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

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https://www.readbyqxmd.com/read/30001913/genetic-rescue-reverses-microglial-activation-in-preclinical-models-of-retinitis-pigmentosa
#1
Lijuan Zhang, Xuan Cui, Ruben Jauregui, Karen Sophia Park, Sally Justus, Yi-Ting Tsai, Jimmy K Duong, Chun-Wei Hsu, Wen-Hsuan Wu, Christine L Xu, Chyuan-Sheng Lin, Stephen H Tsang
Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted...
June 21, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29937418/optimized-cholesterol-sirna-chemistry-improves-productive-loading-onto-extracellular-vesicles
#2
Reka Agnes Haraszti, Rachael Miller, Marie-Cecile Didiot, Annabelle Biscans, Julia F Alterman, Matthew R Hassler, Loic Roux, Dimas Echeverria, Ellen Sapp, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
Extracellular vesicles are promising delivery vesicles for therapeutic RNAs. Small interfering RNA (siRNA) conjugation to cholesterol enables efficient and reproducible loading of extracellular vesicles with the therapeutic cargo. siRNAs are typically chemically modified to fit an application. However, siRNA chemical modification pattern has not been specifically optimized for extracellular vesicle-mediated delivery. Here we used cholesterol-conjugated, hydrophobically modified asymmetric siRNAs (hsiRNAs) to evaluate the effect of backbone, 5'-phosphate, and linker chemical modifications on productive hsiRNA loading onto extracellular vesicles...
June 21, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29934254/highlighting-the-field-of-cardiovascular-regenerative-medicine
#3
EDITORIAL
Wolfram-Hubertus Zimmermann, Seppo Yla-Herttuala, Roger J Hajjar
No abstract text is available yet for this article.
June 19, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29929789/atorvastatin-inhibits-the-hif1%C3%AE-ppar-axis-which-is-essential-for-maintaining-the-function-of-human-induced-pluripotent-stem-cells
#4
Yoshiki Nakashima, Chika Miyagi-Shiohira, Hirofumi Noguchi, Takeshi Omasa
We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice...
June 19, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29929787/t%C3%AE-4-increases-neovascularization-and-cardiac-function-in-chronic-myocardial-ischemia-of-normo-and-hypercholesterolemic-pigs
#5
Tilman Ziegler, Andrea Bähr, Andrea Howe, Katharina Klett, Wira Husada, Christian Weber, Karl-Ludwig Laugwitz, Christian Kupatt, Rabea Hinkel
Translations of new therapeutic options for cardiovascular disease from animal studies into a clinical setting have been hampered, in part by an improper reflection of a relevant patient population in animal models. In this study, we investigated the impact of thymosin β4 (Tβ4), which promotes collateralization and capillarization, during hypercholesterolemia, a known risk factor of coronary artery disease. Initial in vitro results highlighted an improved endothelial cell function upon Tβ4 treatment under control conditions and during hypercholesterolemic stress (scratch area [pixels]: oxidized low-density lipoprotein [oxLDL], 191,924 ± 7,717; and oxLDL + Tβ4, 105,621 ± 11,245)...
July 5, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29929790/development-proliferation-and-growth-of-the-mammalian-heart
#6
REVIEW
Marie Günthel, Phil Barnett, Vincent M Christoffels
During development, the embryonic heart grows by addition of cells from a highly proliferative progenitor pool and by subsequent precisely controlled waves of cardiomyocyte proliferation. In this period, the heart can compensate for cardiomyocyte loss by an increased proliferation rate of the remaining cardiomyocytes. This proliferative capacity is lost soon after birth, with heart growth continuing by an increase in cardiomyocyte volume. The failure of the injured adult heart to regenerate often leads to the development of heart failure, a major cause of death...
June 18, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29929788/therapeutic-silencing-of-mir-214-inhibits-tumor-progression-in-multiple-mouse-models
#7
Daniela Dettori, Francesca Orso, Elisa Penna, Désirée Baruffaldi, Serena Brundu, Federica Maione, Emilia Turco, Enrico Giraudo, Daniela Taverna
We previously demonstrated that miR-214 is upregulated in malignant melanomas and triple-negative breast tumors and promotes metastatic dissemination by affecting a complex pathway including the anti-metastatic miR-148b. Importantly, tumor dissemination could be reduced by blocking miR-214 function or increasing miR-148b expression or by simultaneous interventions. Based on this evidence, with the intent to explore the role of miR-214 as a target for therapy, we evaluated the capability of new chemically modified anti-miR-214, R97/R98, to inhibit miR-214 coordinated metastatic traits...
