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

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https://www.readbyqxmd.com/read/28648665/mir-491-inhibits-osteosarcoma-lung-metastasis-and-chemoresistance-by-targeting-%C3%AE-b-crystallin
#1
Shu-Nan Wang, Song Luo, Chang Liu, Zhenghao Piao, Wenlong Gou, Yun Wang, Wei Guan, Qing Li, Hua Zou, Zhen-Zhou Yang, Dong Wang, Yan Wang, Meng Xu, Hua Jin, Cheng-Xiong Xu
Dysregulated microRNAs (miRNAs) play an important role in osteosarcoma (OS) progression. In the present study, we investigate the clinical significance of serum miR-491 level and the potential role of miR-491 in OS lung metastasis and chemoresistance. Clinical data show that the level of miR-491 was decreased in serum from OS patients compared with healthy control subjects, and that a decreased serum miR-491 level is correlated with increased metastasis, poor chemoresponse, and lower survival rate in OS patients...
June 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28647464/data-against-a-common-assumption-xenogeneic-mouse-models-can-be-used-to-assay-suppression-of-immunity-by-human-mscs
#2
REVIEW
Darwin J Prockop, Joo Youn Oh, Ryang Hwa Lee
Much of what we know about immunology suggests that little is to be gained from experiments in which human cells are administered to immunocompetent mice. Multiple reports have demonstrated that this common assumption does not hold for experiments with human mesenchymal stem/stromal cells (hMSCs). The data demonstrate that hMSCs can suppress immune responses to a variety of stimuli in immunocompetent mice by a range of different mechanisms that are similar to those employed by mouse MSCs. Therefore, further experiments with hMSCs in mice will make it possible to generate preclinical data that will improve both the efficacy and safety of the clinical trials with the cells that are now in progress...
June 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28641935/fatty-acid-modified-gapmer-antisense-oligonucleotide-and-serum-albumin-constructs-for-pharmacokinetic-modulation
#3
Michael Lykke Hvam, Yunpeng Cai, Frederik Dagnæs-Hansen, Jesper Sejrup Nielsen, Jesper Wengel, Jørgen Kjems, Kenneth A Howard
Delivery technologies are required for realizing the clinical potential of molecular medicines. This work presents an alternative technology to preformulated delivery systems by harnessing the natural transport properties of serum albumin using endogenous binding of gapmer antisense oligonucleotides (ASOs)/albumin constructs. We show by an electrophoretic mobility assay that fatty acid-modified gapmer and human serum albumin (HSA) can self-assemble into constructs that offer favorable pharmacokinetics. The interaction was dependent on fatty acid type (either palmitic or myristic acid), number, and position within the gapmer ASO sequence, as well as phosphorothioate (PS) backbone modifications...
June 19, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28633863/targeted-deletion-of-an-entire-chromosome-using-crispr-cas9
#4
LETTER
Fatwa Adikusuma, Nicole Williams, Frank Grutzner, James Hughes, Paul Thomas
CRISPR/Cas9 genome editing can facilitate efficient deletion of genomic region, but it has not been used to delete an entire chromosome. Here, Adikusuma et al. show proof-of-concept for efficient CRISPR-mediated selective chromosome deletion by removing the centromere or shredding the chromosome arm in mouse embryonic stem cells and zygotes.
June 17, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28629822/structure-based-designed-nano-dysferlin-significantly-improves-dysferlinopathy-in-bla-j-mice
#5
Telmo Llanga, Nadia Nagy, Laura Conatser, Catherine Dial, R Bryan Sutton, Matthew L Hirsch
Dysferlinopathy is an autosomal recessive muscular dystrophy characterized by the progressive loss of motility that is caused by mutations throughout the DYSF gene. There are currently no approved therapies that ameliorate or reverse dysferlinopathy. Gene delivery using adeno-associated vectors (AAVs) is a leading therapeutic strategy for genetic diseases; however, the large size of dysferlin cDNA (6.2 kB) precludes packaging into a single AAV capsid. Therefore, using 3D structural modeling and hypothesizing dysferlin C2 domain redundancy, a 30% smaller, dysferlin-like molecule amenable to single AAV vector packaging was engineered (termed Nano-Dysferlin)...
June 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28629821/glycogen-reduction-in-myotubes-of-late-onset-pompe-disease-patients-using-antisense-technology
#6
Elisa Goina, Paolo Peruzzo, Bruno Bembi, Andrea Dardis, Emanuele Buratti
Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c...
June 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28625572/nanoparticle-technology-having-impact-but-needing-further-optimization
#7
EDITORIAL
S Moein Moghimi, Ernst Wagner
No abstract text is available yet for this article.
June 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28625570/progress-toward-fulfilling-the-potential-of-immunomodulation-in-childhood-neurodegeneration
#8
Jonathan D Cooper, Hemanth R Nelvagal
No abstract text is available yet for this article.
