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Molecular Therapy: the Journal of the American Society of Gene Therapy

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https://www.readbyqxmd.com/read/30414722/addressing-the-value-of-gene-therapy-and-enhancing-patient-access-to-transformative-treatments
#1
REVIEW
Rachel Salzman, Francesca Cook, Timothy Hunt, Harry L Malech, Philip Reilly, Betsy Foss-Campbell, David Barrett
Although high upfront costs for the high value of gene therapy have resulted in concerns about sufficient reimbursement to allow patient access to these therapies, the significant benefits of gene therapies will not be realized unless patients have access to them. Stakeholders are discussing these issues, and the payment models being developed for the newly approved gene therapies provide an early indication of the flexibility that will be needed from treatment manufacturers, payers, and policy makers to optimize patient access...
October 30, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30389355/gesicle-mediated-delivery-of-crispr-cas9-ribonucleoprotein-complex-for-inactivating-the-hiv-provirus
#2
Lee A Campbell, Lamarque M Coke, Christopher T Richie, Lowella V Fortuno, Aaron Y Park, Brandon K Harvey
Investigators have utilized the CRISPR/Cas9 gene-editing system to specifically target well-conserved regions of HIV, leading to decreased infectivity and pathogenesis in vitro and ex vivo. We utilized a specialized extracellular vesicle termed a "gesicle" to efficiently, yet transiently, deliver Cas9 in a ribonucleoprotein form targeting the HIV long terminal repeat (LTR). Gesicles are produced through expression of vesicular stomatitis virus glycoprotein and package protein as their cargo, thus bypassing the need for transgene delivery, and allowing finer control of Cas9 expression...
October 11, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30343890/deamidation-of-amino-acids-on-the-surface-of-adeno-associated-virus-capsids-leads-to-charge-heterogeneity-and-altered-vector-function
#3
April R Giles, Joshua J Sims, Kevin B Turner, Lakshmanan Govindasamy, Mauricio R Alvira, Martin Lock, James M Wilson
Post-translational modification of the adeno-associated virus capsids is a poorly understood factor in the development of these viral vectors into pharmaceutical products. Here we report the extensive capsid deamidation of adeno-associated virus serotype 8 and seven other diverse adeno-associated virus serotypes, with supporting evidence from structural, biochemical, and mass spectrometry approaches. The extent of deamidation at each site depended on the vector's age and multiple primary-sequence and three-dimensional structural factors...
October 9, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30391141/cd7-car-t-cells-for-the-therapy-of-acute-myeloid-leukemia
#4
Diogo Gomes-Silva, Erden Atilla, Pinar Ataca Atilla, Feiyan Mo, Haruko Tashiro, Madhuwanti Srinivasan, Premal Lulla, Rayne H Rouce, Joaquim M S Cabral, Carlos A Ramos, Malcolm K Brenner, Maksim Mamonkin
Chimeric antigen receptor (CAR) T cell therapy for the treatment of acute myeloid leukemia (AML) has the risk of toxicity to normal myeloid cells. CD7 is expressed by the leukemic blasts and malignant progenitor cells of approximately 30% of AML patients but is absent on normal myeloid and erythroid cells. Since CD7 expression by malignant blasts is also linked with chemoresistance and poor outcomes, targeting this antigen may be beneficial for this subset of AML patients. Here, we show that expression of a CD7-directed CAR in CD7 gene-edited (CD7KO ) T cells effectively eliminates CD7+ AML cell lines, primary CD7+ AML, and colony-forming cells but spares myeloid and erythroid progenitor cells and their progeny...
October 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30341011/loss-of-shp2-rescues-bdnf-trkb-signaling-and-contributes-to-improved-retinal-ganglion-cell-neuroprotection
#5
Nitin Chitranshi, Yogita Dheer, Mehdi Mirzaei, Yunqi Wu, Ghasem H Salekdeh, Mojdeh Abbasi, Veer Gupta, Roshana Vander Wall, Yuyi You, Stuart L Graham, Vivek Gupta
Glaucoma is characterized by the loss of retinal ganglion cells (RGC), and accordingly the preservation of RGCs and their axons has recently attracted significant attention to improve therapeutic outcomes in the disease. Here, we report that Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) undergoes activation in the RGCs, in animal model of glaucoma as well as in the human glaucoma tissues and that Shp2 dephosphorylates tropomyosin receptor kinase B (TrkB) receptor, leading to reduced BDNF/TrkB neuroprotective survival signaling...
