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Gene Therapy

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https://www.readbyqxmd.com/read/28346436/detailed-comparison-of-retroviral-vectors-and-promoter-configurations-for-stable-and-high-transgene-expression-in-human-induced-pluripotent-stem-cells
#1
D Hoffmann, J W Schott, F K Geis, L Lange, F-J Müller, D Lenz, D Zychlinski, D Steinemann, M Morgan, T Moritz, A Schambach
Correction of patient-specific induced pluripotent stem cells (iPSC) upon gene delivery through retroviral vectors offers new treatment perspectives for monogenetic diseases. Gene-modified iPSC clones can be screened for safe integration sites and differentiated into transplantable cells of interest. However, the current bottleneck is epigenetic vector silencing. In order to identify the most suitable retroviral expression system in iPSC, we systematically compared vectors from different retroviral genera, different promoters and their combination with ubiquitous chromatin opening elements (UCOE), and several envelope pseudotypes...
March 27, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28346435/aav9-mediated-engineering-of-autotransplanted-kidney-of-non-human-primates
#2
S Tomasoni, P Trionfini, N Azzollini, L Zentilin, M Giacca, S Aiello, L Longaretti, E Cozzi, N Baldan, G Remuzzi, A Benigni
Ex vivo gene transfer to the graft before transplantation is an attractive option for circumventing systemic side effects of chronic anti-rejection therapy. Gene delivery of the immunomodulatory protein CTLA4-Ig prevented chronic kidney rejection in a rat model of allotransplantation without the need for systemic immunosuppression. Here, we generated AAV2 and AAV9 vectors encoding for LEA29Y, an optimized version of CTLA4-Ig. Both LEA29Y vectors were equally efficient for reducing T-cell proliferation in vitro...
March 27, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28346434/optimization-of-adeno-associated-virus-vector-mediated-gene-transfer-to-the-respiratory-tract
#3
F Kurosaki, R Uchibori, N Mato, Y Sehara, Y Saga, M Urabe, H Mizukami, Y Sugiyama, A Kume
An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters, and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter...
March 27, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28300083/mr-guided-parenchymal-delivery-of-adeno-associated-viral-vector-serotype-5-in-non-human-primate-brain
#4
L Samaranch, B Blits, W San Sebastian, P Hadaczek, J Bringas, V Sudhakar, M Macayan, P J Pivirotto, H Petry, K S Bankiewicz
The present study was designed to characterize transduction of non-human primate brain and spinal cord with AAV5 viral vector after parenchymal delivery. AAV5-CAG-GFP (1 × 10(13) vector genomes per milliliter (vg ml(-1))) was bilaterally infused either into putamen, thalamus or with the combination left putamen and right thalamus. Robust expression of GFP was seen throughout infusion sites and also in other distal nuclei. Interestingly, thalamic infusion of AAV5 resulted in the transduction of the entire corticospinal axis, indicating transport of AAV5 over long distances...
March 16, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28276446/systemic-injection-of-aav9-gdnf-provides-modest-functional-improvements-in-the-sod1-g93a-als-rat-but-has-adverse-side-effects
#5
G M Thomsen, M Alkaslasi, J-P Vit, G Lawless, M Godoy, G Gowing, O Shelest, C N Svendsen
Injecting proteins into the central nervous system that stimulate neuronal growth can lead to beneficial effects in animal models of disease. In particular, glial cell line-derived neurotrophic factor (GDNF) has shown promise in animal and cell models of Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS). Here, systemic AAV9-GDNF was delivered via tail vein injections to young rats to determine whether this could be a safe and functional strategy to treat the SOD1(G93A) rat model of ALS and, therefore, translated to a therapy for ALS patients...
March 9, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28221337/modulation-of-digital-flexor-tendon-healing-by-vascular-endothelial-growth-factor-gene-transfection-in-a-chicken-model
#6
W F Mao, Y F Wu, Q Q Yang, Y L Zhou, J B Tang
A major challenge in tendon injury is the weak intrinsic healing capacity of tendon, which may cause re-rupture after surgery. Growth factors are believed to be critical during tendon healing. This study aimed to investigate the effects of vascular endothelial growth factor (VEGF) genes delivered by adeno-associated virus (AAV) vectors on tendon healing and molecular events involved in a chicken model. One hundred and twenty eight deep flexor tendons in the long toes of chickens were completely transected and injected with 2 × 10(9) particles of AAV2-VEGF or saline before surgically repaired...
