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

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https://www.readbyqxmd.com/read/29103909/rna-aptamers-recognizing-murine-ccl17-inhibit-t-cell-chemotaxis-and-reduce-contact-hypersensitivity-in%C3%A2-vivo
#1
Lorenz Fülle, Nancy Steiner, Markus Funke, Fabian Gondorf, Franziska Pfeiffer, Julia Siegl, Friederike V Opitz, Silvana K Haßel, Anna Belen Erazo, Oliver Schanz, H James Stunden, Michael Blank, Carsten Gröber, Kristian Händler, Marc Beyer, Heike Weighardt, Eicke Latz, Joachim L Schultze, Günter Mayer, Irmgard Förster
The chemokine CCL17, mainly produced by dendritic cells (DCs) in the immune system, is involved in the pathogenesis of various inflammatory diseases. As a ligand of CCR4, CCL17 induces chemotaxis and facilitates T cell-DC interactions. We report the identification of two novel RNA aptamers, which were validated in vitro and in vivo for their capability to neutralize CCL17. Both aptamers efficiently inhibited the directed migration of the CCR4(+) lymphoma line BW5147.3 toward CCL17 in a dose-dependent manner...
October 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29103911/cyclic-peptides-to-improve-delivery-and-exon-skipping-of-antisense-oligonucleotides-in-a-mouse-model-for-duchenne-muscular-dystrophy
#2
Silvana M G Jirka, Peter A C 't Hoen, Valeriano Diaz Parillas, Christa L Tanganyika-de Winter, Ruurd C Verheul, Begona Aguilera, Peter C de Visser, Annemieke M Aartsma-Rus
Duchenne muscular dystrophy (DMD) is a severe, progressive muscle wasting disorder caused by reading frame disrupting mutations in the DMD gene. Exon skipping is a therapeutic approach for DMD. It employs antisense oligonucleotides (AONs) to restore the disrupted open reading frame, allowing the production of shorter, but partly functional dystrophin protein as seen in less severely affected Becker muscular dystrophy patients. To be effective, AONs need to be delivered and effectively taken up by the target cells, which can be accomplished by the conjugation of tissue-homing peptides...
October 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29103910/nanotherapeutics-for-gene-modulation-that-prevents-apoptosis-in-the-brain-and-fatal-neuroinflammation
#3
Sang-Soo Kim, Antonina Rait, Emilio R Garrido-Sanabria, Kathleen F Pirollo, Joe B Harford, Esther H Chang
The failure of therapeutic agents to cross the blood-brain barrier (BBB) has been a major impediment in the treatment of neurological disorders and brain tumors. We have addressed this issue using an immunoliposome nanocomplex (designated scL) that delivers therapeutic nucleic acids across the BBB into the deep brain via transcytosis mediated by transferrin receptors. We validated brain delivery of payloads after systemic administration by monitoring uptake of fluorescently labeled payloads and by confirming up- or down-modulation of specific target gene expression in the brain, mainly in neuronal cells...
October 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29107477/contribution-of-implanted-genetically-modified-muscle-progenitor-cells-expressing-bmp-2-to-new-bone-formation-in-a-rat-osseous-defect
#4
Rodolfo E De La Vega, Consuelo Lopez De Padilla, Miguel Trujillo, Nicholas Quirk, Ryan M Porter, Christopher H Evans, Elisabeth Ferreira
Because muscle contains osteoprogenitor cells and has a propensity to form bone, we have explored its utility in healing large osseous defects. Healing is achieved by the insertion of muscle fragments transduced with adenovirus encoding BMP-2 (Ad.BMP-2). However, it is not known whether the genetically modified muscle contributes osteoprogenitor cells to healing defects or merely serves as a local source of BMP-2. This question is part of the larger debate on the fate of progenitor cells introduced into sites of tissue damage to promote regeneration...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29103912/optimization-of-il13r%C3%AE-2-targeted-chimeric-antigen-receptor-t-cells-for-improved-anti-tumor-efficacy-against-glioblastoma
