title: Preclinical Biosafety Evaluation of Genetically Modified Human Adipose Tissue-Derived Mesenchymal Stem Cells for Clinical Applications to Brainstem Glioma.
abstract: Stem-cell based gene therapy is a promising novel therapeutic approach for inoperable invasive tumors, including brainstem glioma. Previously, we demonstrated the therapeutic potential of human adipose tissue-derived mesenchymal stem cells (hAT-MSC) genetically engineered to express a secreted form of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) against brainstem glioma. However, safety concerns should be comprehensively investigated before clinical applications of hAT-MSC.sTRAIL. At first, we injected stereotactically low (1.2 × 10(5) cells/18 μL), medium (2.4 × 10(5)/18 μL), or high dose (3.6 × 10(5)/18 μL) of hAT-MSC.sTRAIL into the brainstems of immunodeficient mice reflecting the plan of the future clinical trial. Local toxicity, systemic toxicity, secondary tumor formation, and biodistribution of hAT-MSC.sTRAIL were investigated. Next, presence of hAT-MSC.sTRAIL was confirmed in the brain and major organs at 4, 9, and 14 weeks in brainstem glioma-bearing mice. In the 15-week subchronic toxicity test, no serious adverse events in terms of body weight, food consumption, clinical symptom, urinalysis, hematology, clinical chemistry, organ weight, and histopathology were observed. In the 26-week tumorigenicity test, hAT-MSC.sTRAIL made no detectable tumors, whereas positive control U-87 MG cells made huge tumors in the brainstem. No remaining hAT-MSC.sTRAIL was observed in any organs examined, including the brainstem at 15 or 26 weeks. In brainstem glioma-bearing mice, injected hAT-MSC.sTRAIL was observed, but gradually decreased over time in the brain. The mRNA of human specific GAPDH and TRAIL was not detected in all major organs. These results indicate that the hAT-MSC.sTRAIL could be applicable to the future clinical trials in terms of biosafety.
authors.affiliation: 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine , Seoul, Korea.|2 Adolescent Cancer Center , Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Seung Ah
authors.initials: SA
authors.lastname: Choi
authors.affiliation: 3 Department of Experimental Animal Research, Biomedical Research Institute , Seoul National University Hospital, Seoul, Korea.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: 4 Department of Health Sciences and Technology, SAIHST , Sungkyunkwan University, Seoul, Korea.|5 Samsung Biomedical Research Institute , Samsung Medical Center, Seoul, Korea.|6 Department of Anatomy and Cell Biology, Sungkyunkwan University , Suwon, Korea.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine , Seoul, Korea.|7 Department of Anatomy, Seoul National University College of Medicine , Seoul, Korea.
authors.forename: Ji Yeoun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine , Seoul, Korea.|2 Adolescent Cancer Center , Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Pil Ae
authors.initials: PA
authors.lastname: Kwak
authors.affiliation: 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine , Seoul, Korea.|4 Department of Health Sciences and Technology, SAIHST , Sungkyunkwan University, Seoul, Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Lee
authors.affiliation: 3 Department of Experimental Animal Research, Biomedical Research Institute , Seoul National University Hospital, Seoul, Korea.
authors.forename: Ji-Ran
authors.initials: JR
authors.lastname: You
authors.affiliation: 3 Department of Experimental Animal Research, Biomedical Research Institute , Seoul National University Hospital, Seoul, Korea.
authors.forename: Euna
authors.initials: E
authors.lastname: Kwon
authors.affiliation: 8 Department of Pathology, Seoul National University College of Medicine , Seoul, Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine , Seoul, Korea.
authors.forename: Kyu-Chang
authors.initials: KC
authors.lastname: Wang
authors.affiliation: 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine , Seoul, Korea.|2 Adolescent Cancer Center , Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Phi
authors.affiliation: 3 Department of Experimental Animal Research, Biomedical Research Institute , Seoul National University Hospital, Seoul, Korea.|9 Graduate School of Translational Medicine, Seoul National University College of Medicine , Seoul, Korea.|10 Designed Animal and Transplantation Research Institute, Institute of GreenBio Science Technology, Seoul National University , Pyeongchang-gun, Gangwon-do, Korea.
authors.forename: Byeong-Cheol
authors.initials: BC
authors.lastname: Kang
authors.affiliation: 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine , Seoul, Korea.|2 Adolescent Cancer Center , Seoul National University Cancer Hospital, Seoul, Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000293:Adolescent; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D020295:Brain Stem Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002648:Child; D015316:Genetic Therapy; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009929:Organ Size; D012995:Solubility; D016019:Survival Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand