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Human Gene Therapy

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https://www.readbyqxmd.com/read/28726522/steerable-induction-of-the-thymosin-%C3%A3-4-mrtf-a-pathway-via-aav-based-overexpression-induces-therapeutic-neovascularization
#1
Tilman Ziegler, Markus Kraus, Wira Husada, Florian Gesenhues, Qui Jiang, Olaf Pinkenburg, Teresa Trenkwalder, Karl-Ludwig Laugwitz, Ferdinand le Noble, Christian Weber, Christian Kupatt, Rabea Hinkel
Viral vectors have been frequently used in a variety of preclinical animal models to deliver genetic constructs into tissues. Among the vectors used, adeno-associated viral vectors (AAVs) may be targeted to specific tissues, depending on the serotype used. Moreover, they show robust expression for prolonged periods of time and have a low immunogenic potential. Furthermore, AAVs, unlike other vector systems, only display a low rate of genomic integration. However, to ensure efficient transgene production, expression is typically driven by constitutively active promoters, such as the CMV promotor...
July 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28726516/targeting-nsg-mice-engrafting-cells-with-a-clinically-applicable-lentiviral-vector-corrects-osteoclasts-in-infantile-malignant-osteopetrosis
#2
Ilana Moscatelli, Henrik Löfvall, Christian Schneider Thudium, Michael Rothe, Carmen Montano, Zsuzsanna Kertész, Mehtap Sirin, Ansgar Schulz, Axel Schambach, Kim Henriksen, Johan Richter
Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by nonfunctional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to develop a clinically applicable lentiviral vector expressing TCIRG1 to correct osteoclast function in IMO. We compared two mammalian promoters: elongation factor 1α short promoter (EFS) and chimeric myeloid promoter (ChimP). EFS was chosen for continued experiments as it performed better...
July 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28707952/systemic-delivery-of-dysferlin-overlap-vectors-provides-long-term-functional-improvement-for-dysferlinopathy
#3
Rachael A Potter, Danielle A Griffin, Patricia C Sondergaard, Ryan W Johnson, Eric R Pozsgai, Kristin N Heller, Ellyn L Peterson, Kimmo K Lehtimaki, Hillarie P Windish, Plavi J Mittal, Doug E Albrecht, Jerry R Mendell, Louise R Rodino-Klapac
Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is required. We have developed dual adeno-associated virus vectors defined by a region of homology to serve as a substrate for reconstitution of the full 6.5 kb dysferlin cDNA. Our previous work studied the efficacy of this treatment through intramuscular and regional delivery routes...
July 14, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28679290/gene-therapy-using-a-minicep290-fragment-delays-photoreceptor-degeneration-in-a-mouse-model-of-leber-congenital-amaurosis-lca
#4
Wei Zhang, Linjing Li, Qin Su, Guangping Gao, Hemant Khanna
Mutations in the cilia-centrosomal protein CEP290 are most frequently observed in autosomal recessive childhood blindness disorder Leber congenital amaurosis (LCA). No treatment or cure currently exists for this disorder. The Cep290rd16 (retinal degeneration 16) (a mouse model of LCA) carries a mutation in the Cep290 gene, which leads to shorter cilia formation and defective photoreceptor structure and function. A roadblock to developing a gene replacement strategy for CEP290 using conventional Adeno-associated Virus (AAV) vectors is its large size...
July 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28665213/twenty-years-of-european-union-support-to-gene-therapy-and-gene-transfer
#5
David Gancberg
For twenty years and throughout its research programmes, the European Union has supported the entire innovation chain for gene transfer and gene therapy. The fruits of this investment are ripening as gene therapy products are reaching the European market and as clinical trials are demonstrating the safety of this approach to treat previously untreatable diseases.
June 30, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28665147/s-mar-element-facilitates-episomal-long-term-persistence-of-adeno-associated-viral-aav-vector-genomes-in-proliferating-cells
#6
Claudia Hagedorn, Maria Schnödt, Philip Boehme, Heba Abdelrazik, Hans Lipps, Hildegard Büning
Adeno-associated viral (AAV) vectors are one of the most frequently applied gene transfer system in research and human clinical trials. Since AAV vectors do not possess an integrase activity, application is restricted to terminally differentiated tissues if transgene expression is required long-term. To overcome this limitation and to generate AAV vectors that persist episomally in dividing cells, we equipped AAV vector genomes with an autonomous replicating unit (Scaffold/matrix attachment region (S/MAR))...
