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Human Gene Therapy

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https://www.readbyqxmd.com/read/28335621/letter-to-the-editor-regarding-manuscript-doi-10-1089-hum-2016-147
#1
Jesse D Riordan
N/A *Note: There is no option for manuscript type "Letter to the Editor". I selected "Review" as the type, but this submission is a Letter to the Editor.
March 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28335619/over-expression-of-the-x-linked-inhibitor-of-apoptosis-protects-against-retinal-degeneration-in-a-feline-model-of-retinal-detachment
#2
Sarah Wassmer, Brian Leonard, Stuart Coupland, Adam Baker, John Hamilton, William W Hauswirth, Catherine Tsilfidis
Retinal detachment is an acute disorder in humans that is caused by trauma or disease, and it can often lead to permanent visual deficits that result from the death of photoreceptors in the retina. The final pathway for photoreceptor cell death is apoptosis and necroptosis. The X-linked inhibitor of apoptosis (XIAP) has been shown to block both of these cell death pathways. We tested the effects of XIAP on photoreceptor survival in a feline model of retinal detachment. The study was performed in 12 cats, divided into 2 experimental groups...
March 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28335618/aav-an-overview-of-unanswered-questions
#3
Kenneth I Berns, Nicholas Muzyczka
Today AAV is one of the most promising and successful gene therapy vectors. AAV vectors have been successful in the treatment of several monogenic diseases in early clinical trials1. Although work in the past has focused primarily on gene replacement, many investigators are now adapting the vector system to new clinical modalities including RNAi and gene modifying strategies such as Crisper/cas91. Moreover, Glybera2 has been licensed for clinical use in the European Union for treatment of a lysosomal storage disease...
March 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28323492/regulatory-and-exhausted-t-cell-responses-to-aav-capsid
#4
Gwladys Gernoux, James M Wilson, Christian Mueller
Recombinant adeno-associated viruses are quickly becoming the preferred viral vector for viral gene delivery for the treatment of a wide variety of genetic disorders. However, since their use in a clinical trial targeting Hemophilia B patients 10 years ago, immune responses to AAV capsid appear to have hampered some of the early clinical gene transfer efficacy. Indeed, AAV-based gene transfer has been shown to reactivate capsid-specific memory T cells which have correlated with a decline in AAV transduced tissue in some patients...
March 21, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28322590/randomized-clinical-trials-of-gene-transfer-for-heart-failure-with-reduced-ejection-fraction
#5
William F Penny, H Kirk Hammond
Despite improvement in drug and device therapy for heart failure, hospitalization rates and mortality have changed little in the past decade. Randomized clinical trials using gene transfer to improve function of the failing heart are the focus of this review. Four randomized clinical trials of gene transfer in heart failure with reduced ejection fraction (HFrEF) have been published. Each enrolled patients with stable symptomatic HFrEF and used either intracoronary delivery of a virus vector or endocardial injection of a plasmid (1 trial)...
March 21, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28293963/raav-integration-and-genotoxicity-insights-from-animal-models
#6
Randy Joseph Chandler, Mark Sands, Charles Paul Venditti
Currently, clinical gene therapy is experiencing a Renaissance with new products for clinical use approved in Europe and clinical trials for multiple diseases reporting positive results, especially those using recombinant adeno-associated viral (rAAV) vectors. Amidst this new success, it is prudent to recall that the field of gene therapy experienced tragic setbacks in 1999 and 2002 because of the serious adverse events related to retroviral and adenoviral gene delivery in two clinical trials that resulted in the death of two patients...
March 15, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28264583/crispr-mediated-knockout-of-i-cybb-i-in-nsg-mice-establishes-a-model-of-chronic-granulomatous-disease-for-human-stem-cell-gene-therapy-transplants
#7
Colin L Sweeney, Uimook Choi, Chengyu Liu, Sherry M Koontz, Seung-Kwon Ha, Harry L Malech
Chronic granulomatous disease (CGD) is characterized by defects in production of microbicidal reactive oxygen species (ROS) by phagocytes. Testing of gene and cell therapies for treatment of CGD in human hematopoietic cells requires pre-clinical transplant models. The use of the lymphocyte-deficient NOD.Cg-Prkdc<sup>scid</sup> Il2rg<sup>tm1Wjl</sup>/SzJ (NSG) mouse strain for human hematopoietic cell xenografts to test CGD therapies is complicated by the presence of functional mouse granulocytes capable of producing ROS for subsequent bacterial and fungal killing...
