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

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https://www.readbyqxmd.com/read/28237839/systemic-aav8-mediated-gene-therapy-drives-whole-body-correction-of-myotubular-myopathy-in-dogs
#1
David L Mack, Karine Poulard, Melissa A Goddard, Virginie Latournerie, Jessica M Snyder, Robert W Grange, Matthew R Elverman, Jérôme Denard, Philippe Veron, Laurine Buscara, Christine Le Bec, Jean-Yves Hogrel, Annie G Brezovec, Hui Meng, Lin Yang, Fujun Liu, Michael O'Callaghan, Nikhil Gopal, Valerie E Kelly, Barbara K Smith, Jennifer L Strande, Fulvio Mavilio, Alan H Beggs, Federico Mingozzi, Michael W Lawlor, Ana Buj-Bello, Martin K Childers
X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28237838/gene-therapeutic-reversal-of-peripheral-olfactory-impairment-in-bardet-biedl-syndrome
#2
Corey L Williams, Cedric R Uytingco, Warren W Green, Jeremy C McIntyre, Kirill Ukhanov, Arthur D Zimmerman, Dana T Shively, Lian Zhang, Darryl Y Nishimura, Val C Sheffield, Jeffrey R Martens
Olfactory dysfunction is a pervasive but underappreciated health concern that affects personal safety and quality of life. Patients with olfactory dysfunctions have limited therapeutic options, particularly those involving congenital diseases. Bardet-Biedl syndrome (BBS) is one such disorder, where olfactory loss and other symptoms manifest from defective cilium morphology and/or function in various cell types/tissues. Olfactory sensory neurons (OSNs) of BBS mutant mice lack the capacity to build/maintain cilia, rendering the cells incapable of odor detection...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28237837/a-novel-dna-vaccine-platform-enhances-neo-antigen-like-t-cell-responses-against-wt1-to-break-tolerance-and-induce-anti-tumor-immunity
#3
Jewell N Walters, Bernadette Ferraro, Elizabeth K Duperret, Kimberly A Kraynyak, Jaemi Chu, Ashley Saint-Fleur, Jian Yan, Hy Levitsky, Amir S Khan, Niranjan Y Sardesai, David B Weiner
Tumor-associated antigens have emerged as important immunotherapeutic targets in the fight against cancer. Germline tumor antigens, such as WT1, Wilms' tumor gene 1, are overexpressed in many human malignancies but have low expression in somatic tissues. Recent vaccination approaches to target WT1 have been hampered by poor in vivo immune potency, likely due to the conserved self-antigen nature of WT1. In this study, we use a novel synthetic micro-consensus SynCon DNA vaccine approach with the goal of breaking tolerance and increasing vaccine immune potency...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28237836/inhibitory-receptors-induced-by-vsv-viroimmunotherapy-are-not-necessarily-targets-for-improving-treatment-efficacy
#4
Kevin G Shim, Shane Zaidi, Jill Thompson, Tim Kottke, Laura Evgin, Karishma R Rajani, Matthew Schuelke, Christopher B Driscoll, Amanda Huff, Jose S Pulido, Richard G Vile
Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28237835/integration-of-a-cd19-car-into-the-tcr-alpha-chain-locus-streamlines-production-of-allogeneic-gene-edited-car-t-cells
#5
Daniel T MacLeod, Jeyaraj Antony, Aaron J Martin, Rachel J Moser, Armin Hekele, Keith J Wetzel, Audrey E Brown, Melissa A Triggiano, Jo Ann Hux, Christina D Pham, Victor V Bartsevich, Caitlin A Turner, Janel Lape, Samantha Kirkland, Clayton W Beard, Jeff Smith, Matthew L Hirsch, Michael G Nicholson, Derek Jantz, Bruce McCreedy
Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19(+) hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28236576/targeted-intraceptor-nanoparticle-for-neovascular-macular-degeneration-preclinical-dose-optimization-and-toxicology-assessment
#6
Xiaohui Zhang, Austin Bohner, Sai Bhuvanagiri, Hironori Uehara, Arun Kumar Upadhyay, Lyska L Emerson, Sailaja Bondalapati, Santosh Kumar Muddana, Daniel Fang, Miaoling Li, Zoya Sandhu, Alya Hussain, Lara S Carroll, Michelle Tiem, Bonnie Archer, Uday Kompella, Rajkumar Patil, Balamurali K Ambati
Neovascular age-related macular degeneration (AMD) is treated with anti-VEGF intravitreal injections, which can cause geographic atrophy, infection, and retinal fibrosis. To minimize these toxicities, we developed a nanoparticle delivery system for recombinant Flt23k intraceptor plasmid (RGD.Flt23k.NP) to suppress VEGF intracellularly within choroidal neovascular (CNV) lesions in a laser-induced CNV mouse model through intravenous administration. In the current study, we examined the efficacy and safety of RGD...