#5
Christine E Brown, Brenda Aguilar, Renate Starr, Xin Yang, Wen-Chung Chang, Lihong Weng, Brenda Chang, Aniee Sarkissian, Alfonso Brito, James F Sanchez, Julie R Ostberg, Massimo D'Apuzzo, Behnam Badie, Michael E Barish, Stephen J Forman
T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8(+) T cells that had shown evidence for bioactivity in patients...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29102563/tgf-%C3%AE-mediates-renal-fibrosis-via-the-smad3-erbb4-ir-long-noncoding-rna-axis
#6
Min Feng, Patrick Ming-Kuen Tang, Xiao-Ru Huang, Si-Fan Sun, Yong-Ke You, Jun Xiao, Lin-Li Lv, An-Ping Xu, Hui-Yao Lan
Transforming growth factor β (TGF-β)/Smad3 signaling plays a role in tissue fibrosis. We report here that Erbb4-IR is a novel long non-coding RNA (lncRNA) responsible for TGF-β/Smad3-mediated renal fibrosis and is a specific therapeutic target for chronic kidney disease. Erbb4-IR was induced by TGF-β1 via a Smad3-dependent mechanism and was highly upregulated in the fibrotic kidney of mouse unilateral ureteral obstructive nephropathy (UUO). Silencing Erbb4-IR blocked TGF-β1-induced collagen I and alpha-smooth muscle actin (α-SMA) expressions in vitro and effectively attenuated renal fibrosis in the UUO kidney by blocking TGF-β/Smad3 signaling...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29102562/prostaglandin-e2-increases-lentiviral-vector-transduction-efficiency-of-adult-human-hematopoietic-stem-and-progenitor-cells
#7
Garrett C Heffner, Melissa Bonner, Lauryn Christiansen, Francis J Pierciey, Dakota Campbell, Yegor Smurnyy, Wenliang Zhang, Amanda Hamel, Seema Shaw, Gretchen Lewis, Kendrick A Goss, Olivia Garijo, Bruce E Torbett, Holly Horton, Mitchell H Finer, Philip D Gregory, Gabor Veres
Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34(+) hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E2 (PGE2) as a positive mediator of lentiviral transduction of CD34(+) cells. Supplementation with PGE2 increased lentiviral vector (LVV) transduction of CD34(+) cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34(+) cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29066165/stem-cell-secretome-and-its-effect-on-cellular-mechanisms-relevant-to-wound-healing
#8
Se-Ra Park, Jae-Wan Kim, Hee-Sook Jun, Joo Young Roh, Hwa-Yong Lee, In-Sun Hong
Stem cells introduced to site of injury primarily act via indirect paracrine effects rather than direct cell replacement of damaged cells. This gives rise to understanding the stem cell secretome. In this study, in vitro studies demonstrate that the secretome activates the PI3K/Akt or FAK/ERK1/2 signaling cascades and subsequently enhances the proliferative and migratory abilities of various types of skin cells, such as fibroblasts, keratinocytes, and vascular epithelial cells, ultimately accelerating wound contraction...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29055623/targeting-of-cell-surface-proteolysis-of-collagen-xvii-impedes-squamous-cell-carcinoma-progression
#9
Célimène Galiger, Stefanie Löffek, Marc P Stemmler, Jasmin K Kroeger, Venugopal R Mittapalli, Lisa Fauth, Philipp R Esser, Johannes S Kern, Frank Meiss, Silke Laßmann, Leena Bruckner-Tuderman, Claus-Werner Franzke
Squamous cell carcinoma (SCC) is one of the most common skin cancers and causes significant morbidity. Although the expression of the epithelial adhesion molecule collagen XVII (ColXVII) has been linked to SCC invasion, only little is known about its mechanistic contribution. Here, we demonstrate that ColXVII expression is essential for SCC cell proliferation and motility. Moreover, it revealed that particularly the post-translational modification of ColXVII by ectodomain shedding is the major driver of SCC progression, because ectodomain-selective immunostaining was mainly localized at the invasive front of human cutaneous SCCs, and exclusive expression of a non-sheddable ColXVII mutant in SCC-25 cells inhibits their matrix-independent growth and invasiveness...
