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Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
In Table 10.1 (Section 10.5), the main properties of the three gene-editing techniques likewise employed for ex vivo and in vivo genome editing are summarized for comparison. In the former case target cells from a patient (blood or bone marrow cells) are isolated (primary culture), further expanded and then returned to the patient via infusion. Isolation and expansion are difficult processes requiring highly complex media formulations as, e.g., reported by Jung et al. (2012) for ex vivo expansion of human mesenchymal stem cells. A variety of delivery platforms resulting in high editing rates are available (see below). Ex vivo editing in addition enables dosage control (e.g., titration of Streptococcus pyogenes Cas9; Hsu et al., 2013) which is of importance in connection with minimizing possible off-target modifications. The main drawback of ex vivo therapy is—apart from ex vivo cell survival and maintenance of vital functional properties being challenging—that engrafting of edited cultured cells is difficult after reintroduction into a patient’s body; engraftment may be improved via non-myeloablative conditioning regimens for hematopoietic cell transplantation that have been reviewed, e.g., by Gyurkocza and Sandmaier (2014). Zonari et al. (2017) reported about promising results in clinical trials with ex vivo gene therapy based on CD34+ hematopoietic stem cells.
Scaffold Applications for Vascular Tissue Engineering
Published in Gilson Khang, Handbook of Intelligent Scaffolds for Tissue Engineering and Regenerative Medicine, 2017
Young Min Ju, Hyunhee Ahn, John Vossler, Sang Jin Lee, James J. Yoo
Various graft surface modifications have been studied to selectively capture EPCs in situ such as antibodies, proteins, and magnetic particles.86 Immobilization of antibodies is an attractive approach to EPC capture. Circulating EPCs have been shown to express CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR-2).64,83,88 Rotmans et al.89 showed that an anti-CD34-coated ePTFE graft endothelialized within 72 hours of implantation in a porcine model. Anti-CD34 antibodies have also been used in clinical trials to improve the EPC capture and subsequent endothelialization of coronary artery stents.90 Antibodies against VEGFR-2 may also be used to capture EPCs. Plouffe et al.91 studied the efficiency with which antibodies to 6 different cell surface antigens captured ovine peripheral blood-derived EPCs. Anti-VEGFR-2-coated surfaces resulted in a 17-fold increase in EPC capture.
Gene Transfer into Human Hematopoietic Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Serguei Kisselev, Tatiana Seregina, Richard K. Burt, Charles J. Link
The main marker useful for isolation and/or enrichment of human hematopoietic progenitor cells for transplantation is a surface antigen termed CD34+ whose function may be the regulation, localization and differentiation of hematopoietic stem cells within the hematopoietic microenvironment.15’ Despite a long history of successful long term hematopoietic engraftment, reports by Ogawa and colleagues indicate that the CD34+ surface antigen expression is a marker of progenitor cell activation, while the main population of quiescent HSC are CD34 negative.17-19 Other research groups have confirmed this data.20-23
Neurovascular devices for the treatment of intracranial aneurysms: emerging and future technologies
Published in Expert Review of Medical Devices, 2020
In 2014, Gao et al. presented an experimental study on the efficacy of stromal cell-derived factor-1alpha (SDF-1α)-coated coils together with endothelial progenitor cell (EPC) transplantation in occluding aneurysms [32]. They tested the migratory function of EPCs in response to SDF-1α in Sprague-Dawley rats treated with coils with and without silk fibroin (SF) (SDF-1α-coated) coils and EPC transplantation in situ. The bone marrow-EPCs could express CD133, CD34, and VEGFR-2 and form tubule-like structures in vitro. In SDF-1α-coated coils + EPC transplantation group, a well-organized fibrous tissue bridging the orifice of aneurysms was shown on days 14 and 28. On day 28, tissue organization was greater in the SDF-1α-coated coil group than in the unmodified coil group. Immunofluorescence showed α-smooth muscle actin-positive cells in organized tissue in aneurysms’ sacs. They concluded that the combined treatment with SDF-1α-coated coils and EPC transplantation is a safe and effective treatment for rat experimental aneurysms and that this may provide a new strategy for endovascular therapy following aneurysmal subarachnoid hemorrhage (aSAH) in the future.
Genetic toxicity assessment using liver cell models: past, present, and future
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Xiaoqing Guo, Ji-Eun Seo, Xilin Li, Nan Mei
As hepatocytes are considered metabolically competent, several hepatotoxic compounds and carcinogens that require metabolic activation were evaluated in a series of proof-of-concept studies. AFB1, B[a]P, DMNA, cyclophosphamide (CPA), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) induced significant concentration-dependent DNA migrations in HepG2 cells (Uhl, Helma, and Knasmuller 1999, 2000). While negative in other in vitro genotoxicity assays, several carcinogens, such as 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), safrole, isatidine, and hexamethylphosphoramide (HMPA), were positive in the HepG2 Comet assay (Uhl, Helma, and Knasmuller 2000). Besides HepG2 cells, AFB1 induced DNA damage in other types of liver cell models, including HepaRG (Josse et al. 2008), primary rat hepatocytes (Hoogenboom et al. 2001), and hepatocyte-like cells derived from mesenchymal stem cells and CD34+ cells isolated from umbilical cord blood (Ghaderi et al. 2011). Based on testing eight genotoxic and two non-genotoxic chemicals in the Comet assay, HepG2 was considered a more appropriate model with a high accuracy of 90% to assess DNA damage as compared to Chinese hamster lung (CHL/IU) and human TK6 cells (Hong et al. 2018). Data demonstrated the efficacy of hepatic cell lines in determining DNA damage induced by genotoxic carcinogens.
Methylglyoxal induced advanced glycation end products (AGE)/receptor for AGE (RAGE)-mediated angiogenic impairment in bone marrow-derived endothelial progenitor cells
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Jeong-Hyeon Kim, Kyeong-A Kim, Young-Jun Shin, Haram Kim, Arshad Majid, Ok-Nam Bae
EPC cultured for 14 days in vitro exhibited two types of morphology, cobblestone-shaped EPC forming the central part of colonies and spindle-shaped EPC surrounding the core region. The characteristics of BM-derived EPCs were examined by fluorescent microscopy and flow cytometry. The expression of CD34, a stem cell marker, was observed in most of the cultured cells (>90%), demonstrating that BM-derived EPCs still retain stem cell characters and were not completely differentiated (Figure 1(a)). To investigate endothelial lineage characteristics of BM-derived cells, the properties of uptake of acetylated low-density lipoprotein (ac-LDL) and binding to lectin were examined. Most of the cultured cells (>90%) showed double-positive fluorescent signals with both characteristics, demonstrating that BM-EPC displayed typical characteristics in endothelial linage (Figure 1(b)). In addition, increased Flk-1 (known as VEGFR-2) protein expression, a typical endothelial marker, was detected in BM-derived EPCs in flow cytometry analysis (Figure 1(c)). Data demonstrated that cells possess both stem cell and EC characteristics.