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Gene Therapy

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https://www.readbyqxmd.com/read/28024081/deletion-of-the-gaa-repeats-from-the-human-frataxin-gene-using-the-crispr-cas9-system-in-yg8r-derived-cells-and-mouse-models-of-friedreich-ataxia
#1
D L Ouellet, K Cherif, J Rousseau, J P Tremblay
The Friedreich ataxia is a monogenic disease due to a hyperexpanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo...
January 19, 2017: Gene Therapy
https://www.readbyqxmd.com/read/27996967/late-responses-to-adenoviral-mediated-transfer-of-the-aquaporin-1-gene-for-radiation-induced-salivary-hypofunction
#2
I Alevizos, C Zheng, A P Cotrim, S Liu, L McCullagh, M E Billings, C M Goldsmith, M Tandon, E J Helmerhorst, M A Catalán, S J Danielides, P Perez, N P Nikolov, J A Chiorini, J E Melvin, F G Oppenheim, G G Illei, B J Baum
We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events...
January 19, 2017: Gene Therapy
https://www.readbyqxmd.com/read/27996966/adenovirus-mediated-foxp3-expression-in-lung-epithelial-cells-ameliorates-acute-radiation-induced-pneumonitis-in-mice
#3
D Shin, G Lee, S Lee, S Park, K-H Jung, J H Lee, J M Lee, J-Y Kim, J Cho, H Bae
Forkhead transcription factor 3 (Foxp3) has a critical role in regulatory T cells (Treg). There are an increasing number of researches concerning the functions of Foxp3 in other cells, including lung epithelial cells besides Treg. However, the roles of Foxp3 in lung epithelial cells remain poorly understood. To examine the potential therapeutic benefits of Foxp3 for lung inflammation, this study investigates the effect of adenovirus-mediated Foxp3 overexpression in a radiation-induced lung damage model. Foxp3-EGFP expressing adenovirus was administered by intratracheal injection three times over 14 days after focal X-ray irradiation...
January 19, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28094775/nanotechnologies-in-delivery-of-mrna-therapeutics-using-nonviral-vector-based-delivery-systems
#4
REVIEW
S Guan, J Rosenecker
Due to its safe and effective protein expression profile, in vitro transcribed messenger RNA (IVT-mRNA) represents a promising candidate in the development of novel therapeutics for genetic diseases, vaccines or gene editing strategies, especially when its inherent shortcomings (e.g. instability and immunogenicity) have been partially addressed via structural modifications. However, numerous unsolved technical difficulties in successful in vivo delivery of IVT-mRNA have greatly hindered the applications of IVT-mRNA in clinical development...
January 17, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28079862/extra-neuronal-pathology-in-a-canine-model-of-cln2-neuronal-ceroid-lipofuscinosis-after-intracerebroventricular-gene-therapy-that-delays-neurological-disease-progression
#5
M L Katz, G C Johnson, S B Leach, B G Williamson, J R Coates, R E H Whiting, D P Vansteenkiste, M S Whitney
CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1 which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of lifespan...
January 12, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28079048/delivering-efficient-liver-directed-aav-mediated-gene-therapy
#6
J Baruteau, S N Waddington, I E Alexander, P Gissen
No abstract text is available yet for this article.
January 12, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28075429/telomerase-specific-oncolytic-adenovirus-expressing-trail-suppresses-peritoneal-dissemination-of-gastric-cancer
#7
W Zhou, S Dai, H Zhu, Z Song, Z Han, Y Cai, J B Lee, Z Li, X Hu, B Fang, C He, X Huang
Peritoneal dissemination is the most common condition of metastasis in gastric cancer. The survival duration of a patient with advanced stage gastric cancer, may be improved by gene therapy. In this study, we used an oncolytic adenovirus vector (Ad/TRAIL-E1) that expresses both the TRAIL and E1A genes under the control of a tumor-specific promoter. We evaluated the anti-tumor effect of Ad/TRAIL-E1 on gastric cancer cells in vitro, as well as in vivo in a xenograft peritoneal carcinomatosis mouse model. Our data showed that Ad/TRAIL-E1 induced TRAIL-mediated apoptosis in gastric cancer cell lines, but not in the normal cell lines...
