Molecular Therapy. Methods & Clinical Development最新文献_第9页

Erratum: Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice. 勘误:自愿跑轮补充微营养不良蛋白基因治疗，以改善mdx小鼠的肌肉功能。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-11-05 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.005

Shelby E Hamm, Daniel D Fathalikhani, Katherine E Bukovec, Adele K Addington, Haiyan Zhang, Justin B Perry, Ryan P McMillan, Michael W Lawlor, Mariah J Prom, Mark A Vanden Avond, Suresh N Kumar, Kirsten E Coleman, J B Dupont, David L Mack, David A Brown, Carl A Morris, J Patrick Gonzalez, Robert W Grange

引用次数: 0

piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. piggyBac系统共同表达NKG2D CAR和IL-15，以增强人外周血NK细胞的体内持久性和抗aml活性。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-11-04 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.014

Zhicheng Du, Yu Yang Ng, Shijun Zha, Shu Wang

{"title":"piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells.","authors":"Zhicheng Du, Yu Yang Ng, Shijun Zha, Shu Wang","doi":"10.1016/j.omtm.2021.10.014","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.014","url":null,"abstract":"Promising progress has been made in adoptive transfer of allogeneic natural killer (NK) cells to treat relapsed or refractory acute myeloid leukemia (AML). In this regard, chimeric antigen receptor (CAR)-modification of NK cells is considered as a compelling approach to augment the specificity and cytotoxicity of NK cells against AML. Using a non-viral piggyBac transposon technology and human peripheral blood-derived primary NK cells, we generated CAR-NK cells to target NKG2D ligands and demonstrated their in vitro activity in lysing cancer cells expressing the ligands and in vivo efficacy in inhibiting tumor growth in a xenograft KG-1 AML model. We further generated CAR-NK cells co-expressing transgenes for the NKG2D CAR and interleukin-15 (IL-15). The ectopic expression of IL-15 improved the in vitro and in vivo persistence of NKG2D CAR-NK cells, leading to enhanced in vivo tumor control and significant prolongation of mouse survival in the KG-1 AML model. Collectively, our findings demonstrate the ectopic expression of IL-15 as an important means to improve the antileukemic activity of NKG2D CAR-NK cells. Our study further illustrates the feasibility of using the piggyBac non-viral platform as an efficient and cost-effective way for CAR-NK cell manufacturing.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"582-596"},"PeriodicalIF":4.7,"publicationDate":"2021-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/17/ab/main.PMC8609108.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39683348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 32

Tips and tricks for successfully culturing and adapting human induced pluripotent stem cells. 成功培养和适应人类诱导多能干细胞的技巧和窍门。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-11-03 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.013

Rocío Castro-Viñuelas, Clara Sanjurjo-Rodríguez, María Piñeiro-Ramil, Silvia Rodríguez-Fernández, Isidoro López-Baltar, Isaac Fuentes-Boquete, Francisco J Blanco, Silvia Díaz-Prado

{"title":"Tips and tricks for successfully culturing and adapting human induced pluripotent stem cells.","authors":"Rocío Castro-Viñuelas, Clara Sanjurjo-Rodríguez, María Piñeiro-Ramil, Silvia Rodríguez-Fernández, Isidoro López-Baltar, Isaac Fuentes-Boquete, Francisco J Blanco, Silvia Díaz-Prado","doi":"10.1016/j.omtm.2021.10.013","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.013","url":null,"abstract":"Reprogramming somatic cells toward pluripotency became possible over a decade ago. Since then, induced pluripotent stem cells (iPSCs) have served as a versatile and powerful tool not only for basic research but also with the long-term goal of using them in human cell transplantation after differentiation. Nonetheless, downstream applications are frequently blurred by the difficulties that researchers have to face when working with iPSCs, such as trouble with clonal selection, in vitro culture and cryopreservation, adaptation to feeder-free conditions, or expansion of the cells. Therefore, in this article we aim to provide other researchers with practical and detailed information to successfully culture and adapt iPSCs. Specifically, we (1) describe the most common problems when in-vitro culturing iPSCs onto feeder cells as well as its possible troubleshooting, and (2) compare different matrices and culture media for adapting the iPSCs to feeder-free conditions. We believe that the troubleshooting and recommendations provided in this article can be of use to other researchers working with iPSCs and who may be experiencing similar issues, hopefully enhancing the appeal of this promising cell source to be used for biomedical investigations, such as tissue engineering or regenerative medicine applications.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"569-581"},"PeriodicalIF":4.7,"publicationDate":"2021-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39720562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors. 20个hbv特异性MHC ii类限制性T细胞受体文库的表征