June 18, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29914758/specific-inhibition-of-hepatic-lactate-dehydrogenase-reduces-oxalate-production-in-mouse-models-of-primary-hyperoxaluria
#8
Chengjung Lai, Natalie Pursell, Jessica Gierut, Utsav Saxena, Wei Zhou, Michael Dills, Rohan Diwanji, Chaitali Dutta, Martin Koser, Naim Nazef, Rachel Storr, Boyoung Kim, Cristina Martin-Higueras, Eduardo Salido, Weimin Wang, Marc Abrams, Henryk Dudek, Bob D Brown
Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end-stage renal disease. One promising strategy to treat PHs is to reduce the hepatic production of oxalate through substrate reduction therapy by inhibiting liver-specific glycolate oxidase (GO), which controls the conversion of glycolate to glyoxylate, the proposed main precursor to oxalate. Alternatively, diminishing the amount of hepatic lactate dehydrogenase (LDH) expression, the proposed key enzyme responsible for converting glyoxylate to oxalate, should directly prevent the accumulation of oxalate in PH patients...
June 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29914757/rnai-based-glun3a-silencing-prevents-and-reverses-disease-phenotypes-induced-by-mutant-huntingtin
#9
Sonia Marco, Alvaro Murillo, Isabel Pérez-Otaño
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs...
June 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29914756/age-related-impaired-efficacy-of-bone-marrow-cell-therapy-for-myocardial-infarction-reflects-a-decrease-in-b-lymphocytes
#10
Songtao An, Xiaoyin Wang, Melissa A Ruck, Hilda J Rodriguez, Dmitry S Kostyushev, Monika Varga, Emmy Luu, Ronak Derakhshandeh, Sergey V Suchkov, Scott C Kogan, Michelle L Hermiston, Matthew L Springer
Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes...
June 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29910177/a-single-multiplex-crrna-array-for-fncpf1-mediated-human-genome-editing
#11
Huihui Sun, Fanfan Li, Jie Liu, Fayu Yang, Zhenhai Zeng, Xiujuan Lv, Mengjun Tu, Yeqing Liu, Xianglian Ge, Changbao Liu, Junzhao Zhao, Zongduan Zhang, Jia Qu, Zongming Song, Feng Gu
Cpf1 has been harnessed as a tool for genome manipulation in various species because of its simplicity and high efficiency. Our recent study demonstrated that FnCpf1 could be utilized for human genome editing with notable advantages for target sequence selection due to the flexibility of the protospacer adjacent motif (PAM) sequence. Multiplex genome editing provides a powerful tool for targeting members of multigene families, dissecting gene networks, modeling multigenic disorders in vivo, and applying gene therapy...
June 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29910175/tlr4-binding-dna-aptamers-show-a-protective-effect-against-acute-stroke-in-animal-models
#12
Gerónimo Fernández, Ana Moraga, María I Cuartero, Alicia García-Culebras, Carolina Peña-Martínez, Jesús M Pradillo, Macarena Hernández-Jiménez, Silvia Sacristán, M Irene Ayuso, Rafael Gonzalo-Gobernado, David Fernández-López, M Elena Martín, María A Moro, Victor M González, Ignacio Lizasoain
Since Toll-like receptor 4 (TLR4) mediates brain damage after stroke, development of TLR4 antagonists is a promising therapeutic strategy for this disease. Our aim was to generate TLR4-blocking DNA aptamers to be used for stroke treatment. From a random oligonucleotide pool, we identified two aptamers (ApTLR#1R, ApTLR#4F) with high affinity for human TLR4 by systematic evolution of ligands by exponential enrichment (SELEX). Optimized truncated forms (ApTLR#1RT, ApTLR#4FT) were obtained. Our data demonstrate specific binding of both aptamers to human TLR4 as well as a TLR4 antagonistic effect...
