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Gene Therapy in Tissue Engineering: Prospects and Challenges
Published in Rajesh K. Kesharwani, Raj K. Keservani, Anil K. Sharma, Tissue Engineering, 2022
This type of gene therapy involves introduction of a suicide gene into certain target cells that initiate apoptosis in them (Figure 3.12). This technique has been found to be most useful in case of cancer cells and called cancer suicide gene therapy (CSGT). The delivery of the suicide genes involves viral or synthetic vectors, which are guided to the target cancer cells by specific antibodies and ligands. Such vector must have the capability to discriminate between target (cancer) and nontarget (normal) cells. The two major suicide gene therapeutic techniques that are currently followed are: cytosine deaminase/5-fluorocytosine and the herpes simplex virus/ganciclovir.
Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Ramasamy Paulmurugan, Uday Kumar Sukumar, Tarik F. Massoud
Small RNAs and full-length genes are extensively used for therapeutic applications in the treatment of many diseases, including cancer. These therapeutic nucleic acid constructs work in different ways to achieve their intended goals, and therefore, their specific selection is mainly based on the end-point research or clinical application. Delivered genes code for full-length proteins, which provide or enhance the function of endogenous proteins that are either defective owing to mutation(s) or they are unavailable owing to deletion in cells. These types of genes are used to treat genetic, metabolic, and biochemical disorders during gene therapy. In contrast, there are genes that produce enzymes that convert delivered non-toxic prodrugs into toxic metabolites and kill the cells that express these enzymes. This strategy is normally applied in cancer therapy as suicide gene therapy. Accordingly, based on the respective applications, the delivered genes expressing full-length proteins can be used to treat genetic disorders during conventional gene therapy for biochemical disorders, or as suicide genes during cancer therapy (Figure 13.1). Similarly, small RNAs can be delivered in cells to alter the function of endogenous genes whose expression contributes to disease pathogenesis. Small RNAs are delivered as synthetic oligonucleotides (microRNA [miRNA] mimics, antisense miRNAs, and small interfering RNAs [siRNAs]), or they are expressed in cells by delivering mammalian expression vectors (short hairpin RNAs [shRNAs], siRNAs, miRNA mimics, and antisense miRNAs). Even though full-length genes and small RNAs are different in size, their delivery across cell membranes in vitro and in vivo is achievable by the adoption of common delivery systems with some minor technical modifications. Here, we will mainly consider small RNA delivery and its associated challenges.
Advances of engineered extracellular vesicles-based therapeutics strategy
Published in Science and Technology of Advanced Materials, 2022
Hiroaki Komuro, Shakhlo Aminova, Katherine Lauro, Masako Harada
Outside of siRNAs and miRNAs, other common genetic-based drugs used for EV-mediated therapeutic delivery include mRNAs, DNA, gRNA, shRNA, CRISPR/Cas9. Rather than indirectly affecting mRNA expression levels, direct mRNA delivery is straightforward and simple. An example of mRNAs delivery by EVs used as a therapeutic can be seen in Erkan et al [288]. They genetically engineered EVs to carry the mRNA of a suicide gene, cytosine deaminase, fused to an uracil phosphoribosyltransferase (UPRT) and injected it into glioblastoma tumor mice models [288]. They found that the mRNA carrying EVs suppressed tumor growth by 70% compared to the control [288]. These researchers also noted the inhibitory effect of the mRNA suicide gene against schwannoma [289]. Alternatively, mediated delivery of DNA by EVs can be seen in Morishita et al. who loaded biotinylated CpG DNA into EVs [290]. They presented the CpG DNA on the surface by first transfecting B16BL6 cells with a fusion of biotin binding protein streptavidin (SAV) and the EV surface protein lactadherin (LA) [290]. The SAV-LA presenting EVs was isolated and combined with biotinylated CpG DNA, which allowed for the binding to SAV and presentation of the DNA [290]. The mediated delivery of CRISPR/Cas9 can be seen with Kim et al. who through electroporation loaded cancer cell-derived EVs with CRISPR/Cas9 and PARP-1 sgRNA [100]. By turning on apoptotic pathways, the researchers found that these EVs inhibited cancer cell proliferation in vivo and in vitro, and cancer cell-derived EVs had better delivery and accumulation compared to epithelial-derived EVs [100]. Besides miRNA and siRNA, other nucleic acids like DNA and mRNA are also being investigated for their EV-mediated therapeutic potential.
Preparation and characterization of polyamidoamine dendrimers conjugated with cholesteryl-dipeptide as gene carriers in HeLa cells
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Le Thi Thuy, Minyoung Choi, Minhyung Lee, Joon Sig Choi
Gene therapy has received considerable attention owing to its potential applications in the biomedical field. Therapeutic genes are used to treat various genetic diseases, such as neurodegenerative diseases, autoimmune diseases, and numerous cancers [1]. In cancer, transfected therapeutic genes can cause cell death or inhibit the growth of cancer cells. Various gene therapy approaches have been studied for cancer treatment, including siRNA therapy, pro-apoptotic gene therapy, anti-angiogenic gene therapy, suicide gene therapy, immunotherapy, oncolytic virotherapy, and gene-directed enzyme prodrug therapy [2–7]. In November 2017, clinical trials of gene therapy were conducted in 38 countries, involving 2,597 genes. According to the results of these trials, over 65% of the tested genes were associated with cancer [8]. Naked genetic molecules cannot be internalized efficiently by target cells because of their serum nuclease sensitivity, phagocyte ingestion, fast renal removal, poor uptake by target cells, and toxic effects arising from immune response stimulation. This limitation severely restricts the clinical application of naked DNA. The development of gene vectors has significant implications for enhancing therapeutic efficacy [9, 10]. Gene vectors are essential for transferring therapeutic genes to the target cells. There are two main classes of gene vectors: viral and non-viral. Viral vectors are well known for their high efficiency in gene transfection compared to non-viral vectors. Nevertheless, there are several drawbacks of viral vectors, such as cytotoxicity, immune response, and high cost. Therefore, non-viral vectors have gained popularity in the field of gene therapy due to their biocompatibility, surface functionality in vivo or in vitro, and low-cost production [9, 11]. Hence, designing an effective non-viral gene carrier with minimized toxicity is currently an important research topic in gene carrier technology.