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-29 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.012

Sophia Schreiber, Melanie Honz, Weeda Mamozai, Peter Kurktschiev, Matthias Schiemann, Klaus Witter, Eugene Moore, Christina Zielinski, Alessandro Sette, Ulrike Protzer, Karin Wisskirchen

{"title":"Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors.","authors":"Sophia Schreiber, Melanie Honz, Weeda Mamozai, Peter Kurktschiev, Matthias Schiemann, Klaus Witter, Eugene Moore, Christina Zielinski, Alessandro Sette, Ulrike Protzer, Karin Wisskirchen","doi":"10.1016/j.omtm.2021.10.012","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.012","url":null,"abstract":"CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and therapeutic tools are missing. Therefore, we identified, cloned, and characterized a comprehensive library of 20 MHC class II-restricted HBV-specific T cell receptors (TCRs) from donors with acute or resolved HBV infection. The TCRs were restricted by nine different MHC II molecules and specific for eight different epitopes derived from intracellularly processed HBV envelope, core, and polymerase proteins. Retroviral transduction resulted in a robust expression of all TCRs on primary T cells. A high functional avidity was measured for all TCRs specific for epitopes S17, S21, S36, and P774 (half-maximal effective concentration [EC50] <10 nM), or C61 and preS9 (EC50 <100 nM). Eight TCRs recognized peptide variants of HBV genotypes A to D. Both CD4+ and CD8+ T cells transduced with the MHC II-restricted TCRs were polyfunctional, producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and granzyme B (GrzB), and killed peptide-loaded target cells. Our set of MHC class II-restricted TCRs represents an important tool for elucidating CD4+ T cell help in viral infection with potential benefit for T cell therapy.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"476-489"},"PeriodicalIF":4.7,"publicationDate":"2021-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39772881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Quantification of cell-free DNAfor the analysis of CD19-CAR-T cells during lymphoma treatment. 在淋巴瘤治疗期间定量分析CD19-CAR-T细胞的游离dna。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-28 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.009

Thomas Mika, Julia Thomson, Verena Nilius-Eliliwi, Deepak Vangala, Alexander Baraniskin, Gerald Wulf, Susanne Klein-Scory, Roland Schroers

{"title":"Quantification of cell-free DNAfor the analysis of CD19-CAR-T cells during lymphoma treatment.","authors":"Thomas Mika, Julia Thomson, Verena Nilius-Eliliwi, Deepak Vangala, Alexander Baraniskin, Gerald Wulf, Susanne Klein-Scory, Roland Schroers","doi":"10.1016/j.omtm.2021.10.009","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.009","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cells are increasingly used for the treatment of hematologic malignancies. Treatment success relies highly upon sufficient expansion of CAR-T effector cells. Accordingly, longitudinal quantification of CAR-T cells during therapy is clinically important. Techniques to quantify CAR-T cells in patient blood samples are based on flow cytometry and PCR. However, cellular kinetics of CAR-T cells are very complex and under current investigation. In this study, feasibility of CAR-T cell quantification by cell-free DNA (cfDNA) was analyzed. cfDNA isolated from 74 blood samples of 12 patients during lymphoma treatment with the anti-CD19 CAR-T cell product axicabtagene ciloleucel (axi-cel) were analyzed. Concentrations of cfDNA specific for the CAR-T gene construct (cfCAR-DNA) and a reference gene were quantified by a newly designed digital-droplet PCR (ddPCR) assay. Detection and quantification of cfCAR-DNA was feasible and reliable for all patients included. Relative quantification of cfCAR-DNA compared to a reference gene, suitable for genomic DNA analysis, was heterogeneous in treatment responders and non-responders. In contrast, parallel analyses of cfCAR-DNA and reference cfDNA in a patient-specific approach gave insight into active lymphoma killing and treatment responses. In summary, plasma cfDNA determination in lymphoma patients is a promising tool for future clinical decision making.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"539-550"},"PeriodicalIF":4.7,"publicationDate":"2021-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39683345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells. 扩增的多克隆T-regs和衣壳特异性嵌合抗原受体t -调节细胞调节对AAV的免疫应答。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-28 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.010