September 27, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29055620/bioengineered-aav-capsids-with-combined-high-human-liver-transduction-in%C3%A2-vivo-and-unique-humoral-seroreactivity
#10
Nicole K Paulk, Katja Pekrun, Erhua Zhu, Sean Nygaard, Bin Li, Jianpeng Xu, Kirk Chu, Christian Leborgne, Allison P Dane, Annelise Haft, Yue Zhang, Feijie Zhang, Chris Morton, Marcus B Valentine, Andrew M Davidoff, Amit C Nathwani, Federico Mingozzi, Markus Grompe, Ian E Alexander, Leszek Lisowski, Mark A Kay
Existing recombinant adeno-associated virus (rAAV) serotypes for delivering in vivo gene therapy treatments for human liver diseases have not yielded combined high-level human hepatocyte transduction and favorable humoral neutralization properties in diverse patient groups. Yet, these combined properties are important for therapeutic efficacy. To bioengineer capsids that exhibit both unique seroreactivity profiles and functionally transduce human hepatocytes at therapeutically relevant levels, we performed multiplexed sequential directed evolution screens using diverse capsid libraries in both primary human hepatocytes in vivo and with pooled human sera from thousands of patients...
September 25, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28958577/targeting-of-aberrant-%C3%AE-v%C3%AE-6-integrin-expression-in-solid-tumors-using-chimeric-antigen-receptor-engineered-t-cells
#11
Lynsey M Whilding, Ana C Parente-Pereira, Tomasz Zabinski, David M Davies, Roseanna M G Petrovic, Y Vincent Kao, Shobhit A Saxena, Alex Romain, Jose A Costa-Guerra, Shelia Violette, Hiroaki Itamochi, Sadaf Ghaem-Maghami, Sabari Vallath, John F Marshall, John Maher
No abstract text is available yet for this article.
September 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29050872/manf-promotes-differentiation-and-migration-of-neural-progenitor-cells-with-potential-neural-regenerative-effects-in-stroke
#12
Kuan-Yin Tseng, Jenni E Anttila, Konstantin Khodosevich, Raimo K Tuominen, Maria Lindahl, Andrii Domanskyi, Mikko Airavaara
Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration...
September 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29033008/safety-and-long-term-efficacy-of-aav4-gene-therapy-in-patients-with-rpe65-leber-congenital-amaurosis
#13
Guylène Le Meur, Pierre Lebranchu, Fanny Billaud, Oumeya Adjali, Sébastien Schmitt, Stéphane Bézieau, Yann Péréon, Romain Valabregue, Catherine Ivan, Christophe Darmon, Philippe Moullier, Fabienne Rolling, Michel Weber
The aim of this study was the evaluation of the safety and efficacy of unilateral subretinal injection of the adeno-associated vector (AAV) serotypes 2 and 4 (AAV2/4) RPE65-RPE65 vector in patients with Leber congenital amaurosis (LCA) associated with RPE65 gene deficiency. We evaluated ocular and general tolerance and visual function up to 1 year after vector administration in the most severely affected eye in nine patients with retinal degeneration associated with mutations in the RPE65 gene. Patients received either low (1...
September 19, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28943274/gene-therapy-induced-antigen-specific-tregs-inhibit-neuro-inflammation-and-reverse-disease-in-a-mouse-model-of-multiple-sclerosis
#14
Geoffrey D Keeler, Sandeep Kumar, Brett Palaschak, Emily L Silverberg, David M Markusic, Noah T Jones, Brad E Hoffman
The devastating neurodegenerative disease multiple sclerosis (MS) could substantially benefit from an adeno-associated virus (AAV) immunotherapy designed to restore a robust and durable antigen-specific tolerance. However, developing a sufficiently potent and lasting immune-regulatory therapy that can intervene in ongoing disease is a major challenge and has thus been elusive. We addressed this problem by developing a highly effective and robust tolerance-inducing in vivo gene therapy. Using a pre-clinical animal model, we designed a liver-targeting gene transfer vector that expresses full-length myelin oligodendrocyte glycoprotein (MOG) in hepatocytes...
September 19, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28988714/genome-wide-mapping-of-off-target-events-in-single-stranded-oligodeoxynucleotide-mediated-gene-repair-experiments
#15
Sarah Radecke, Klaus Schwarz, Frank Radecke
Short single-stranded oligodeoxynucleotides are versatile molecular tools used in different applications. They enable gene repair and genome editing, and they are central to the antisense technology. Because the usability of single-stranded oligodeoxynucleotides depends on their efficiencies, as well as their specificities, analyzing their genotoxic off-target activities is important. Thus, we have developed a protocol that follows the fate of a biotin-labeled single-stranded oligodeoxynucleotide in human cells based on its physical incorporation into the targeted genome...