January 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28075428/balanced-secretion-of-anti-cea-x-anti-cd3-diabody-chains-using-the-2a-self-cleaving-peptide-maximizes-diabody-assembly-and-tumor-specific-cytotoxicity
#8
K Mølgaard, M Compte, N Nuñez-Prado, S L Harwood, L Sanz, L Alvarez-Vallina
Adoptive transfer of genetically engineered human cells secreting bispecific T cell engagers has shown encouraging therapeutic effects in preclinical models of cancer. However, reducing the toxicity and improving the effectiveness of this emerging immunotherapeutic strategy will be critical to its successful application. We have demonstrated that for gene-based bispecific antibody strategies, two-chain diabodies have a better safety profile than single-chain tandem scFvs, because their reduced tendency to form aggregates reduces the risk of inducing antigen-independent T cell activation...
January 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28054582/gene-therapy-approaches-for-prevention-of-retinal-degeneration-in-usher-syndrome
#9
D S Williams, A Chadha, R Hazim, D Gibbs
No abstract text is available yet for this article.
January 5, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28054581/do-we-need-marker-gene-studies-in-humans-to-improve-clinical-aav-gene-therapy
#10
T Weber
No abstract text is available yet for this article.
January 5, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28024082/evidence-for-the-in-vivo-safety-of-insulated-foamy-viral-vectors
#11
D L Browning, E M Everson, D J Leap, J D Hocum, H Wang, G Stamatoyannopoulos, G D Trobridge
Retroviral vector mediated stem cell gene therapy is a promising approach for the treatment of hematopoietic disorders. However, genotoxic side effects from integrated vector proviruses are a significant concern for the use of retroviral vectors in the clinic. Insulated foamy viral (FV) vectors are potentially safer retroviral vectors for hematopoietic stem cell gene therapy. We evaluated two newly identified human insulators, A1 and A2 for use in FV vectors. These insulators had moderate insulating capacity and higher titers than previously developed insulated FV vectors...
December 26, 2016: Gene Therapy
https://www.readbyqxmd.com/read/28004656/co-delivery-of-indoleamine-2-3-dioxygenase-prevents-loss-of-expression-of-an-antigenic-transgene-in-dystrophic-mouse-muscles
#12
D Sharma, R Al-Khalidi, S Edgar, Q An, Y Wang, C Young, D Nowis, D C Gorecki
A significant problem affecting gene therapy approaches aiming at achieving long-term transgene expression is the immune response against the protein product of the therapeutic gene, which can reduce or eliminate the therapeutic effect. The problem is further exacerbated when therapy involves targeting an immunogenic tissue and/or one with a pre-existing inflammatory phenotype, such as dystrophic muscles. In this proof-of-principle study, we co-expressed a model antigen, bacterial β-galactosidase, with an immunosuppressive factor, indoleamine 2,3-dioxygenase 1 (IDO1), in muscles of the mdx mouse model of Duchenne muscular dystrophy...
December 22, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27834948/the-antitumor-efficacy-of-anti-p21ras-scfv-mediated-by-the-dual-promoter-regulated-recombinant-adenovirus-kghv300
#13
X Y Pan, X J Liu, J Li, S J Zhen, D X Liu, Q Feng, W X Zhao, Y Luo, Y L Zhang, H W Li, J L Yang
Ras mutations and overexpression of the Ras protein, p21Ras, are main causes of cancer development and progression, which has made the Ras gene and p21Ras important targets for therapy of Ras-driven cancers. We previously prepared recombinant adenovirus KGHV100 based on replication-defective adenovirus type 5, which could intracellularly express anti-p21Ras single chain fragment viable antibodies (scFv) and repress tumor growth in vitro and in vivo. However, the anti-tumor effects of this anti-p21Ras scFv were limited by short-term scFv expression due to a replication defect of KGHV100...
December 22, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27983718/adeno-associated-virus-mediated-expression-of-myostatin-propeptide-improves-the-growth-of-skeletal-muscle-and-attenuates-hyperglycemia-in-db-db-mice
#14
J Jiang, G Shen, J Li, C Qiao, B Xiao, H Yan, D W Wang, Xiao Xiao
Inhibition of myostatin, a negative growth modulator for muscle, can functionally enhance muscle mass and improve glucose and fat metabolism in myostatin propeptide (MPRO) transgenic mice. This study was to investigate whether myostatin inhibition by adeno-associated virus (AAV) mediated gene delivery of MPRO could improve muscle mass and achieve therapeutic effects on glucose regulation and lipid metabolism in the db/db mice and the mechanisms involved in that process. Eight-week-old male db/db mice were administered saline, AAV-GFP, AAV-MPRO/Fc vectors and monitored random blood glucose levels and body weight for 36 weeks...