Motahareh Arjomandnejad, Katelyn Sylvia, Meghan Blackwood, Thomas Nixon, Qiushi Tang, Manish Muhuri, Alisha M Gruntman, Guangping Gao, Terence R Flotte, Allison M Keeler

{"title":"Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells.","authors":"Motahareh Arjomandnejad, Katelyn Sylvia, Meghan Blackwood, Thomas Nixon, Qiushi Tang, Manish Muhuri, Alisha M Gruntman, Guangping Gao, Terence R Flotte, Allison M Keeler","doi":"10.1016/j.omtm.2021.10.010","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.010","url":null,"abstract":"Immune responses to adeno-associated virus (AAV) capsids limit the therapeutic potential of AAV gene therapy. Herein, we model clinical immune responses by generating AAV capsid-specific chimeric antigen receptor (AAV-CAR) T cells. We then modulate immune responses to AAV capsid with AAV-CAR regulatory T cells (Tregs). AAV-CAR Tregs in vitro display phenotypical Treg surface marker expression, and functional suppression of effector T cell proliferation and cytotoxicity. In mouse models, AAV-CAR Tregs mediated continued transgene expression from an immunogenic capsid, despite antibody responses, produced immunosuppressive cytokines, and decreased tissue inflammation. AAV-CAR Tregs are also able to bystander suppress immune responses to immunogenic transgenes similarly mediating continued transgene expression, producing immunosuppressive cytokines, and reducing tissue infiltration. Taken together, AAV-CAR T cells and AAV-CAR Tregs are directed and powerful immunosuppressive tools to model and modulate immune responses to AAV capsids and transgenes in the local environment.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"490-506"},"PeriodicalIF":4.7,"publicationDate":"2021-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/07/3f/main.PMC8605179.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39772882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Peripheral leukemia burden at time of apheresis negatively affects the clinical efficacy of CART19 in refractory or relapsed B-ALL. 采珠时外周血白血病负荷对CART19治疗难治性或复发性B-ALL的临床疗效有负面影响。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-27 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.006

Biping Deng, Jing Pan, Zhaoli Liu, Shuangyou Liu, Yunlong Chen, Xiaomin Qu, Yu'e Zhang, Yuehui Lin, Yanlei Zhang, Xinjian Yu, Zhongxin Zhang, Xuansha Niu, Rong Luan, Ming Ma, Xiaomei Li, Tingting Liu, Xi'ai Wu, Huan Niu, Alex H Chang, Chunrong Tong