March 6, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28181816/induction-of-oxidants-distinguishes-susceptibility-of-prostate-carcinoma-cell-lines-to-p53-gene-transfer-mediated-by-an-improved-adenoviral-vector
#8
Rodrigo Esaki Tamura, Aline Hunger, Denise C Fernandes, Francisco R Laurindo, Eugenia Costanzi-Strauss, Bryan E Strauss
Previously, the authors developed an adenoviral vector, Ad-PG, where transgene expression is regulated by a p53-responsive promoter. When used to transfer the p53 cDNA, a positive feedback mechanism is established. In the present study, a critical comparison is performed between Ad-PGp53 and AdRGD-PGp53, where the RGD motif was incorporated in the adenoviral fiber protein. AdRGD-PGp53 provided superior transgene expression levels and resulted in the killing of prostate carcinoma cell lines DU145 and PC3. In vitro, this effect was associated with increased production of cytoplasmic and mitochondrial oxidants, DNA damage as revealed by detection of phosphorylated H2AX, as well as cell death consistent with apoptosis...
February 6, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28142259/ace2-inhibits-angiotensin-ii-induced-abdominal-aortic-aneurysm-in-mice
#9
QingQing Hao, XueFei Dong, Xu Chen, Feng Yan, Xiaoyu Wang, Haishui Shi, Bo Dong
Recent study have demonstrated that ACE2 plays an important role in the pathogenesis of abdominal Aortic Aneurysm (AAA). But, little study was reported about the direct effect of ACE2 overexpression on the aneurysm. In this study, we hypothesize that overexpression of ACE2 may prevent the pathogenesis of aneurysm by decreasing RAS activation. Thirty-nine Mice were assigned to 3 groups randomly (n=13 in each group), ACE2 group, Ad.EGFP group and Control group. After 8-week treatment, abdominal aortas with AAA were obtained for HE staining, VVG, immunohistochemistry and Western blotting...
January 31, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28132521/direct-intracranial-injection-of-aavrh8-encoding-monkey-%C3%AE-n-acetylhexosaminidase-causes-neurotoxicity-in-primate-brain
#10
Diane Golebiowski, Imramsjah Martijn J van der Bom, Churl-Su Kwon, Andrew D Miller, Keiko Petrosky, Allison M Bradbury, Stacy Maitland, Anna Luisa Kühn, Nina Bishop, Elizabeth Curran, Nilsa Silva, Dwijit GuhaSarkar, Susan V Westmoreland, Douglas R Martin, Matthew J Gounis, Wael F Asaad, Miguel Sena-Esteves
GM2 gangliosidoses, including Tay-Sachs disease (TSD) and Sandhoff disease (SD), are lysosomal storage disorders caused by deficiencies in β-N-acetylhexosaminidase (Hex). Patients are afflicted primarily with progressive central nervous system dysfunction (CNS). Studies in mice, cats, and sheep have indicated safety and widespread distribution of Hex in the CNS after intracranial vector infusion of AAVrh8 vectors encoding species-specific Hex α- or β-subunits at a 1:1 ratio. Here we conducted a safety study in cynomolgus macaques (cm) modeling our previous animal studies with bilateral infusion in the thalamus as well as in left lateral ventricle of AAVrh8 vectors encoding cm Hex α- and β-subunits...
January 28, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28132518/stem-cell-treatment-in-crohn-s-disease
#11
Xiao-Mei Zhang, Yu-Jing Zhang, Wei Wang, Yu-Quan Wei, Hongxin Deng
Crohn's disease which mainly affects the gastrointestinal tract and impairs patient's quality of life, is a refractory inflammatory disease with clinical manifestations of abdominal pain, fever, bowel obstruction and diarrhoea with blood or mucus. Besides the common complication of intestinal obstruction, the formation of fistulas should also be concerned about and anorectal fistula is the most typical. The disease is difficult to radical cure and easy to relapse, which urges people to find other effective treatment in addition to surgery...