October 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30391142/long-term-persistence-of-anti-hiv-broadly-neutralizing-antibody-secreting-hematopoietic-cells-in-humanized-mice
#6
Anne-Sophie Kuhlmann, Kevin G Haworth, Isaac M Barber-Axthelm, Christina Ironside, Morgan A Giese, Christopher W Peterson, Hans-Peter Kiem
Broadly neutralizing antibodies (bNAbs) are among the most promising strategies to achieve long-term control of HIV-1 in the absence of combination antiretroviral therapy. Passive administration of such antibodies in patients efficiently decreases HIV-1 viremia, but is limited by the serum half-life of the protein. Here, we investigated whether antibody-secreting hematopoietic cells could overcome this problem. We genetically modified human CD34+ hematopoietic stem and progenitor cells (HSPCs) to secrete bNAbs and transplanted them into immunodeficient mice...
September 27, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30341010/promoter-methylation-regulated-mir-145-5p-inhibits-laryngeal-squamous-cell-carcinoma-progression-by-targeting-fscn1
#7
Wei Gao, Chunming Zhang, Wenqi Li, Huizheng Li, Jiangwei Sang, Qinli Zhao, Yunfeng Bo, Hongjie Luo, Xiwang Zheng, Yan Lu, Yong Shi, Dongli Yang, Ruiping Zhang, Zhenyu Li, Jiajia Cui, Yuliang Zhang, Min Niu, Jun Li, Zhongqiang Wu, Huina Guo, Caixia Xiang, Juan Wang, Juan Hou, Lu Zhang, Rick F Thorne, Yongping Cui, Yongyan Wu, Shuxin Wen, Binquan Wang
Laryngeal squamous cell carcinoma (LSCC) is a common form of head and neck cancer with poor prognosis. However, the mechanism underlying the pathogenesis of LSCC remains unclear. Here, we demonstrated increased expression of fascin actin-bundling protein 1 (FSCN1) and decreased expression of microRNA-145-5p (miR-145-5p) in a clinical cohort of LSCC. Luciferase assay revealed that miR-145-5p is a negative regulator of FSCN1. Importantly, low miR-145-5p expression was correlated with TNM (tumor, node, metastasis) status and metastasis...
September 27, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30341009/bioselection-reveals-mir-99b-and-mir-485-as-enhancers-of-adenoviral-oncolysis-in-pancreatic-cancer
#8
Maria Rovira-Rigau, Giulia Raimondi, Miguel Ángel Marín, Meritxell Gironella, Ramon Alemany, Cristina Fillat
Oncolytic viruses are designed for cancer treatment. Cell-virus interactions are key determinants for successful viral replication. Therefore, the extensive reprogramming of gene expression that occurs in tumor cells might create a hurdle for viral propagation. We used a replication-based approach of a microRNA (miRNA) adenoviral library encoding up to 243 human miRNAs as a bioselection strategy to identify miRNAs that facilitate adenoviral oncolytic activity in pancreatic ductal adenocarcinoma. We identify two miRNAs, miR-99b and miR-485, that function as enhancers of adenoviral oncolysis by improving the intra- and extracellular yield of mature virions...
September 27, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30341012/exosomes-produced-from-3d-cultures-of-mscs-by-tangential-flow-filtration-show-higher-yield-and-improved-activity
#9
Reka Agnes Haraszti, Rachael Miller, Matteo Stoppato, Yves Y Sere, Andrew Coles, Marie-Cecile Didiot, Rachel Wollacott, Ellen Sapp, Michelle Dubuke, Xuni Li, Scott Shaffer, Marian DiFiglia, Yang Wang, Neil Aronin, Anastasia Khvorova
Exosomes can deliver therapeutic RNAs to neurons. The composition and the safety profile of exosomes depend on the type of the exosome-producing cell. Mesenchymal stem cells are considered to be an attractive cell type for therapeutic exosome production. However, scalable methods to isolate and manufacture exosomes from mesenchymal stem cells are lacking, a limitation to the clinical translation of exosome technology. We evaluate mesenchymal stem cells from different sources and find that umbilical cord-derived mesenchymal stem cells produce the highest exosome yield...
September 22, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30301668/4mu-decreases-cd47-expression-on-hepatic-cancer-stem-cells-and-primes-a-potent-antitumor-t-cell-response-induced-by-interleukin-12
#10
Marcelo M Rodríguez, Esteban Fiore, Juan Bayo, Catalina Atorrasagasti, Mariana García, Agostina Onorato, Luciana Domínguez, Mariana Malvicini, Guillermo Mazzolini
The tumor microenvironment (TME) represents a complex interplay between different cellular components, including tumor cells and cancer stem cells (CSCs), with the associated stroma; such interaction promotes tumor immune escape and sustains tumor growth. Several experimental approaches for cancer therapy are focused on TME remodeling, resulting in increased antitumor effects. We previously demonstrated that the hyaluronan synthesis inhibitor 4-methylumbelliferone (4Mu) decreases liver fibrosis and induces antitumor activity in hepatocellular carcinoma (HCC)...