{"title":"Peripheral leukemia burden at time of apheresis negatively affects the clinical efficacy of CART19 in refractory or relapsed B-ALL.","authors":"Biping Deng, Jing Pan, Zhaoli Liu, Shuangyou Liu, Yunlong Chen, Xiaomin Qu, Yu'e Zhang, Yuehui Lin, Yanlei Zhang, Xinjian Yu, Zhongxin Zhang, Xuansha Niu, Rong Luan, Ming Ma, Xiaomei Li, Tingting Liu, Xi'ai Wu, Huan Niu, Alex H Chang, Chunrong Tong","doi":"10.1016/j.omtm.2021.10.006","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.006","url":null,"abstract":"Our previous clinical study achieved complete remission (CR) rates of >90% following chimeric antigen receptor T cells targeting CD19 (CART19) treatment of refractory/relapsed B cell acute lymphoblastic leukemia (r/r B-ALL); however, the influence of the leukemia burden in peripheral blood (PB) blasts remains unclear. Here, we retrospectively analyzed 143 patients treated with CART19 (including 36 patients with PB blasts) to evaluate the effect of peripheral leukemia burden at the time of apheresis. One hundred seventeen patients with high disease burdens achieved 91.5% CR or incomplete count recovery CR and 86.3% minimal residual disease-negative CR, and 26 patients with low disease burdens obtained 96.2% MRD- CR. Collectively, 9 of 36 (25%) patients with PB blasts and 2 of 107 (1.87%) patients without PB blasts did not respond to CART19 therapy. The leukemia burden in PB negatively influenced ex vivo cell characteristics, including the transduction efficiency of CD3+ T cells and their fold expansion, and in vivo cell dynamics, including peak CART19 proportion and absolute count, fold expansion, and persistence duration. Further studies showed that these patients had higher programmed death-1 expression in CART19 products. Our data imply that PB blasts negatively affected CART19 production and the clinical efficacy of CART19 therapy in patients with r/r B-ALL.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"633-643"},"PeriodicalIF":4.7,"publicationDate":"2021-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e8/43/main.PMC8640733.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39720565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Inclusion of a degron reduces levelsof undesired inteins after AAV-mediated proteintrans-splicing in the retina. 在aav介导的视网膜蛋白反式剪接后，degron的包含降低了不需要的蛋白水平。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-19 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.004

Patrizia Tornabene, Ivana Trapani, Miriam Centrulo, Elena Marrocco, Renato Minopoli, Mariangela Lupo, Carolina Iodice, Carlo Gesualdo, Francesca Simonelli, Enrico M Surace, Alberto Auricchio

{"title":"Inclusion of a degron reduces levelsof undesired inteins after AAV-mediated proteintrans-splicing in the retina.","authors":"Patrizia Tornabene, Ivana Trapani, Miriam Centrulo, Elena Marrocco, Renato Minopoli, Mariangela Lupo, Carolina Iodice, Carlo Gesualdo, Francesca Simonelli, Enrico M Surace, Alberto Auricchio","doi":"10.1016/j.omtm.2021.10.004","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.004","url":null,"abstract":"Split intein-mediated protein trans-splicing expands AAV transfer capacity, thus overcoming the limited AAV cargo. However, non-mammalian inteins persist as trans-splicing by-products, and this could raise safety concerns for AAV intein clinical applications. In this study, we tested the ability of several degrons to selectively decrease levels of inteins after protein trans-splicing and found that a version of E. coli dihydrofolate reductase, which we have shortened to better fit into the AAV vector, is the most effective. We show that subretinal administration of AAV intein armed with this short degron is both safe and effective in a mouse model of Stargardt disease (STGD1), which is the most common form of inherited macular degeneration in humans. This supports the use of optimized AAV intein for gene therapy of both STGD1 and other conditions that require transfer of large genes.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"448-459"},"PeriodicalIF":4.7,"publicationDate":"2021-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39630200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 9

Digital PCR to quantify ChAdOx1 nCoV-19 copies in blood and tissues. 数字PCR定量血液和组织中ChAdOx1 nCoV-19拷贝数

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-16 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.002

Anita Badbaran, Reiner K Mailer, Christine Dahlke, Jannis Woens, Anahita Fathi, Sibylle C Mellinghoff, Thomas Renné, Marylyn M Addo, Kristoffer Riecken, Boris Fehse