December 16, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27824330/effect-of-sustained-pdgf-nonviral-gene-delivery-on-repair-of-tooth-supporting-bone-defects
#15
A B Plonka, B Khorsand, N Yu, J V Sugai, A K Salem, W V Giannobile, S Elangovan
Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) promotes soft tissue and bone healing, and is Food and Drug Administration-approved for treatment of diabetic ulcers and periodontal defects. The short half-life of topical rhPDGF-BB protein application necessitates bolus, high-dose delivery. Gene therapy enables sustained local growth factor production. A novel gene activated matrix delivering polyplexes of polyethylenimine (PEI)-plasmid DNA encoding PDGF was evaluated for promotion of periodontal wound repair in vivo...
December 8, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27906162/activation-of-myeloid-and-endothelial-cells-by-cd40l-gene-therapy-supports-t-cell-expansion-and-migration-into-the-tumor-microenvironment
#16
E Eriksson, R Moreno, I Milenova, L Liljenfeldt, L C Dieterich, L Christiansson, H Karlsson, G Ullenhag, S Mangsbo, A Dimberg, R Alemany, A Loskog
CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate Th1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer...
December 1, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27858942/interferon-beta-overexpression-attenuates-adipose-tissue-inflammation-and-high-fat-diet-induced-obesity-and-maintains-glucose-homeostasis
#17
M Alsaggar, M Mills, D Liu
The worldwide prevalence of obesity is increasing, raising health concerns regarding obesity-related complications. Chronic inflammation has been characterized as a major contributor to the development of obesity and obesity-associated metabolic disorders. The purpose of the current study is to assess whether the overexpression of interferon beta (IFNβ1), an immune-modulating cytokine, will attenuate high-fat diet-induced adipose inflammation and protect animals against obesity development. Using hydrodynamic gene transfer to elevate and sustain blood concentration of IFNβ1 in mice fed a high-fat diet, we showed that the overexpression of Ifnβ1 gene markedly suppressed immune cell infiltration into adipose tissue, and attenuated production of pro-inflammatory cytokines...
December 1, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27834949/direct-interaction-of-human-serum-proteins-with-aav-virions-to-enhance-aav-transduction-immediate-impact-on-clinical-applications
#18
M Wang, J Sun, A Crosby, K Woodard, M L Hirsch, R J Samulski, C Li
Recent hemophilia B clinical trials using adeno-associated virus (AAV) gene delivery have demonstrated much lower coagulation factor IX (FIX) production in patients compared with the high levels observed in animal models and AAV capsid-specific cytotoxic T lymphocyte response elicited at high doses of AAV vectors. These results emphasize the necessity to explore effective approaches for enhancement of AAV transduction. Initially, we found that incubation of all AAV vectors with human serum enhanced AAV transduction...
December 1, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27797355/non-viral-delivery-of-genome-editing-nucleases-for-gene-therapy
#19
REVIEW
M Wang, Z A Glass, Q Xu
Manipulating the genetic makeup of mammalian cells using programmable nuclease-based genome-editing technology has recently evolved into a powerful avenue that holds great potential for treating genetic disorders. There are four types of genome-editing nucleases, including meganucleases, zinc finger nucleases, transcription activator-like effector nucleases and clustered, regularly interspaced, short palindromic repeat-associated nucleases such as Cas9. These nucleases have been harnessed to introduce precise and specific changes of the genome sequence at virtually any genome locus of interest...
December 1, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27779616/prime-boost-using-separate-oncolytic-viruses-in-combination-with-checkpoint-blockade-improves-anti-tumour-therapy
#20
E Ilett, T Kottke, J Thompson, K Rajani, S Zaidi, L Evgin, M Coffey, C Ralph, R Diaz, H Pandha, K Harrington, P Selby, R Bram, A Melcher, R Vile
The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity...
December 1, 2016: Gene Therapy
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