips.2023.03.003 -
Biomolecules Jun 2020Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson's disease (PD) and must be developed concurrently because of... (Review)
Review
Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson's disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (), leucine-rich repeat kinase-2 () and glucocerebrosidase (. Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements.
Topics: Animals; Biomarkers; Genetic Heterogeneity; Genetic Therapy; History, 21st Century; Humans; Molecular Targeted Therapy; Mutation; Parkinson Disease
PubMed: 32560161
DOI: 10.3390/biom10060912 -
Journal of Controlled Release :... Jan 2023Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects.... (Review)
Review
Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro, in vivo, and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics.
Topics: Drug Delivery Systems; Colon; Pharmaceutical Preparations; Administration, Oral; Biological Availability
PubMed: 36528195
DOI: 10.1016/j.jconrel.2022.12.029 -
International Journal of Molecular... Jul 2020Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in... (Review)
Review
Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for hair loss treatment. Whereas a variety of growth factors and signaling pathways have been implicated in hair cycling process, the activation of Wnt/β-catenin signaling plays a central role in hair follicle regeneration. Several plant-derived chemicals have been reported to promote hair growth by activating Wnt/β-catenin signaling in various in vitro and in vivo studies. This mini-review sheds light on the role of Wnt/β-catenin in promoting hair growth and the current progress in designing hair loss therapies by targeting this signaling pathway.
Topics: Alopecia; Animals; Biological Products; Combined Modality Therapy; Female; Hair; Hair Follicle; Hair Preparations; Humans; Male; Mesenchymal Stem Cell Transplantation; Mice; Mice, Nude; Molecular Targeted Therapy; Phytotherapy; Regeneration; Wnt Signaling Pathway
PubMed: 32664659
DOI: 10.3390/ijms21144915 -
International Journal of Molecular... Oct 2021Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new... (Review)
Review
Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new therapies that have contributed to the advances in treatment of certain malignancies. Immunotherapy, which has repeatedly proven to be a breakthrough therapy in melanoma, as well as B-ALL therapy with CAR T cells, are of great merit in this progress. These therapies are currently being developed by modifying bispecific antibodies and CAR T cells to improve their efficiency and bioavailability. Work on improving the therapy with oncolytic viruses is also progressing, and efforts are being made to improve the immunogenicity and stability of cancer vaccines. Combining various biological therapies, immunotherapy with oncolytic viruses or cancer vaccines is gaining importance in cancer therapy. New therapeutic targets are intensively sought among neoantigens, which are not immunocompromised, or antigens associated with tumor stroma cells. An example is fibroblast activation protein α (FAPα), the overexpression of which is observed in the case of tumor progression. Universal therapeutic targets are also sought, such as the neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a key genetic driver present in many types of cancer. This review also raises the problem of the tumor microenvironment. Stromal cells can protect tumor cells from chemotherapy and contribute to relapse and progression. This publication also addresses the problem of cancer stem cells resistance to treatment and presents attempts to avoid this phenomenon. This review focuses on the most important strategies used to improve the selectivity of biological therapies.
Topics: Animals; Antibodies; Biological Therapy; Cancer Vaccines; Humans; Molecular Targeted Therapy; Neoplasms; Recombinant Proteins; T-Lymphocytes
PubMed: 34769123
DOI: 10.3390/ijms222111694 -
Bioconjugate Chemistry Nov 2015Western medicine often aims to specifically treat diseased tissues or organs. However, the majority of current therapeutics failed to do so owing to their limited... (Review)
Review
Western medicine often aims to specifically treat diseased tissues or organs. However, the majority of current therapeutics failed to do so owing to their limited selectivity and the consequent "off-target" side effects. Targeted therapy aims to enhance the selectivity of therapeutic effects and reduce adverse side effects. One approach toward this goal is to utilize disease-specific ligands to guide the delivery of less-specific therapeutics, such that the therapeutic effects can be guided specifically to diseased tissues or organs. Among these ligands, aptamers, also known as chemical antibodies, have emerged over the past decades as a novel class of targeting ligands that are capable of specific binding to disease biomarkers. Compared with other types of targeting ligands, aptamers have an array of unique advantageous features, which make them promising for developing aptamer-drug conjugates (ApDCs) for targeted therapy. In this Review, we will discuss ApDCs for targeted drug delivery in chemotherapy, gene therapy, immunotherapy, photodynamic therapy, and photothermal therapy, primarily of cancer.
Topics: Animals; Antineoplastic Agents; Aptamers, Nucleotide; Drug Carriers; Drug Delivery Systems; Genetic Therapy; Humans; Immunotherapy; Models, Molecular; Neoplasms; Nucleic Acids; Photosensitizing Agents; Proteins
PubMed: 26083153
DOI: 10.1021/acs.bioconjchem.5b00291