January 28, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28125921/systemic-and-persistent-muscle-gene-expression-in-rhesus-monkeys-with-a-liver-de-targeted-adeno-associated-virus-aav-vector
#12
Alice F Tarantal, Charles C Lee, Michele L Martinez, Asokan Aravind, R Jude Samulski
The liver is a major off-target organ in gene therapy approaches for cardiac and musculoskeletal disorders. Intravenous administration of most of the naturally occurring adeno-associated virus (AAV) strains invariably results in vector genome sequestration within the liver. In the current study, we compared the muscle tropism and transduction efficiency of a liver de-targeted AAV variant to AAV9 following systemic administration in newborn rhesus monkeys. In vivo bioluminescence imaging was performed to monitor transgene expression (firefly luciferase) post-administration...
January 26, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28114818/functional-screening-identifies-human-mirnas-that-modulate-adenovirus-propagation-in-prostate-cancer-cells
#13
Jasmina Hodzic, Daoud Sie, Annaleen Vermeulen, Victor W van Beusechem
Oncolytic adenoviruses represent a novel class of anticancer agents. Their efficacy in killing cancer cells is variable, suggesting that there is room for improvement. Host miRNAs have been shown to play important roles in susceptibility of cells to replication of different viruses. This study investigated if adenovirus replication in human prostate cancer cells is influenced by host cell miRNA expression. To this end, human miRNA expression in response to adenovirus infection was analyzed, and functional screens for lytic adenovirus replication were performed using synthetic miRNA mimic and inhibitor libraries...
January 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28073291/future-of-raav-gene-therapy-platform-for-rnai-gene-editing-and-beyond
#14
Paul N Valdmanis, Mark A Kay
The use of recombinant adeno-associated viruses (rAAVs) ushered in a new millennium of gene transfer for therapeutic treatment of a number of conditions, including congenital blindness, hemophilia, and spinal muscular atrophy. rAAV vectors have remarkable staying power from a therapeutic standpoint, withstanding several ebbs and flows. As new technologies such as clustered regularly interspaced short palindromic repeat genome editing emerge, it is now the delivery tool-the AAV vector-that is the stalwart. The long-standing safety of this vector in a multitude of clinical settings makes rAAV a selling point in the advancement of approaches for gene replacement, gene knockdown, gene editing, and genome modification/engineering...
January 10, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28056565/characterization-of-aav-mediated-human-factor-viii-gene-therapy-in-hemophilia-a-mice
#15
Jenny A Greig, Qiang Wang, Amanda L Reicherter, Shu-Jen Chen, Alexandra L Hanlon, Christopher H Tipper, K Reed Clark, Samuel Wadsworth, Lili Wang, James M Wilson
Adeno-associated viral (AAV) vectors are promising vehicles for hemophilia gene therapy, with favorable clinical trial data seen in the treatment of hemophilia B. In an effort to optimize the expression of human coagulation factor VIII (hFVIII) for the treatment of hemophilia A, we performed an extensive study with numerous combinations of liver-specific promoter and enhancer elements with a codon-optimized hFVIII transgene. After generating 42 variants of three reduced-size promoters and three small enhancers, transgene cassettes were packaged within a single AAV capsid, AAVrh10, to eliminate performance differences due to the capsid type...