June 30, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28648139/mutagenic-analysis-of-an-adeno-associated-virus-variant-capable-of-simultaneously-promoting-immune-resistance-and-robust-gene-delivery
#7
Yoojin Kim, Eunmi Kim, Seokmin Oh, Ye-Eun Yoon, Jae-Hyung Jang
In addition to the ability to boost gene delivery efficiency in many therapeutically relevant cells, the capability of circumventing neutralizing antibody (NAb) inactivation is a key prerequisite that gene carriers must fulfill for their extensive applications as therapeutic agents in many gene therapy trials, especially for cancer treatments. This study revealed that a genetically engineered adeno-associated viral (AAV) variant, AAVr3.45, inherently possesses dual beneficial properties as a gene carrier: i) efficiently delivering therapeutic genes to many clinically valuable cells (e...
June 24, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28622065/leptin-gene-transfer-improves-symptoms-of-type-2-diabetic-mice-by-regulating-leptin-signaling-pathway-and-insulin-resistance-of-peripheral-tissues
#8
Lan Xiang, Jing Li, Qian Wang, Ruiqi Tang, Jianhua Qi
The leptin gene was transferred into the liver of streptozocin- and high fat diet-induced type 2 diabetic (T2D) mice by hydrodynamic-based gene delivery. The food intake, water consumption, glucose concentration, and triglyceride, total cholesterol levels of T2D mice were significantly decreased. Meanwhile, plasma leptin was remarkably increased after gene transfer for 2, 3, 5, and 7 days, while plasma adiponectin was also significantly increased at day 2. To understand the mechanism of action of leptin on T2D mice, gene expressions related to glycometabolism and energy metabolism in the liver, epididymal adipose tissue, hypothalamus, and muscle were measured...
June 16, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28599597/simultaneous-knockout-of-cxcr4-and-ccr5-genes-in-cd4-t-cells-via-crispr-cas9-confers-resistance-to-both-x4-and-r5-tropic-human-immunodeficiency-virus-type-1-infection
#9
Songlin Yu, Yongchao Yao, Hongkui Xiao, Jiaojiao Li, Quan Liu, Yijun Yang, Dickson Adah, Junnan Lu, Siting Zhao, Li Qin, Xiaoping Chen
Previous research has proven that disruption of either the CCR5 or the CXCR4 gene confers resistance to R5-tropic or X4-tropic human immunodeficiency virus type 1 (HIV-1) infection, respectively. However, the urgent need to ablate both of the co-receptors in individual post-thymic CD4+ T cells for dual protection remains. This study ablated the CCR5 and CXCR4 genes in human CD4+ cell lines and primary CD4+ T cells simultaneously using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, a well-developed, highly efficient genetic engineering tool...
June 9, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28578603/aav-gene-therapy-for-alcoholism-inhibition-of-mitochondrial-aldehyde-dehydrogenase-enzyme-expression-in-hepatoma-cells
#10
Anamaria C Sanchez, Chengwen Li, Barbara Andrews, Juan A Asenjo, R Jude Samulski
Most ethanol is broken down in the liver in two steps by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2) enzymes, which metabolize down ethanol into acetaldehyde and then acetate. Some individuals from the Asian population who carry a mutation in the aldehyde dehydrogenase gene (ALDH2*2) cannot metabolize acetaldehyde as efficiently, producing strong effects, including facial flushing, dizziness, hypotension, and palpitations. This results in an aversion to alcohol intake and protection against alcoholism...