{"title":"Digital PCR to quantify ChAdOx1 nCoV-19 copies in blood and tissues.","authors":"Anita Badbaran, Reiner K Mailer, Christine Dahlke, Jannis Woens, Anahita Fathi, Sibylle C Mellinghoff, Thomas Renné, Marylyn M Addo, Kristoffer Riecken, Boris Fehse","doi":"10.1016/j.omtm.2021.10.002","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.002","url":null,"abstract":"Vaccination with the adenoviral-vector-based AstraZeneca ChAdOx1 nCov-19 (Vaxzevria) vaccine is efficient and safe. However, in rare cases vaccinated individuals developed life-threatening thrombotic complications, including thrombosis in cerebral sinus and splanchnic veins. Monitoring of the applied vector in vivo represents an important precondition to study the molecular mechanisms underlying vaccine-driven adverse effects now referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). We previously have shown that digital PCR (dPCR) is an excellent tool to quantify transgene copies in vivo. Here, we present a highly sensitive dPCR for in situ quantification of ChAdOx1 nCoV-19 copies. Using this method, we quantified vector copies in human plasma 24, 72, and 168 h post vaccination and in a variety of murine tissues in an experimental vaccination model 30 min post injection. We describe a method for high-sensitivity quantitative detection of ChAdOx1 nCoV-19 with possible implications to elucidate the mechanisms of severe ChAdOx1 nCov-19 vaccine complications.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"418-423"},"PeriodicalIF":4.7,"publicationDate":"2021-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bf/9b/main.PMC8566940.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39630197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Nonconditioned ADA-SCID gene therapy reveals ADA requirement in the hematopoietic system and clonal dominance of vector-marked clones. 非条件ADA- scid基因治疗揭示了造血系统对ADA的需求和载体标记克隆的克隆优势。

IF 4.7

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-16 eCollection Date: 2021-12-10 DOI: 10.1016/j.omtm.2021.10.003

Toru Uchiyama, Sirirat Takahashi, Kazuhiko Nakabayashi, Kohji Okamura, Kaori Edasawa, Masafumi Yamada, Nobuyuki Watanabe, Emi Mochizuki, Toru Yasuda, Akane Miura, Motohiro Kato, Daisuke Tomizawa, Makoto Otsu, Tadashi Ariga, Masafumi Onodera

{"title":"Nonconditioned ADA-SCID gene therapy reveals ADA requirement in the hematopoietic system and clonal dominance of vector-marked clones.","authors":"Toru Uchiyama, Sirirat Takahashi, Kazuhiko Nakabayashi, Kohji Okamura, Kaori Edasawa, Masafumi Yamada, Nobuyuki Watanabe, Emi Mochizuki, Toru Yasuda, Akane Miura, Motohiro Kato, Daisuke Tomizawa, Makoto Otsu, Tadashi Ariga, Masafumi Onodera","doi":"10.1016/j.omtm.2021.10.003","DOIUrl":"https://doi.org/10.1016/j.omtm.2021.10.003","url":null,"abstract":"Two patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID) received stem cell-based gene therapy (SCGT) using GCsapM-ADA retroviral vectors without preconditioning in 2003 and 2004. The first patient (Pt1) was treated at 4.7 years old, and the second patient (Pt2), who had previously received T cell gene therapy (TCGT), was treated at 13 years old. More than 10 years after SCGT, T cells showed a higher vector copy number (VCN) than other lineages. Moreover, the VCN increased with differentiation toward memory T and B cells. The distribution of vector-marked cells reflected variable levels of ADA requirements in hematopoietic subpopulations. Although neither patient developed leukemia, clonal expansion of SCGT-derived clones was observed in both patients. The use of retroviral vectors yielded clonal dominance of vector-marked clones, irrespective of the lack of leukemic changes. Vector integration sites common to all hematopoietic lineages suggested the engraftment of gene-marked progenitors in Pt1, who showed severe osteoblast (OB) insufficiency compared to Pt2, which might cause a reduction in the stem/progenitor cells in the bone marrow (BM). The impaired BM microenvironment due to metabolic abnormalities may create space for the engraftment of vector-marked cells in ADA-SCID, despite the lack of preconditioning.","PeriodicalId":517056,"journal":{"name":"Molecular Therapy. Methods & Clinical Development","volume":" ","pages":"424-433"},"PeriodicalIF":4.7,"publicationDate":"2021-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39630198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1