January 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28052693/safety-and-efficacy-of-ex-vivo-donor-lung-adenoviral-il-10-gene-therapy-in-a-large-animal-lung-transplant-survival-model
#16
Tiago N Machuca, Marcelo Cypel, Riccardo Bonato, Jonathan C Yeung, Yi-Min Chun, Stephen Juvet, Zehong Guan, David M Hwang, Manyin Chen, Tomohito Saito, Constantine Harmantas, Beverly L Davidson, Thomas K Waddell, Mingyao Liu, Shaf Keshavjee
Ex vivo normothermic lung perfusion (EVLP) is a novel platform and method developed to facilitate functional assessment and implementation of advanced therapies for donor lungs prior to transplantation. This study aimed to determine the safety and immunological and functional benefits of ex vivo adenoviral human interleukin-10 (AdhIL-10) gene delivery to prevent the development of primary graft dysfunction in a large animal survival model. Pig donor lungs were retrieved, preserved for 6 h at 4°C, and then randomly assigned to four groups: (1) AdhIL-10 gene therapy: 12 h EVLP + AdhIL-10 intra-bronchial delivery; (2) EVLP-control: 12 h EVLP; (3) Vector-control: 12 h EVLP + adenoviral vector intra-bronchial delivery; and (4) prolonged hypothermic preservation: additional 12 h of cold ischemia...
January 4, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042948/bacmam-delivery-of-a-protective-gene-to-reduce-renal-ischemia-reperfusion-injury
#17
Elisabetta Hitchman, Richard Brian Hitchman, Linda A King
Ischaemia-reperfusion (I/R) injury remains the primary contributor to delayed graft function in kidney transplantation. The beneficial application of manganese superoxide dismutase (sod), delivered by a BacMam vector, against renal I/R injury has not been evaluated previously. Therefore, in this study we overexpressed sod-2 in proximal tubular epithelial (HK-2) cells and porcine kidney organs during simulated renal I/R injury. Incubation of HK-2 cells with antimycin A and 2-deoxyglucose resulted in a significant decrease in intracellular ATP levels; following reperfusion, ATP levels significantly increased overtime in cells overexpressing sod-2...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042945/minicircle-orip-mir-31-as-a-novel-ebna1-specific-mirna-therapy-approach-for-nasopharyngeal-carcinoma
#18
Jiang-Xue Wu, Xin Tan, Jiaxin Lin, Luping Yuan, Jiemin Chen, Lin Qiu, Wen-Lin Huang
MicroRNAs (miRNAs) are important post-transcriptional regulators that control cancer development and progression. However, the application of miRNA therapy in cancer has been hampered by a lack of an efficient and targeted delivery system. In our previous studies, an oriP promoter-based minicircle system successfully mediated targeted foreign gene expression in EBNA1-positive nasopharyngeal carcinoma (NPC). However, it remains to be evaluated whether this system can be applied for tumor miRNA therapy. miR-31-5p, a tumor suppressive miRNA involved in the tumorigenesis of EBV-positive NPC, was selected as the therapeutic miRNA to be transferred...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042944/comparison-of-serum-raav-serotype-specific-antibodies-in-patients-with-duchenne-muscular-dystrophy-becker-muscular-dystrophy-inclusion-body-myositis-or-gne-myopathy
#19
Deborah Zygmunt, Kelly E Crowe, Kevin Flanigan, Paul T Martin
Recombinant Adeno-associated virus (rAAV) is a commonly used gene therapy vector for the delivery of therapeutic transgenes in a variety of human diseases, but pre-existing serum antibodies to viral capsid proteins can greatly inhibit rAAV transduction of tissues. We have assayed serum from patients with Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (DMD), Inclusion Body Myositis (IBM), and GNE myopathy (GNE). These were compared to serum from otherwise normal human subjects to determine the extent of pre-existing serum antibodies to rAAVrh74, rAAV1, rAAV2, rAAV6, rAAV8 and rAAV9...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042943/the-impact-of-aav-capsid-specific-t-cell-responses-on-design-and-outcome-of-clinical-gene-transfer-trials-with-recombinant-aav-vectors-an-evolving-controversy
#20
Hildegund Cj Ertl, Katherine A High
Recombinant adenovirus-associated (rAAV) vectors due to their ease of construction, wide tissue tropism and lack of pathogenicity remain at the forefront for long-term gene replacement therapy. In spite of very encouraging pre-clinical results, clinical trials were initially unsuccessful; expression of the rAAV vector-delivered therapeutic protein was transient. Loss of expression was linked to an expansion of AAV capsid-specific T cell responses, leading to the hypothesis that rAAV vectors recall pre-existing memory T cells that had been induced by natural infections with AAV together with a helper virus...
January 2, 2017: Human Gene Therapy
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