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Helper virus-free gutless adenovirus (HF-GLAd): a new platform for gene therapy
Jida Liu,Dai-Wu Seol 생화학분자생물학회 2020 BMB Reports Vol.53 No.11
Gene therapy is emerging as a treatment option for inherited genetic diseases. The success of this treatment approach greatly depends upon gene delivery vectors. Researchers have attempted to harness the potential of viral vectors for gene therapy applications over many decades. Among the viral vectors available, gutless adenovirus (GLAd) has been recognized as one of the most promising vectors for in vivo gene delivery. GLAd is constructed by deleting all the viral genes from an adenovirus. Owing to this structural feature, the production of GLAd requires a helper that supplies viral proteins in trans. Conventionally, the helper is an adenovirus. Although the helper adenovirus efficiently provides helper functions, it remains as an unavoidable contaminant and also generates replicationcompetent adenovirus (RCA) during the production of GLAd. These two undesirable contaminants have raised safety concerns and hindered the clinical applications of GLAd. Recently, we developed helper virus-free gutless adenovirus (HF-GLAd), a new version of GLAd, which is produced by a helper plasmid instead of a helper adenovirus. Utilization of this helper plasmid eliminated the helper adenovirus and RCA contamination in the production of GLAd. HF-GLAd, devoid of helper adenovirus and RCA contaminants, will facilitate its clinical applications. In this review, we discuss the characteristics of adenoviruses, the evolution and production of adenoviral vectors, and the unique features of HF-GLAd as a new platform for gene therapy. Furthermore, we highlight the potential applications of HF-GLAd as a gene delivery vector for the treatment of various inherited genetic diseases.
( Geun Seon Ahn ),( Dai Wu Seol ),( Sung Gyu Pyo ),( Donghyun Lee ) 한국조직공학·재생의학회 2011 조직공학과 재생의학 Vol.8 No.4
Calcium phosphate cements (CPCs) have been widely used as bone substitute materials in medical and dental fields. Carbon nanotubes (CNTs) are promising materials as substrates for tissue engineering or for the use as implant materials. With a purpose to evaluate the potential of CPC-CNT based materials as bone grafting materials, we synthesized calcium phosphate cement-multi-walled carbon nanotube hybrid (CPC-MWCNT hybrid) and inves-tigated the effect of CNT on enhancing the bioactivity of osteoblasts. The results were evaluated by cell proliferation and differentiation of MC3T3-E1 cells. No significant difference between CPC and CPC-MWCNT hybrid was found with respect to the proliferation of MC3T3-E1 cells. However in contrast, we found that the differentiation ofMC3T3-E1 was significantly enhanced in the presence of MWCNT which is demonstrated by ALP activity analysis and RT-PCR. The results of the current study indicate that CPC-MWCNT hybrid which promotes the osteogenic differentiation of osteoblasts could serve well as bone repairing graft material.
Piya, Sujan,Moon, Ae Ran,Song, Peter I,Hiscott, John,Lin, Rongtuan,Seol, Dai-Wu,Kim, Tae-Hyoung American Association for Cancer Research 2011 Molecular cancer research Vol.9 No.10
<P>IFN-gamma plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-gamma is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPS-induced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-gamma might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-gamma and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-gamma alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-gamma, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. Mol Cancer Res; 9(10); 1356-65. (C) 2011 AACR.</P>
Hypoxia inhibition of camptothecin-induced apoptosis by Bax loss
Park, Kyoungsook,Woubit, Abdela,Fermin, Cesar,Reddy, Gopal,Habtemariam, Tsegaye,Chung, Jin,Park, Minseo,Seol, Dai-Wu,Kim, Moonil De Gruyter Open Sp. z o.o. 2012 BIOLOGIA -BRATISLAVA- Vol.67 No.3
<B>Abstract</B><P>Tumor cell hypoxia is linked to the resistance of human solid tumors to the various anti-cancer therapies: thus, its exploitation has been considered to be a potential target for cancer treatment. Previously, we demonstrated for the first time that hypoxia inhibits apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) through blocking translocation of Bax, a pro-apoptotic protein, from the cytosol to the mitochondria. Nevertheless, the molecular mechanism coupling hypoxia to resistance for drugs, especially for anti-cancer chemotherapeutics, still remains to be elucidated. Here, we demonstrate that hypoxia attenuates camptothecin (CPT)-induced apoptosis by decreasing the protein levels of Bax, thereby leading to resistance to the drug. DNA damage after exposure to CPT resulted in an increase of p53, and a concomitant up-regulation of p21, regardless of oxygen content. Under normoxic condition, CPT induced expression of p53 and its down-stream target molecule Bax as well, in the presence of increased p21. In contrast, when preexposed to hypoxia, Bax-inducing activity of CPT was completely lost and the Bax level was even decreased, although CPT increased both p53 and p21 as observed under normoxic condition. Our data indicate that hypoxia attenuates apoptosis via Bax. Our data also suggest that hypoxia regulates tumor cell apoptosis differentially, through regulating Bax translocation or through down-regulating Bax levels, depending on death-inducing signals as shown by TRAIL- or CPT-induced apoptosis.</P>
Dongwoo Lee,Jida Liu,Hyun Jung Junn,Eun-Joo Lee,Kyu-Shik Jeon,Dai-Wu Seol 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-
Gene therapy is emerging as an effective treatment option for various inherited genetic diseases. Gutless adenovirus(GLAd), also known as helper-dependent adenovirus (HDAd), has many notable characteristics as a gene deliveryvector for this particular type of gene therapy, including broad tropism, high infectivity, a large transgene cargocapacity, and an absence of integration into the host genome. Additionally, GLAd ensures long-term transgeneexpression in host organisms owing to its minimal immunogenicity, since it was constructed following the deletion ofall the genes from an adenovirus. However, the clinical use of GLAd for the treatment of inherited genetic diseases hasbeen hampered by unavoidable contamination of the highly immunogenic adenovirus used as a helper for GLAdproduction. Here, we report the production of GLAd in the absence of a helper adenovirus, which was achieved with ahelper plasmid instead. Utilizing this helper plasmid, we successfully produced large quantities of recombinant GLAd. Importantly, our helper plasmid-based system exclusively produced recombinant GLAd with no generation of helperplasmid-originating adenovirus and replication-competent adenovirus (RCA). The recombinant GLAd that wasproduced efficiently delivered transgenes regardless of their size and exhibited therapeutic potential for Huntington’sdisease (HD) and Duchenne muscular dystrophy (DMD). Our data indicate that our helper plasmid-based GLAdproduction system could become a new platform for GLAd-based gene therapy.
Kim, Chae-Young,Park, Soon-Hye,Jeong, Moon-Sup,Kwon, O-Seo,Doh, Hyoun-Mie,Kang, Su-Hyung,Robbins, Paul D.,Kim, Byong-Moon,Seol, Dai-Wu,Kim, Byung-Gee Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.10
Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.