doi: 10.1124/jpet.114.213645, 11. Therefore, a new perspective on creating a conducive atmosphere for improving this modern cutting-edge gene therapy technology is necessary to transform the lives of patients with severe genetic illnesses, infectious diseases, and disorders. Diseases. Edwards TL, Jolly JK, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, et al. J Clin Invest. Therefore, applying AAV particles to patients through immune-privileged sites, such as the central nervous system, mucosal surfaces, eye, placenta, fetus, testicles, and articular cartilage, could be a better option to avoid T-cell response. doi: 10.1016/s0379–4172(06)60111-x, 203. They have been extensively used for tumor therapy and vaccine development. (2015) 520:186–91. The use of advanced RV vectors carrying the woodchuck posttranscriptional regulatory element (wPRE) to increase transgene mRNA stability, export, and translatability will help to accomplish better clinical outcome (240). Hum Gene Ther. Lentivirus has been used to treat X-SCID, cancers and monogenic diseases. 249. However, the ethical acceptance and advancement in the technology to avoid unwanted clinical outcomes are critical for driving its market growth. 1. Because of their abundance on the earth and difference in genetic makeup, many viruses are being used in preclinical and clinical investigations but each comes with its own unique advantages and disadvantages. This modern approach has the potential to offer complete protection against lethal nerve gases (13, 19–22) and treat monogenic and cardiovascular diseases, immunodeficiency, cancer, and more (23–27). The world's first gene therapy clinical study was conducted to test a viral-mediated drug at the NIH in 1989, and now 3704 gene therapy studies from 204 countries are listed in the US Government's clinical trials database to date (Figure 4A). This breakthrough hematologic cancer drug is a customized treatment generated using an NHL patient's own T-cells to help fight lymphoma. Oncolytic herpes simplex virus vectors fully retargeted to tumor- associated antigens. (2018) 18:162–70. Walsh G. Biopharmaceutical benchmarks 2014. MicroRNA-145 regulates oncolytic herpes simplex virus-1 for selective killing of human non-small cell lung cancer cells. Additionally, genome-editing technology is an up-and-coming method of delivering DNA to specific parts of the genome. Chattopadhyay S, Sen GC. doi: 10.1007/s10815-016-0753-x, 46. |, Cancer Molecular Targets and Therapeutics, AV-Mediated Gene Therapies in Clinical Trials, AAV-Mediated Gene Therapies in Clinical Trials, HSV-Mediated Gene Therapies in Clinical Trials, RV-Mediated Gene Therapies in Clinical Trials, Creative Commons Attribution License (CC BY). doi: 10.1073/pnas.050581197, 217. (2010) 84:7360–8. 204. (2007) 81:4654–63. doi: 10.1038/nbt.3440, 160. doi: 10.1089/hum.2013.2527, 74. After being re-introduced into the patient's blood, these genetically engineered T cells will have greater ability to target cancer cells. doi: 10.1016/j.cbi.2008.05.020, 13. doi: 10.1126/scitranslmed.3005795, 214. doi: 10.1089/hgtb.2016.151, 226. Regulation of the tumor microenvironment by high molecular weight kininogen. This diagram depicts the multiple challenges for chimeric antigen receptor (CAR) T cells. The LTRs of RV serve as promoters, enhancers, binding sites for various nuclear proteins, chromatin modulators, and polyadenylation signals. (2011) 29:5203–9. doi: 10.1371/journal.pone.0045550, 127. 1. Attempts are being made to improve the safety of AV vectors by treating with chemicals and developing chimeric and hybrid vectors to minimize inflammation and immunogenicity (108, 109). doi: 10.1038/sj.gt.3302622, 171. Majima T, Funahashi Y, Takai S, Goins WF, Gotoh M, Tyagi P, et al. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens ...Read More. (2017) 16:662–70. Clinical results showed 24% anti-sickling (NCT03207009). Transient retrovirus-based CRISPR/Cas9 all-in-one particles for efficient, targeted gene knockout. (1965) 149:754–6. For instance, further improvement in vector development technologies is essential to avoid activation of the endogenous signal transduction pathways and production of cytokines due to anti-vector immune responses that can potentially complicate the clinical outcomes. (2011) 807:1–23. One particularly popular use of viral vectors, such as adenovirus, Seneca Valley virus, poliovirus, vaccinia virus, herpes simplex virus, reovirus, Coxsackievirus, parvovirus, Newcastle disease virus, vesicular stomatitis virus, and measles virus, is in the form of oncolytic viruses (OV). (2014) 134:248e–56e. Less side effects than other methods, no risk of reaching germ-line cells, minimized immune response, and less renal clearance are other advantages of ex vivo method (52–54). A pH-Responsive Detachable PEG shielding strategy for gene delivery system in cancer therapy. doi: 10.1089/jir.2014.0034, 247. Intramuscular injection of a single dose of this drug, costing less than $50, delivers a plasmid DNA-carrying VEGF gene cloned under a CMV promoter and stimulates angiogenesis and blood supply to decrease the risk of amputation and death in patients suffering from PAD. Using zinc finger nucleases or including certain sequences such as the β-globin locus control region to direct the site of integration to specific chromosomal sites is yet another way to minimize the risks. Ma H, Liu Y, Liu S, Kung HF, Sun X, Zheng D, et al. (2011) 3:677–713. Cohen IG, Adashi EY. 120. Diseases. Nishimoto T, Yamamoto Y, Yoshida K, Goto N, Ohnami S, Aoki K. Development of peritoneal tumor-targeting vector by in vivo screening with a random peptide-displaying adenovirus library. Cre-recombination-based AAV variants are also developed to allow efficient transgene expression in the central nervous system, muscle, and liver (159, 160). AAV2 is the only serotype that can infect and delivery a therapeutic gene to kidney. The cellular and gene therapy products available in the market. Strobel B, Duechs MJ, Schmid R, Stierstorfer BE, Bucher H, Quast K, et al. Sci Transl Med. Loading of viral particles with a therapeutic gene during production is mostly done by transient transfections, a rate-limiting step in large scale production of viral particles. Recent developments in the production of high quality AAV particles from transfection efficient HEK293 cell suspensions in shaker flasks and WAVE bioreactors free of all animal and human products will certainly improve the success of gene therapy application (224). 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