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An Overview of Parasite Diversity
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
Among the most prominent of all parasites, also falling into the Discoba lineage, are the kinetoplastids, represented by Trypanosoma (see Figure 2.9C) and Leishmania. Representatives of the former genus cause sleeping sickness and Chagas disease whereas Leishmania species cause a variety of forms of leishmaniasis. These parasites are discussed extensively throughout the book. Others, like Phytomonas, are important parasites of plants like coffee and palm trees. Kinetoplastids are unusual in possessing a single mitochondrion that contains a kinetoplast. The kinetoplast contains a network of concatenated circular DNA molecules (assembled like the chain mail in armor), some of which are maxicircles that encode in a peculiar, encrypted fashion the usual mitochondrial gene products. Many minicircles are also present and encode guide RNAs, which are used to decode the encrypted maxicircles. Guide RNAs either insert or delete uridine residues in maxicircle transcripts to accomplish this. It is not clear why kinetoplastids use this unusual RNA editing process. It may have been derived from genes transferred horizontally from viruses. Whatever the origin or purpose, it is clear that disabling RNA editing is lethal for kinetoplastids. Kinetoplastids are also unusual for sequestering the enzymes of glycolysis within distinct, membrane-bound glycosomes.
Application of Bioresponsive Polymers in Gene Delivery
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Tamgue Serges William, Drashti Pathak, Deepa H. Patel
Gaspar et al. [43] have synthesized a bioreducible PLA-PEI-SS triblock copolymer micelles for minicircle DNA and doxorubicin (DOX) co-delivery which is based on a poly(2-ethyl-2-oxazoline)-poly(L-lactide) grafted with bioreducible polyethyleneimine (PEOz-PLA-g-PEI-SS). The micelles have shown high gene expression compared with non-bioreducible carriers in vitro into tumor spheroids models. The co-delivery of mcDNA-Dox to B16F10-Lucif-erase tumor-bearing mice resulted in a reduction in tumor volume and cancer cell viability. That suggests the triblock copolymer as a promising tool for an efficient protection and co-delivery of DNA minicircles (mcDNA) and DOX, even if there is some cytotoxicity problem remaining [43].
Use of Enzymes in the Downstream Processing of Biopharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Precise enzyme-catalyzed structural modifications have also targeted key impurities with the goal of facilitating their separation from the target molecule. Two notable examples can be found in the case of the very challenging purification of minicircle (MC) DNA vectors. MCs are produced in vivo in Escherichia coli by first replicating a parental plasmid (PP) backbone and then promoting an intramolecular site-specific recombination between two strategically placed multimer resolution sites (Simcikova et al., 2016). This generates a replication-deficient MC, which contains the expression cassette with therapeutically useful transgene, and a miniplasmid (MP), which contains the prokaryotic replication segment used for PP amplification. The separation of MCs from the MP impurities is very difficult to perform since the two species are very similar in terms of structure and size (Alves et al., 2016).
Cancer vaccines as a targeted immunotherapy approach for breast cancer: an update of clinical evidence
Published in Expert Review of Vaccines, 2022
Maryam Abbaspour, Vajihe Akbari
In recent years, nucleic acid vaccines due to rapid design, ease of development and production, and cost-effectiveness have been considered as a robust strategy to selectively fight cancer. However, there are barriers to the clinical use of nucleic acid-based vaccines; one of the most important challenges is the presence of cross-membrane barriers which leads to low immunogenicity [138]. DNA vaccines need to cross the nuclear membrane barrier and mRNA vaccines have to cross lipid-based plasma membranes. DNA vaccines also cause chromosomal instability due to their integration into the host genome, which can lead to inactivation or dysfunction of a gene [139]. Furthermore, many tumors develop immune evasion or tolerance to endogenous autoantigens and therefore nucleic acid vaccines are required to be improved to induce stronger antitumor humoral and cellular responses. There are several ways to improve the effectiveness of nucleic acid vaccines such as using adequate adjuvants, cytokines, chemokines to overcome immunosuppression [140]. It was observed that ministring DNA and minicircle DNA can reduce the potential insertional mutagenesis and improve cellular barriers transportation [141]. Fusion of genes encoding cytokines such as IL-4, GM-CSF to the target antigen coding sequence is another approach to overcome low immunogenicity and increase the immune response [142].
Research Progress in Bioinspired Drug Delivery Systems
Published in Expert Opinion on Drug Delivery, 2020
Qirong Tong, Na Qiu, Jianbo Ji, Lei Ye, Guangxi Zhai
In addition to directly using modified RBCs, researchers have employed RBC membrane-coated NPs to achieve the desired drug delivery. Recently, Wang and the coworkers constructed RBC membrane-coated albumin NPs encapsulating gambogic acid and indocyanine green. Capitalizing on the ability of RBCs to provide long-term circulation and prevent drug leakage, and that of albumin to confer high-loading efficiency, NPs exhibited an attractive synergistic chemo-photothermal therapeutic effect. These NPs provided a novel strategy for combining the benefits associated with different biological components [10]. Moreover, through the RBC membrane, cargos such as nucleic acids, which are easily oxidized by heamoglobin inside the RBC, can be successfully delivered. An RBC-mimetic gene delivery system was constructed by Hao and the coworkers by coating gene complexes with nanosized RBC membranes through electrostatic interactions [11]. Similarly, Huang et al. successfully loaded minicircle DNA into carriers composed of the RBC membrane and cationic polymers [12]. Both RBC membrane-based gene delivery platforms demonstrated high transfection efficiency and low cytotoxicity. Additionally, another novel hybrid RBC liposome was constructed, and its ability to load small molecules was verified by Himbert and the coworkers [13].
Phenylketonuria in the adult patient
Published in Expert Opinion on Orphan Drugs, 2019
Leticia Ceberio, Álvaro Hermida, Eva Venegas, Francisco Arrieta, Montserrat Morales, Maria Forga, Montserrat Gonzalo
The use of pharmacological chaperones, molecules that can modify the three-dimension of PAH and increase the residual enzymatic activity, represent a promising new approach in the treatment of PKU. As with BH4, these small molecules assist in the correct folding of mutant PAH. At least four compounds have been identified as chaperones that increase PAH activity in animal models [57,58]. Further studies are necessary before these compounds can be used in clinical practice. The gene therapy, that integrates a functional recombinant PAH gene in the liver cells, is currently under investigation in animal models. Different types of vectors have been studied with successful results in the normalization of plasma Phe levels. However, some viral vectors have shown some limitations including a host immune response and gender-dependent response (higher dose for female mice) [59]. The use of minicircle naked plasmid-DNA to transfer the PAH gene offers an enhanced safety profile. However, the gene transfer efficacy should be further improved since the gene transfer rate is very low [60]. Another alternative under investigation is the therapeutic liver repopulation, which has proved to be effective [61]. However, the aggressivity of this technique compared to the dietary treatment does not justify its use.