June 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28625571/micromanaging-tolerance-in-hemophilia-a-gene-therapy
#9
Jennielle Jobson, Brian D Brown
No abstract text is available yet for this article.
June 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28624262/dibenzazepine-loaded-nanoparticles-induce-local-browning-of-white-adipose-tissue-to-counteract-obesity
#10
Chunhui Jiang, Mario Alberto Cano-Vega, Feng Yue, Liangju Kuang, Naagarajan Narayanan, Gozde Uzunalli, Madeline P Merkel, Shihuan Kuang, Meng Deng
Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ)...
June 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28619647/using-crispr-cas9-to-generate-gene-corrected-autologous-ipscs-for-the-treatment-of-inherited-retinal-degeneration
#11
Erin R Burnight, Manav Gupta, Luke A Wiley, Kristin R Anfinson, Audrey Tran, Robinson Triboulet, Jeremy M Hoffmann, Darcey L Klaahsen, Jeaneen L Andorf, Chunhua Jiao, Elliott H Sohn, Malavika K Adur, Jason W Ross, Robert F Mullins, George Q Daley, Thorsten M Schlaeger, Edwin M Stone, Budd A Tucker
Patient-derived induced pluripotent stem cells (iPSCs) hold great promise for autologous cell replacement. However, for many inherited diseases, treatment will likely require genetic repair pre-transplantation. Genome editing technologies are useful for this application. The purpose of this study was to develop CRISPR-Cas9-mediated genome editing strategies to target and correct the three most common types of disease-causing variants in patient-derived iPSCs: (1) exonic, (2) deep intronic, and (3) dominant gain of function...
June 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28606376/enhanced-delivery-and-effects-of-acid-sphingomyelinase-by-icam-1-targeted-nanocarriers-in-type-b-niemann-pick-disease-mice
#12
Carmen Garnacho, Rajwinder Dhami, Melani Solomon, Edward H Schuchman, Silvia Muro
Acid sphingomyelinase deficiency in type B Niemann-Pick disease leads to lysosomal sphingomyelin storage, principally affecting lungs, liver, and spleen. Infused recombinant enzyme is beneficial, yet its delivery to the lungs is limited and requires higher dosing than liver and spleen, leading to potentially adverse reactions. Previous studies showed increased enzyme pulmonary uptake by nanocarriers targeted to ICAM-1, a protein overexpressed during inflammation. Here, using polystyrene and poly(lactic-co-glycolic acid) nanocarriers, we optimized lung delivery by varying enzyme dose and nanocarrier concentration, verified endocytosis and lysosomal trafficking in vivo, and evaluated delivered activity and effects...
June 9, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28606375/circulating-lipoproteins-a-trojan-horse-guiding-squalenoylated-drugs-to-ldl-accumulating-cancer-cells
#13
Dunja Sobot, Simona Mura, Marie Rouquette, Branko Vukosavljevic, Fanny Cayre, Eric Buchy, Grégory Pieters, Sébastien Garcia-Argote, Maike Windbergs, Didier Desmaële, Patrick Couvreur
Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both in vitro and in vivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression...
June 9, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28602436/car-t-cells-administered-in-combination-with-lymphodepletion-and-pd-1-inhibition-to-patients-with-neuroblastoma
#14
Andras Heczey, Chrystal U Louis, Barbara Savoldo, Olga Dakhova, April Durett, Bambi Grilley, Hao Liu, Mengfeng F Wu, Zhuyong Mei, Adrian Gee, Birju Mehta, Huimin Zhang, Nadia Mahmood, Haruko Tashiro, Helen E Heslop, Gianpietro Dotti, Cliona M Rooney, Malcolm K Brenner
Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor...
June 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28596114/successful-repeated-hepatic-gene-delivery-in-mice-and-non-human-primates-achieved-by-sequential-administration-of-aav5-ch-and-aav1
#15
Anna Majowicz, David Salas, Nerea Zabaleta, Estefania Rodríguez-Garcia, Gloria González-Aseguinolaza, Harald Petry, Valerie Ferreira
In the gene therapy field, re-administration of adeno-associated virus (AAV) is an important topic because a decrease in therapeutic protein expression might occur over time. However, an efficient re-administration with the same AAV serotype is impossible due to serotype-specific, anti-AAV neutralizing antibodies (NABs) that are produced after initial AAV treatment. To address this issue, we explored the feasibility of using chimeric AAV serotype 5 (AAV5(ch)) and AAV1 for repeated liver-targeted gene delivery...
