Engineering extracellular vesicles as novel treatment options: exploiting herpesviral immunity in CLL.
Ontology highlight
ABSTRACT:
SUBMITTER: Gartner K
PROVIDER: S-EPMC6374966 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:After impressive developments in recent years with the rise of new targeted agents, chemoimmunotherapy (CIT) only plays a minor role in the treatment of patients with chronic lymphocytic leukemia (CLL). Inhibitors of the Bruton tyrosine kinase (BTK), such as ibrutinib or more recently acalabrutinib, are highly effective, even in poor-risk or chemo-refractory patients. Venetoclax, an inhibitor of the anti-apoptotic BCL2 protein and, to a lesser extent, phosphoinositide-3 kinase (PI3K) delta inhibitors, add to the armamentarium of targeted agents for the treatment of CLL. Furthermore, anti-CD20 monoclonal antibodies are used very successfully either alone or in combination with BTK, BCL2 or PI3K inhibitors. Despite these advances, there is still an ongoing pursuit for new therapeutic approaches in the treatment of CLL. An even bigger challenge poses the determination of the optimal combination and sequence of those drugs. Here, we give an overview of current treatment options in CLL, weighing the advantages and disadvantages of each approach in the light of different clinical settings.
| S-EPMC8158749 | biostudies-literature
Project description:Over the past 40 years, p53 has been the most widely studied protein in cancer biology. Originally thought to be an oncogene due to its stabilization in many cancers, it is now considered to be one of the most critical tumor suppressors in a cell's ability to combat neoplastic transformation. Due to its critical roles in apoptosis, cell-cycle arrest, and senescence, TP53 deletions and mutations are commonly observed and are often a portent of treatment failures and poor clinical outcomes. This is particularly true in chronic lymphocytic leukemia (CLL), as patients with p53 alterations have historically had dismal outcomes. As such, the tremendous efforts made to better understand the functions of p53 in CLL have contributed substantially to recent advances in treating patients with p53-pathway-deficient CLL.
| S-EPMC6896129 | biostudies-literature
Project description:Gastrointestinal nematodes, such as Trichuris trichiura (human whipworm), are a major source of morbidity in humans and their livestock. There is a paucity of commercially available vaccines against these parasites, and vaccine development for T. trichiura has been impeded by a lack of known host protective antigens. Experimental vaccinations with T. muris (murine whipworm) soluble Excretory/Secretory (ES) material have demonstrated that it is possible to induce protective immunity in mice; however, the potential for extracellular vesicles (EVs) as a source of antigenic material has remained relatively unexplored. Here, we demonstrate that EVs isolated from T. muris ES can induce protective immunity in mice when administered as a vaccine without adjuvant and show that the protective properties of these EVs are dependent on intact vesicles. We also identified several proteins within EV preparations that are targeted by the host antibodies following vaccination and subsequent infection with T. muris. Many of these proteins, including VWD and vitellogenin N and DUF1943-domain-containing protein, vacuolar protein sorting-associated protein 52 and TSP-1 domain-containing protein, were detected in both soluble ES and EV samples and have homologues in other parasites of medical and veterinary importance, and as such are possible protective antigens.
| S-EPMC6055854 | biostudies-other
Project description:Long thought of to be vesicles that primarily recycled waste biomolecules from cells, extracellular vesicles (EVs) have now emerged as a new class of nanotherapeutics for regenerative medicine. Recent studies have proven their potential as mediators of cell proliferation, immunomodulation, extracellular matrix organization and angiogenesis, and are currently being used as treatments for a variety of diseases and injuries. They are now being used in combination with a variety of more traditional biomaterials and tissue engineering strategies to stimulate tissue repair and wound healing. However, the clinical translation of EVs has been greatly slowed due to difficulties in EV isolation and purification, as well as their limited yields and functional heterogeneity. Thus, a field of EV engineering has emerged in order to augment the natural properties of EVs and to recapitulate their function in semi-synthetic and synthetic EVs. Here, we have reviewed current technologies and techniques in this growing field of EV engineering while highlighting possible future applications for regenerative medicine.