June 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29910179/autologous-cd19-targeted-car-t-cells-in-patients-with-residual-cll-following-initial-purine-analog-based-therapy
#13
Mark B Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J Purdon, Meier Hsu, Sean M Devlin, Elizabeth Halton, Nicole Lamanna, Jurgen Rademaker, Michel Sadelain, Renier J Brentjens, Jae H Park
Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29910178/lipid-nanoparticle-delivered-chemically-modified-mrna-restores-chloride-secretion-in-cystic-fibrosis
#14
Ema Robinson, Kelvin D MacDonald, Kai Slaughter, Madison McKinney, Siddharth Patel, Conroy Sun, Gaurav Sahay
The promise of gene therapy for the treatment of cystic fibrosis has yet to be fully clinically realized despite years of effort toward correcting the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR). mRNA therapy via nanoparticle delivery represents a powerful technology for the transfer of genetic material to cells with large, widespread populations, such as airway epithelia. We deployed a clinically relevant lipid-based nanoparticle (LNP) for packaging and delivery of large chemically modified CFTR mRNA (cmCFTR) to patient-derived bronchial epithelial cells, resulting in an increase in membrane-localized CFTR and rescue of its primary function as a chloride channel...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29910176/emapii-monoclonal-antibody-ameliorates-influenza-a-virus-induced-lung-injury
#15
Hongyan Lu, Sarvesh Chelvanambi, Christophe Poirier, Jacob Saliba, Keith L March, Matthias Clauss, Natalia V Bogatcheva
Influenza A virus (IAV) remains a major worldwide health threat, especially to high-risk populations, including the young and elderly. There is an unmet clinical need for therapy that will protect the lungs from damage caused by lower respiratory infection. Here, we analyzed the role of EMAPII, a stress- and virus-induced pro-inflammatory and pro-apoptotic factor, in IAV-induced lung injury. First, we demonstrated that IAV induces EMAPII surface translocation, release, and apoptosis in cultured endothelial and epithelial cells...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29908843/mir-210-enhances-the-therapeutic-potential-of-bone-marrow-derived-circulating-proangiogenic-cells-in-the-setting-of-limb-ischemia
#16
Marie Besnier, Stefano Gasparino, Rosa Vono, Elena Sangalli, Amanda Facoetti, Valentina Bollati, Laura Cantone, Germana Zaccagnini, Biagina Maimone, Paola Fuschi, Daniel Da Silva, Michele Schiavulli, Sezin Aday, Massimo Caputo, Paolo Madeddu, Costanza Emanueli, Fabio Martelli, Gaia Spinetti
Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29861327/piggybac-engineered-t-cells-expressing-cd19-specific-cars-that-lack-igg1-fc-spacers-have-potent-activity-against-b-all-xenografts
#17
David C Bishop, Ning Xu, Benjamin Tse, Tracey A O'Brien, David J Gottlieb, Alla Dolnikov, Kenneth P Micklethwaite
Clinical trials of CD19-specific chimeric antigen receptor (CAR19) T cells have demonstrated remarkable efficacy against relapsed and refractory B cell malignancies. The piggyBac transposon system offers a less complex and more economical means for generating CAR19 T cells compared to viral vectors. We have previously optimized a protocol for the generation of CAR19 T cells using the piggyBac system, but we found that CAR19 T cells had poor in vivo efficacy and persistence, probably due to deleterious FcγR interactions with the CAR's IgG1 Fc-containing spacer domain...
June 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29853274/rapid-and-complete-reversal-of-sensory-ataxia-by-gene-therapy-in-a-novel-model-of-friedreich-ataxia
#18
Françoise Piguet, Charline de Montigny, Nadège Vaucamps, Laurence Reutenauer, Aurélie Eisenmann, Hélène Puccio
Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency...
May 28, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29843955/microrna-148b-targets-the-tgf-%C3%AE-pathway-to-regulate-angiogenesis-and-endothelial-to-mesenchymal-transition-during-skin-wound-healing
#19
Vladislav Miscianinov, Andrea Martello, Lorraine Rose, Elisa Parish, Ben Cathcart, Tijana Mitić, Gillian A Gray, Marco Meloni, Ayman Al Haj Zen, Andrea Caporali
Transforming growth factor beta (TGF-β) is crucial for regulation of the endothelial cell (EC) homeostasis. Perturbation of TGF-β signaling leads to pathological conditions in the vasculature, causing cardiovascular disease and fibrotic disorders. The TGF-β pathway is critical in endothelial-to-mesenchymal transition (EndMT), but a gap remains in our understanding of the regulation of TGF-β and related signaling in the endothelium. This study applied a gain- and loss-of function approach and an in vivo model of skin wound healing to demonstrate that miR-148b regulates TGF-β signaling and has a key role in EndMT, targeting TGFB2 and SMAD2...
May 8, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29804932/therapeutic-benefit-of-autophagy-modulation-in-pompe-disease
#20
Jeong-A Lim, Baodong Sun, Rosa Puertollano, Nina Raben
The complexity of the pathogenic cascade in lysosomal storage disorders suggests that combination therapy will be needed to target various aspects of pathogenesis. The standard of care for Pompe disease (glycogen storage disease type II), a deficiency of lysosomal acid alpha glucosidase, is enzyme replacement therapy (ERT). Many patients have poor outcomes due to limited efficacy of the drug in clearing muscle glycogen stores. The resistance to therapy is linked to massive autophagic buildup in the diseased muscle...
May 3, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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