September 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28988712/antimicrobial-peptide-combined-with-bmp2-modified-mesenchymal-stem-cells-promotes-calvarial-repair-in-an-osteolytic-model
#16
Zunpeng Liu, Xue Yuan, Min Liu, Gabriela Fernandes, Yejia Zhang, Shuting Yang, Ciprian N Ionita, Shuying Yang
Repair and regeneration of inflammation-induced bone loss remains a clinical challenge. LL37, an antimicrobial peptide, plays critical roles in cell migration, cytokine production, apoptosis, and angiogenesis. Migration of stem cells to the affected site and promotion of vascularization are essential for tissue engineering therapy, including bone regeneration. However, it is largely unknown whether LL37 affects mesenchymal stem cell (MSC) behavior and bone morphogenetic protein 2 (BMP2)-mediated bone repair during the bone pathologic remodeling process...
September 14, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29037594/epigenetic-modification-of-microrna-200b-contributes-to-diabetic-vasculopathy
#17
Kanhaiya Singh, Durba Pal, Mithun Sinha, Subhadip Ghatak, Surya C Gnyawali, Savita Khanna, Sashwati Roy, Chandan K Sen
Hyperglycemia (HG) induces genome-wide cytosine demethylation. Our previous work recognized miR-200b as a critical angiomiR, which must be transiently downregulated to initiate wound angiogenesis. Under HG, miR-200b downregulation is not responsive to injury. Here, we demonstrate that HG may drive vasculopathy by epigenetic modification of a miR promoter. In human microvascular endothelial cells (HMECs), HG also lowered DNA methyltransferases (DNMT-1 and DNMT-3A) and compromised endothelial function as manifested by diminished endothelial nitric oxide (eNOS), lowered LDL uptake, impaired Matrigel tube formation, lower NO production, and compromised VE-cadherin expression...
September 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28970045/absence-of-replication-competent-lentivirus-in-the-clinic-analysis-of-infused-t-cell-products
#18
Kenneth Cornetta, Lisa Duffy, Cameron J Turtle, Michael Jensen, Stephen Forman, Gwendolyn Binder-Scholl, Terry Fry, Anne Chew, David G Maloney, Carl H June
Exposure to replication-competent lentivirus (RCL) is a theoretical safety concern for individuals treated with lentiviral gene therapy. For certain ex vivo gene therapy applications, including cancer immunotherapy trials, RCL detection assays are used to screen the vector product as well as the vector-transduced cells. In this study, we reviewed T cell products screened for RCL using methodology developed in the National Gene Vector Biorepository. All trials utilized third-generation lentiviral vectors produced by transient transfection...
September 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28988713/otx2-genetically-modified-retinal-pigment-epithelial-cells-rescue-photoreceptors-after-transplantation
#19
Christo Kole, Laurence Klipfel, Ying Yang, Vanessa Ferracane, Frederic Blond, Sacha Reichman, Géraldine Millet-Puel, Emmanuelle Clérin, Najate Aït-Ali, Delphine Pagan, Hawa Camara, Marie-Noëlle Delyfer, Emeline F Nandrot, Jose-Alain Sahel, Olivier Goureau, Thierry Léveillard
Inherited retinal degenerations are blinding diseases characterized by the loss of photoreceptors. Their extreme genetic heterogeneity complicates treatment by gene therapy. This has motivated broader strategies for transplantation of healthy retinal pigmented epithelium to protect photoreceptors independently of the gene causing the disease. The limited clinical benefit for visual function reported up to now is mainly due to dedifferentiation of the transplanted cells that undergo an epithelial-mesenchymal transition...
September 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28988711/in%C3%A2-vivo-selection-of-a-computationally-designed-schema-aav-library-yields-a-novel-variant-for-infection-of-adult-neural-stem-cells-in-the-svz
#20
David S Ojala, Sabrina Sun, Jorge L Santiago-Ortiz, Mikhail G Shapiro, Philip A Romero, David V Schaffer
Directed evolution continues to expand the capabilities of complex biomolecules for a range of applications, such as adeno-associated virus vectors for gene therapy; however, advances in library design and selection strategies are key to develop variants that overcome barriers to clinical translation. To address this need, we applied structure-guided SCHEMA recombination of the multimeric adeno-associated virus (AAV) capsid to generate a highly diversified chimeric library with minimal structural disruption...
September 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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