June 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28557574/the-hydrophobic-effect-from-conjugated-chemicals-or-drugs-on-in-vivo-biodistribution-of-rna-nanoparticles
#11
Daniel L Jasinski, Hongran Yin, Zhefeng Li, Peixuan Guo
liver or other organ accumulation of drugs is one of the major problems that leads to toxicity and side effects in therapy using chemicals or other macromolecules. It has been shown that specially designed RNA nanoparticles can specifically target cancer cells, silence oncogenic genes, and stop cancer growth with little or no accumulation in the liver or other vital organs. It is well known that physical properties of nanoparticles such as size, shape, and surface chemistry affect biodistribution and pharmacokinetic profiles <i></i>in vivo<i></i>...
May 30, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28557533/induced-cell-turnover-a-novel-therapeutic-modality-for-in-situ-tissue-regeneration
#12
Francesco Albert Bosco Cortese, Sebastian Aguiar, Giovanni Santostasi
Induced Cell Turnover (ICT) is a theoretical intervention in which the targeted ablation of damaged, diseased and/or nonfunctional cells is coupled with replacement by partially differentiated induced pluripotent stem cells in a gradual and multi-phasic manner. Tissue-specific ablation can be achieved using pro-apoptotic small molecule cocktails, peptide mimetics, and/or tissue-tropic AAV-delivered suicide genes driven by cell-type specific promoters. Replenishment with new cells can be mediated by systemic administration of cells engineered for homing, robustness, and even enhanced function and disease resistance...
May 30, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28530155/an-oncolytic-adenovirus-encoding-decorin-and-gm-csf-inhibits-tumor-growth-in-a-colorectal-tumor-model-by-targeting-pro-tumorigenic-signals-and-via-immune-activation
#13
Zhao Liu, Yuefeng Yang, Xiaoyan Zhang, Hao Wang, Weidong Xu, Hua Wang, FengJun Xiao, Zhigang Bai, Hongwei Yao, Xuemei Ma, Lan Jin, Chu-Tse Wu, Prem Seth, Zhongtao Zhang, Lisheng Wang
In advanced and metastatic stages of colorectal cancer (CRC), reduced sensitivity to conventional strategies is still a major obstacle to successful treatments. Decorin is an important regulator in the development and progression of various cancers. To examine if CRC patients have altered decorin levels, expression of decorin and its target genes, Met and vascular endothelial growth factor A (VEGFA) were analyzed in their tumors. Compared to normal tissues, decorin expression was reduced in CRC patients' tumors, while, there were increased Met and VEGFA levels...
May 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28530128/in-vivo-endocrine-secretion-of-prostacyclin-following-expression-of-a-cox-1-pgis-fusion-protein-in-the-salivary-glands-of-rats-via-non-viral-gene-therapy
#14
Zhimin Wang, Raymond L Benza, Lee Zourelias, Angela Sanguino, Ramaz Geguchadze, Kelly J Shields, Changgong Wu, Kristin B Highland, Michael J Passineau
Pulmonary arterial hypertension is a progressive disease that culminates in right heart failure and death. Prostacyclin(PGI2) and its derivatives are effective treatments for PAH when administered as continuous parenteral infusions. This treatment paradigm requires medical sophistication, and patients are at risk for complications from an indewelling catheter; drug interruptions may result in rebound pulmonary hypertension and death. We hypothesized that the salivary gland can be repurposed into an endogenous production site for circulating PGI2 through the expression of a fusion protein embodying cyclooxygenase-1(Cox1) and prostacyclin synthase(PGIS) domains...
May 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28530127/an-oncolytic-adenovirus-expressing-snord44-and-gas5-exhibits-anti-tumor-effect-in-colorectal-cancer-cells
#15
Sujing Yuan, Yu Wu, Yigang Wang, Jianhua Chen, Liang Chu
SNORD44 is a C/D box small nucleolar RNA, and low expresses in breast cancer and head and neck squamous cell carcinoma tissues. Its host gene is growth arrest specific transcript 5 (GAS5), which is a long noncoding RNA. GAS5 is down-regulated in colorectal cancer (CRC), and overexpression of GAS5 suppresses cell proliferation. However, the function of SNORD44 in CRC remains largely unknown, and the application of SNORD44 combined with GAS5 in CRC treatment has not been reported. In this study, the expression levels of SNORD44 and GAS5 were measured in CRC tissues by qRT-PCR...