February 21, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28218744/live-cell-imaging-to-compare-the-transfection-and-gene-silencing-efficiency-of-calcium-phosphate-nanoparticles-and-a-liposomal-transfection-agent
#7
S Chernousova, M Epple
The processing of DNA (for transfection) and siRNA (for gene silencing), introduced into HeLa cells by triple-shell calcium phosphate nanoparticles, was followed by live-cell imaging. For comparison, the commercial liposomal transfection agent Lipofectamine(TM) was used. The cells were incubated with these delivery systems, carrying either eGFP-encoding DNA or siRNA against eGFP. In the latter case, HeLa cells which stably expressed eGFP were used. The expression of eGFP started after 5 h in the case of nanoparticles and after 4 h in the case of Lipofectamine...
February 20, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28206989/il-4-mediated-by-hsv-vector-suppresses-morphine-withdrawal-response-through-decreasing-tnf%C3%AE-nr2b-and-pc-ebp%C3%AE-in-the-periaqueductal-gray-in-rats
#8
H Yi, T Iida, S Liu, D Ikegami, Q Liu, A Iida, D A Lubarsky, S Hao
Chronic opiates induce the development of physical dependence. Opioid physical dependence characterized by withdrawal symptoms, may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. Elucidation of the mechanisms involved in physical dependence is crucial to developing more effective treatment strategies for opioid dependence. Chronic morphine induces production of proinflammatory cytokines in regional-specific sites of the brain. Interleukin-4 (IL-4) is a prototypical anti-inflammatory cytokine that globally suppresses proinflammatory cytokines...
February 16, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28165447/an-aavrh10-cag-cyp21-ha-vector-allows-persistent-correction-of-21-hydroxylase-deficiency-in-a-cyp21-mouse-model
#9
M Perdomini, C Dos Santos, C Goumeaux, V Blouin, P Bougnères
The treatment of severe forms of 21-hydroxylase deficiency (21OHD) remains unsatisfactory in many respects. As a monogenic disease caused by loss-of-function mutations, 21OHD is a potential candidate for a gene therapy (GT) approach. The first step of GT is to demonstrate positive effects of the therapeutic vector in the Cyp21(-/--) mouse model. Thus we tested the adrenal tropism of an AAVrh10-CAG-GFP vector ('GFP vector') then attempted to correct the phenotypic and biochemical alterations in Cyp21(-/-) mice using an AAVrh10-CAG-humanCYP21A2-HA vector ('CYP21 vector')...
February 6, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28150697/neutralizing-antibodies-against-adeno-associated-viruses-in-sj%C3%A3-gren-s-patients-implications-for-gene-therapy
#10
A Corden, B Handelman, H Yin, A Cotrim, I Alevizos, J A Chiorini
One potential setback to the use of gene therapy for the treatment of Sjögren's syndrome is the presence of neutralizing antibodies (nAb) against adeno-associated virus (AAV) serotypes. In order to evaluate the efficacy of this treatment option, nAb titers were measured in both healthy individuals and Sjögren's patients. Several serotypes with known transduction activity in mouse salivary glands were tested and only AAV5 showed a statistically significant change in the prevalence of nAbs between Sjögren's and healthy participants...
February 2, 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...
February 2, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28140387/extracellular-vesicles-for-nucleic-acid-delivery-progress-and-prospects-for-safe-rna-based-gene-therapy
#12
REVIEW
L Jiang, P Vader, R M Schiffelers
Nucleic acid-based drugs offer a potentially effective tool for treatment of a variety of diseases, including cancer, cardiovascular diseases, neurological disorders, and infectious diseases. However, clinical applications are hindered by instability of RNA molecules in the circulation and lack of efficient vectors that can deliver RNAs to target tissues and into diseased target cells. Synthetic polymer and lipids as well as virus-based vectors are among the most widely explored vehicles for RNA delivery, but clinical progress has been limited as a result of issues related to toxicity, immunogenicity and low efficiency...
January 31, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28121307/genetic-pharmacology-progresses-in-sirna-dealivery-and-therapeutic-applications
#13
REVIEW
D Scherman, A Rousseau, P Bigey, V Escriou
In the RNA interference process, the catalytic degradation of an endogenous mRNA results from the Watson-Crick complementary recognition by either a small silencing synthetic double-stranded ribonucleotide (siRNA), or by a small hairpin RNA (shRNA) produced in the cell by transcription from a DNA template. This interference process ideally results in an exquisitely specific mRNA suppression. The present review is dedicated to siRNAs. It describes the mechanism of RNA silencing and the main siRNA delivery techniques, with a focus on siRNA self-complexing to cationic lipids to form nanoparticles which are called lipoplexes...
January 25, 2017: Gene Therapy
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
#14
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
#15
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/28094775/nanotechnologies-in-delivery-of-mrna-therapeutics-using-nonviral-vector-based-delivery-systems
#16
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
#17
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
#18
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
#19
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
#20
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
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