September 18, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30309819/in-vivo-fate-and-activity-of-second-versus-third-generation-cd19-specific-car-t-cells-in-b-cell-non-hodgkin-s-lymphomas
#11
Carlos A Ramos, Rayne Rouce, Catherine S Robertson, Amy Reyna, Neeharika Narala, Gayatri Vyas, Birju Mehta, Huimin Zhang, Olga Dakhova, George Carrum, Rammurti T Kamble, Adrian P Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M Rooney, Helen E Heslop, Malcolm K Brenner, Barbara Savoldo, Gianpietro Dotti
Second-generation (2G) chimeric antigen receptors (CARs) targeting CD19 are highly active against B cell malignancies, but it is unknown whether any of the costimulatory domains incorporated in the CAR have superior activity to others. Because CD28 and 4-1BB signaling activate different pathways, combining them in a single third-generation (3G) CAR may overcome the limitations of each individual costimulatory domain. We designed a clinical trial in which two autologous CD19-specific CAR-transduced T cell products (CD19...
September 13, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30301667/mir-30-family-reduction-maintains-self-renewal-and-promotes-tumorigenesis-in-nsclc-initiating-cells-by-targeting-oncogene-tm4sf1
#12
Yu-Shui Ma, Fei Yu, Xiao-Ming Zhong, Gai-Xia Lu, Xian-Ling Cong, Shao-Bo Xue, Wen-Ting Xie, Li-Kun Hou, Li-Juan Pang, Wei Wu, Wei Zhang, Le-Le Cong, Tie Liu, Hui-Deng Long, Ran Sun, Hong-Yan Sun, Zhong-Wei Lv, Chun-Yan Wu, Da Fu
Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS)...
September 13, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30301666/development-of-targeted-sirna-nanocomplexes-to-prevent-fibrosis-in-experimental-glaucoma-filtration-surgery
#13
Owen Fernando, Aristides D Tagalakis, Sahar Awwad, Steve Brocchini, Peng T Khaw, Stephen L Hart, Cynthia Yu-Wai-Man
RNAi induced by double-stranded small interfering RNA (siRNA) molecules has attracted great attention as a naturally occurring approach to silence gene expression with high specificity. The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway is a master regulator of cytoskeletal gene expression and, thus, represents a promising target to prevent fibrosis. A major hurdle to implementing siRNA therapies is the method of delivery, and we have, thus, optimized lipid-peptide-siRNA (LPR) nanoparticles containing MRTF-B siRNAs as a targeted approach to prevent conjunctival fibrosis...
September 11, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30287074/therapeutic-potential-of-ome-ps-mir-29b1-for-treating-liver-fibrosis
#14
Virender Kumar, Vinod Kumar, Jiangtao Luo, Ram I Mahato
Trans-differentiation of quiescent hepatic stellate cells (HSCs) into active myofibroblasts secretes excess amounts of extracellular matrix (ECM) proteins. miR-29b1 has the potential to treat liver fibrosis, because it targets several profibrotic genes. We previously demonstrated that miR-29b1 and the hedgehog (Hh) pathway inhibitor GDC-0449 could, together, inhibit the activation of HSCs and ECM production in common bile-duct-ligated (CBDL) mice. Herein, we determined the effect of chemical modifications of miR-29b1 on its stability, immunogenicity, and Argonaute-2 (Ago2) loading in vitro, after modifying its antisense strand with phosphorothioate (PS-miR-29b1), 2'-O-methyl-phosphorothioate (OMe-miR-29b1), locked nucleic acid (LNA-miR-29b1), and N,N'-diethyl-4-(4-nitronaphthalen-1-ylazo)-phenylamine (ZEN-miR-29b1)...
September 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30274790/recombinant-bcg-overexpressing-phop-phor-confers-enhanced-protection-against-tuberculosis
#15
Sang Kyun Ahn, Vanessa Tran, Andrea Leung, Mark Ng, Ming Li, Jun Liu
The live tuberculosis vaccine Mycobacterium bovis BCG (Bacille Calmette-Guérin) comprises a number of genetically distinct substrains. In BCG-Prague, phoP of the PhoP-PhoR two-component system is a pseudogene due to a single insertion mutation. We hypothesized that this mutation partially accounts for the low immunogenicity of BCG-Prague observed in the 1970s. In this study, we showed that complementation with the M. bovis allele of phoP restored BCG-Prague's immunogenicity. Furthermore, we showed that overexpression of the M...