| S-EPMC7023093 | biostudies-literature
Project description:In the past decade, extracellular vesicles (EVs) have emerged as a key cell-free strategy for the treatment of a range of pathologies, including cancer, myocardial infarction, and inflammatory diseases. Indeed, the field is rapidly transitioning from promising in vitro reports toward in vivo animal models and early clinical studies. These investigations exploit the high physicochemical stability and biocompatibility of EVs as well as their innate capacity to communicate with cells via signal transduction and membrane fusion. This review focuses on methods in which EVs can be chemically or biologically modified to broaden, alter, or enhance their therapeutic capability. We examine two broad strategies, which have been used to introduce a wide range of nanoparticles, reporter systems, targeting peptides, pharmaceutics, and functional RNA molecules. First, we explore how EVs can be modified by manipulating their parent cells, either through genetic or metabolic engineering or by introducing exogenous material that is subsequently incorporated into secreted EVs. Second, we consider how EVs can be directly functionalized using strategies such as hydrophobic insertion, covalent surface chemistry, and membrane permeabilization. We discuss the historical context of each specific technology, present prominent examples, and evaluate the complexities, potential pitfalls, and opportunities presented by different re-engineering strategies.
| S-EPMC5604727 | biostudies-literature
Project description:Mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) are emerging therapeutic tools. Hypoxic pre-conditioning (HPC) of MSCs altered the production of microRNAs (miRNAs) in EVs, and enhanced the cytoprotective, anti-inflammatory, and neuroprotective properties of their derivative EVs in retinal cells. EV miRNAs were identified as the primary contributors of these EV functions. Through miRNA seq analyses, miRNA-424 was identified as a candidate for the retina to overexpress in EVs for enhancing cytoprotection and anti-inflammatory effects. FEEs (functionally engineered EVs) overexpressing miR424 (FEE424) significantly enhanced neuroprotection and anti-inflammatory activities in vitro in retinal cells. FEE424 functioned by reducing inflammatory cytokine production in retinal microglia, and attenuating oxygen free radicals in retinal Muller cells and microvascular endothelial cells, providing a multi-pronged approach to enhancing recovery after retinal ischemic insult. In an in vivo model of retinal ischemia, native, HPC, and FEE424 MSC EVs robustly and similarly restored function to close to baseline, and prevented loss of retinal ganglion cells, but HPC EVs provided the most effective attenuation of apoptosis-related and inflammatory cytokine gene expression. These results indicate the potential for EV engineering to produce ameliorative effects for retinal diseases with a significant inflammatory component. STATEMENT OF SIGNIFICANCE: We show that functionally engineered extracellular vesicles (FEEs) from mesenchymal stem cells (MSCs) provide cytoprotection in rat retina subjected to ischemia. FEEs overexpressing microRNA 424 (FEE424) function by reducing inflammatory cytokine production in retinal microglia, and attenuating oxygen free radicals in Muller cells and microvascular endothelial cells, providing a multi-pronged approach to enhancing recovery. In an in vivo model of retinal ischemia in rats, native, hypoxic-preconditioned (HPC), and FEE424 MSC EVs robustly and similarly restored function, and prevented loss of retinal ganglion cells, but HPC EVs provided the most effective attenuation of apoptosis-related and inflammatory cytokine gene expression. The results indicate the potential for EV engineering to produce ameliorative effects for retinal diseases with a significant inflammatory component.
| S-EPMC10005109 | biostudies-literature
Project description:Extracellular vesicles have shown good potential in disease treatments including ischemic injury such as myocardial infarction. However, the efficient production of highly active extracellular vesicles is one of the critical limitations for their clinical applications. Here, we demonstrate a biomaterial-based approach to prepare high amounts of extracellular vesicles with high bioactivity from endothelial progenitor cells (EPCs) by stimulation with silicate ions derived from bioactive silicate ceramics. We further show that hydrogel microspheres containing engineered extracellular vesicles are highly effective in the treatment of myocardial infarction in male mice by significantly enhancing angiogenesis. This therapeutic effect is attributed to significantly enhanced revascularization by the high content of miR-126a-3p and angiogenic factors such as VEGF and SDF-1, CXCR4 and eNOS in engineered extracellular vesicles, which not only activate endothelial cells but also recruit EPCs from the circulatory system.