June 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28578991/oncolytic-vsv-primes-differential-responses-to-immuno-oncology-therapy
#16
Nicholas M Durham, Kathy Mulgrew, Kelly McGlinchey, Noel R Monks, Hong Ji, Ronald Herbst, JoAnn Suzich, Scott A Hammond, Elizabeth J Kelly
Vesicular stomatitis virus encoding the IFNβ transgene (VSV-IFNβ) is a mediator of potent oncolytic activity and is undergoing clinical evaluation for the treatment of solid tumors. Emerging preclinical and clinical data suggest treatment of tumors with oncolytic viruses may sensitize tumors to checkpoint inhibitors and increase the anti-tumor immune response. New generations of immuno-oncology molecules including T cell agonists are entering clinical development and could be hypothesized to enhance the activity of oncolytic viruses, including VSV-IFNβ...
June 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28571917/targeting-mir-21-with-sophocarpine-inhibits-tumor-progression-and-reverses-epithelial-mesenchymal-transition-in-head-and-neck-cancer
#17
Wei Liu, Beilei Zhang, Guo Chen, Wenjiao Wu, Lin Zhou, Yaru Shi, Qi Zeng, Yanqiu Li, Youwei Sun, Xingming Deng, Fu Wang
A major challenge for cancer chemotherapy is the development of safe and clinically effective chemotherapeutic agents. With its low toxicity profile, sophocarpine (SC), a naturally occurring tetracyclic quinolizidine alkaloid derived from Sophora alopecuroides L, has shown promising therapeutic properties, including anti-inflammatory, anti-nociceptive, and antivirus activities. However, the antitumor efficacy of SC and its underlying mechanisms have not been completely delineated. In the present study, the inhibitory effect of SC on head and neck squamous cell carcinoma (HNSCC) progression and possible mechanisms for this effect involving microRNA-21 (miR-21) regulation were investigated...
May 29, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28566226/optimization-of-retinal-gene-therapy-for-x-linked-retinitis-pigmentosa-due-to-rpgr-mutations
#18
William A Beltran, Artur V Cideciyan, Shannon E Boye, Guo-Jie Ye, Simone Iwabe, Valerie L Dufour, Luis Felipe Marinho, Malgorzata Swider, Mychajlo S Kosyk, Jin Sha, Sanford L Boye, James J Peterson, C Douglas Witherspoon, John J Alexander, Gui-Shuang Ying, Mark S Shearman, Jeffrey D Chulay, William W Hauswirth, Paul D Gamlin, Samuel G Jacobson, Gustavo D Aguirre
X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is an early onset and severe cause of blindness. Successful proof-of-concept studies in a canine model have recently shown that development of a corrective gene therapy for RPGR-XLRP may now be an attainable goal. In preparation for a future clinical trial, we have here optimized the therapeutic AAV vector construct by showing that GRK1 (rather than IRBP) is a more efficient promoter for targeting gene expression to both rods and cones in non-human primates...
May 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28552407/a-novel-platform-for-immune-tolerance-induction-in-hemophilia-a-mice
#19
Simone Merlin, Elvira Stefania Cannizzo, Ester Borroni, Valentina Bruscaggin, Piercarla Schinco, Warut Tulalamba, Marinee K Chuah, Valder R Arruda, Thierry VandenDriessche, Maria Prat, Guido Valente, Antonia Follenzi
Hemophilia A (HA) is an X-linked bleeding disease caused by factor VIII (FVIII) deficiency. We previously demonstrated that FVIII is produced specifically in liver sinusoid endothelial cells (LSECs) and to some degree in myeloid cells, and thus, in the present work, we seek to restrict the expression of FVIII transgene to these cells using cell-specific promoters. With this approach, we aim to limit immune response in a mouse model by lentiviral vector (LV)-mediated gene therapy encoding FVIII. To increase the target specificity of FVIII expression, we included miRNA target sequences (miRTs) (i...
May 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28549772/codon-optimized-rpgr-improves-stability-and-efficacy-of-aav8-gene-therapy-in-two-mouse-models-of-x-linked-retinitis-pigmentosa
#20
M Dominik Fischer, Michelle E McClements, Cristina Martinez-Fernandez de la Camara, Julia-Sophia Bellingrath, Daniyar Dauletbekov, Simon C Ramsden, Doron G Hickey, Alun R Barnard, Robert E MacLaren
X-linked retinitis pigmentosa (XLRP) is generally a severe form of retinitis pigmentosa, a neurodegenerative, blinding disorder of the retina. 70% of XLRP cases are due to mutations in the retina-specific isoform of the gene encoding retinitis pigmentosa GTPase regulator (RPGR(ORF15)). Despite successful RPGR(ORF15) gene replacement with adeno-associated viral (AAV) vectors being established in a number of animal models of XLRP, progression to human trials has not yet been possible. The inherent sequence instability in the purine-rich region of RPGR(ORF15) (which contains highly repetitive nucleotide sequences) leads to unpredictable recombination errors during viral vector cloning...
May 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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