September 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30274787/microrna-532-5p-regulates-pericyte-function-by-targeting-the-transcription-regulator-bach1-and-angiopoietin-1
#16
Sadie C Slater, Eva Jover, Andrea Martello, Tijana Mitić, Iker Rodriguez-Arabaolaza, Rosa Vono, Valeria V Alvino, Simon C Satchell, Gaia Spinetti, Andrea Caporali, Paolo Madeddu
MicroRNAs regulate endothelial function and angiogenesis, but their implication in pericyte biology remains undetermined. A PCR array, covering a panel of 379 human microRNAs, showed microRNA-532-5p to be one of the most differentially modulated by hypoxia, which was confirmed by qPCR in both skeletal muscle and adventitial pericytes. Furthermore, microRNA-532-5p was upregulated in murine muscular pericytes early after experimentally induced ischemia, decreasing below baseline after reperfusion. Transfection of human pericytes with anti-microRNA, microRNA-mimic, or controls indicates microRNA-532-5p modulates pro-angiogenic activity via transcriptional regulation of angiopoietin-1...
September 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30266653/targeting-endothelial-erk1-2-akt-axis-as-a-regeneration-strategy-to-bypass-fibrosis-during-chronic-liver-injury-in-mice
#17
Yuanxiang Lao, Yanyan Li, Ping Zhang, Qianqian Shao, Weiran Lin, Bintao Qiu, Yongzhuang Lv, Lichun Tang, Shishuai Su, Hongyu Zhang, Chunyan Tian, Aihua Sun, Handong Wei, Pumin Zhang, Yan Wu, Ying Jiang, Fuchu He
Liver sinusoidal endothelial cells (LSECs) have great capacity for liver regeneration, and this capacity can easily switch to profibrotic phenotype, which is still poorly understood. In this study, we elucidated a potential target in LSECs for regenerative treatment that can bypass fibrosis during chronic liver injury. Proregenerative LSECs can be transformed to profibrotic phenotype after 4 weeks of carbon tetrachloride administration or 10 days of bile duct ligation. This phenotypic alternation of LSECs was mediated by extracellular regulated protein kinases 1 and 2 (Erk1/2)-Akt axis switch in LSECs during chronic liver injury; Erk1/2 was normally associated with maintenance of the LSEC proregenerative phenotype, inhibiting hepatic stellate cell (HSC) activation and promoting tissue repair by enhancing nitric oxide (NO)/reactive oxygen species (ROS) ratio and increasing expression of hepatic growth factor (HGF) and Wingless-type MMTV integration site family member 2 (Wnt2)...
August 24, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30217729/upregulation-of-lncrna-adamts9-as2-promotes-salivary-adenoid-cystic-carcinoma-metastasis-via-pi3k-akt-and-mek-erk-signaling
#18
Shule Xie, Xin Yu, Yingru Li, Hanyu Ma, Song Fan, Weixiong Chen, Guokai Pan, Weiwei Wang, Hanqing Zhang, Jinsong Li, Zhaoyu Lin
Neurotropic infiltrative growth and distant metastasis are the main causes of death in salivary adenoid cystic carcinoma (SACC) patients. Long noncoding RNAs (lncRNAs) are involved in many human neoplasms, however, their potential roles in SACC are unclear. In our study, we found that ADAM metallopeptidase with thrombospondin type 1 motif, 9 (ADAMTS9) antisense RNA 2 (ADAMTS9-AS2) was significantly upregulated in SACC patients with metastasis and SACC-lung metastasis (LM) cells. Moreover, ADAMTS9-AS2 expression was closely associated with the prognosis and distant metastasis in SACC patients...
August 24, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30415659/long-noncoding-rna-lncmuma-reverses-established-skeletal-muscle-atrophy-following-mechanical-unloading
#19
Zong-Kang Zhang, Jie Li, Daogang Guan, Chao Liang, Zhenjian Zhuo, Jin Liu, Aiping Lu, Ge Zhang, Bao-Ting Zhang
Reversing established muscle atrophy following mechanical unloading is of great clinical challenge. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in myogenesis. Here we identified a lncRNA (mechanical unloading-induced muscle atrophy-related lncRNA [lncMUMA]) enriched in muscle, which was the most downregulated lncRNA during muscle atrophy development in hindlimb suspension (HLS) mice. The in vitro and in vivo data demonstrated that the decreased expression levels of lncMUMA closely associated with a reduction of myogenesis during mechanical unloading...
November 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/30415658/low-dose-radiation-conditioning-enables-car-t-cells-to-mitigate-antigen-escape
#20
Carl DeSelm, M Lia Palomba, Joachim Yahalom, Mohamad Hamieh, Justin Eyquem, Vinagolu K Rajasekhar, Michel Sadelain
CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA+ but also sLeA- tumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigen-negative tumor relapse...
November 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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