| S-EPMC10102163 | biostudies-literature
Project description:The coronavirus disease (COVID-19) is responsible for more than 5 million deaths worldwide, with respiratory failure being the most common clinical presentation. COVID-19 complications still present a considerable burden on healthcare systems, and signs of the post-COVID syndrome are concerns for potential long-term damages. An increasing body of evidence highlights extracellular vesicles' (EVs) relevance in modulating inflammation and cell death in the diseases related to these processes. Several types of EVs-based investigational new drugs against COVID-19 have been approved by the US Food and Drug Administration to initiate a Phase I/II trial under an Investigational New Drug protocol. EVs can be employed as natural drug delivery nanoparticle-based systems due to their inherent potential in transferring material between cells, their natural origin, and their capability to encapsulate various biological molecules, offering an exciting alternative for administering drugs acting on the cell cycle control. In this context, small-molecule inhibitors of Mouse Double Minute 2 (MDM2) such as Nutlin-3 and Idasanutlin by promoting p53 survival and its antiviral activity might be helpful to modulate the IFN signalling pathway and reduce the overall pro-inflammatory burden.
| S-EPMC9164251 | biostudies-literature
Project description:Peptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which post-translationally convert arginine into citrulline in target proteins in an irreversible manner, causing functional and structural changes in target proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for protein moonlighting. Furthermore, PADs have been found to be a phylogenetically conserved regulator for extracellular vesicle (EVs) release. EVs are found in most body fluids and participate in cellular communication via transfer of cargo proteins and genetic material. In this study, post-translationally deiminated proteins in serum and serum-EVs are described for the first time in camelids, using the llama (Lama glama L. 1758) as a model animal. We report a poly-dispersed population of llama serum EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In serum, 103 deiminated proteins were overall identified, including key immune and metabolic mediators including complement components, immunoglobulin-based nanobodies, adiponectin and heat shock proteins. In serum, 60 deiminated proteins were identified that were not in EVs, and 25 deiminated proteins were found to be unique to EVs, with 43 shared deiminated protein hits between both serum and EVs. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in llama serum. PAD homologues were identified in llama serum by Western blotting, via cross reaction with human PAD antibodies, and detected at an expected 70?kDa size. This is the first report of deiminated proteins in serum and EVs of a camelid species, highlighting a hitherto unrecognized post-translational modification in key immune and metabolic proteins in camelids, which may be translatable to and inform a range of human metabolic and inflammatory pathologies.
| S-EPMC7112542 | biostudies-literature
Project description:Extracellular vesicles (EVs) have recently gained significant attention as important mediators of intercellular communication, potential drug carriers, and disease biomarkers. These natural cell-derived nanoparticles are postulated to be biocompatible, stable under physiological conditions, and to show reduced immunogenicity as compared to other synthetic nanoparticles. Although initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off-target activity and potential "dilution effects" upon systemic administration which may affect their ability to reach their target tissues. To fully exploit their therapeutic potential, EVs are embedded into implantable biomaterials designed to achieve local delivery of therapeutics taking advantage of enzyme prodrug therapy (EPT). In this first application of EVs for an EPT approach, EVs are used as smart carriers for stabilizing enzymes in a hydrogel for local controlled conversion of benign prodrugs to active antiinflammatory compounds. It is shown that the natural EVs' antiinflammatory potential is comparable or superior to synthetic carriers, in particular upon repeated long-term incubations and in different macrophage models of inflammation. Moreover, density-dependent color scanning electron microscopy imaging of EVs in a hydrogel is presented herein, an impactful tool for further understanding EVs in biological settings.
| S-EPMC5901706 | biostudies-literature