May 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28490200/human-bocavirus-type-1-capsid-facilitates-the-transduction-of-ferret-airways-by-adeno-associated-virus-genomes
#16
Ziying Yan, Zehua Feng, Xingshen Sun, Yulong Zhang, Wei Zou, Zekun Wang, Chandler Jensen-Cody, Bo Liang, Soo-Yeun Park, Jianming Qiu, John F Engelhardt
Human bocavirus type-1 (HBoV1) has a high tropism for the apical membrane of human airway epithelia. The packaging of a recombinant adeno-associated virus 2 (rAAV2) genome into HBoV1 capsid produces a chimeric vector (rAAV2/HBoV1) that also efficiently transduces human airway epithelia. As such, this vector is attractive for use in gene therapies to treat lung diseases such as cystic fibrosis. However, preclinical development of rAAV2/HBoV1 vectors has been hindered by the fact that humans are the only known host for HBoV1 infection...
May 10, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28478695/prevention-of-neurocognitive-deficiency-in-mucopolysaccharidosis-type-ii-mice-by-central-nervous-system-directed-aav9-mediated-iduronate-sulfatase-gene-transfer
#17
Kanut Laoharawee, Kelly M Podetz-Pedersen, Tam T Nguyen, Laura B Evenstar, Kelley F Kitto, Zhenhong Nan, Carolyn A Fairbanks, Walter C Low, Karen F Kozarsky, R Scott McIvor
Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive lysosomal disorder caused by defective iduronate-2-sulfatase (IDS), resulting in accumulation of heparan sulfate and dermatan sulfate glycosaminoglycans (GAGs). Enzyme replacement is the only Food and Drug Administration-approved therapy available for MPS II, but it is expensive and does not improve neurologic outcomes in MPS II patients. This study evaluated the effectiveness of adeno-associated virus (AAV) vector encoding human IDS delivered intracerebroventricularly in a murine model of MPS II...
May 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28478688/gene-delivery-of-activated-factor-vii-using-alternative-adeno-associated-virus-serotype-improves-hemostasis-in-hemophiliac-mice-with-fviii-inhibitors-and-adeno-associated-virus-neutralizing-antibodies
#18
Junjiang Sun, Baolai Hua, Xiaojing Chen, Richard J Samulski, Chengwen Li
While therapeutic expression of coagulation factors from adeno-associated virus (AAV) vectors has been successfully achieved in patients with hemophilia, neutralizing antibodies to the vector and inhibitory antibodies to the transgene severely limit efficacy. Indeed, approximately 40% of mice transduced with human factor VIII using the AAV8 serotype developed inhibitory antibodies to factor VIII (FVIII inhibitor), as well as extremely high titers (≥1:500) of neutralizing antibodies to AAV8. To correct hemophilia in these mice, AAV9, a serotype with low in vitro cross-reactivity (≤1:5) to anti-AAV8, was used to deliver mouse-activated factor VII (mFVIIa)...
May 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28719250/sleeping-beauty-awakens-new-interest
#19
Terence R Flotte
No abstract text is available yet for this article.
July 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28530135/prolonged-expression-of-secreted-enzymes-in-dogs-after-liver-directed-delivery-of-sleeping-beauty-transposons-implications-for-non-viral-gene-therapy-of-systemic-disease
#20
Elena L Aronovich, Kendra A Hyland, Bryan C Hall, Jason B Bell, Erik R Olson, Myra Urness Rusten, David W Hunter, N Matthew Ellinwood, R Scott McIvor, Perry B Hackett
The non-viral, integrating Sleeping Beauty (SB) transposon system is efficient in treating systemic monogenic disease in mice, including hemophilia A and B caused by deficiency of blood clotting factors and mucopolysaccharidosis types I and VII caused by α-L-iduronidase (IDUA) and β-glucuronidase (GUSB) deficiency, respectively. Modified approaches of the hydrodynamics-based procedure to deliver transposons to the liver in dogs were recently reported. Using the transgenic canine reporter secreted alkaline phosphatase (cSEAP), transgenic protein in the plasma was demonstrated for up to 6 weeks post infusion...
July 2017: Human Gene Therapy
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