February 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28236575/unravelling-endogenous-microrna-system-dysfunction-as-a-new-pathophysiological-mechanism-in-machado-joseph-disease
#7
Vitor Carmona, Janete Cunha-Santos, Isabel Onofre, Ana Teresa Simões, Udaya Vijayakumar, Beverly L Davidson, Luís Pereira de Almeida
Machado-Joseph disease (MJD) is a genetic neurodegenerative disease caused by an expanded polyglutamine tract within the protein ataxin-3 (ATXN3). Despite current efforts, MJD's mechanism of pathogenesis remains unclear and no disease-modifying treatment is available. Therefore, in this study, we investigated (1) the role of the 3' UTR of ATXN3, a putative microRNA (miRNA) target, (2) whether miRNA biogenesis and machinery are dysfunctional in MJD, and (3) which specific miRNAs target ATXN3-3' UTR and whether they can alleviate MJD neuropathology in vivo...
February 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28236574/novel-biomarkers-of-human-gm1-gangliosidosis-reflect-the-clinical-efficacy-of-gene-therapy-in-a-feline-model
#8
Heather L Gray-Edwards, Debra S Regier, Jamie L Shirley, Ashley N Randle, Nouha Salibi, Sarah E Thomas, Yvonne L Latour, Jean Johnston, Gretchen Golas, Annie S Maguire, Amanda R Taylor, Donald C Sorjonen, Victoria J McCurdy, Peter W Christopherson, Allison M Bradbury, Ronald J Beyers, Aime K Johnson, Brandon L Brunson, Nancy R Cox, Henry J Baker, Thomas S Denney, Miguel Sena-Esteves, Cynthia J Tifft, Douglas R Martin
GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated viral (AAV) gene therapy in GM1 mice and cats have prompted consideration of human clinical trials, yet there remains a paucity of objective biomarkers to track disease status. We developed a panel of biomarkers using blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, and magnetic resonance spectroscopy in GM1 cats-either untreated or AAV treated for more than 5 years-and compared them to markers in human GM1 patients where possible...
February 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28236573/modifying-antigen-encapsulating-liposomes-with-kala-facilitates-mhc-class-i-antigen-presentation-and-enhances-anti-tumor-effects
#9
Naoya Miura, Hidetaka Akita, Naho Tateshita, Takashi Nakamura, Hideyoshi Harashima
For a successful anti-cancer vaccine, antigen presentation on the major histocompatibility complex (MHC) class I is a requirement. To accomplish this, an antigen must be delivered to the cytoplasm by overcoming the endosome/lysosome. We previously reported that a lipid nanoparticle modified with a KALA peptide (WEAKLAKALAKALAKHLAKALAKALKA), an α-helical cationic peptide, permits the encapsulated pDNA to be efficiently delivered to the cytoplasm in bone marrow-derived dendritic cells (BMDCs). Herein, we report on the use of KALA-modified liposomes as an antigen carrier, in an attempt to induce potent antigen-specific cellular immunity...
February 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28215995/pericardial-fluid-exosomes-a%C3%A2-new-material-to-treat-cardiovascular-disease
#10
Susmita Sahoo, Prabhu Mathiyalagan, Roger J Hajjar
No abstract text is available yet for this article.
February 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28215994/safe-recombinant-outer-membrane-vesicles-that-display-m2e-elicit-heterologous-influenza-protection
#11
Hannah C Watkins, C Garrett Rappazzo, Jaclyn S Higgins, Xiangjie Sun, Nicole Brock, Annie Chau, Aditya Misra, Joseph P B Cannizzo, Michael R King, Taronna R Maines, Cynthia A Leifer, Gary R Whittaker, Matthew P DeLisa, David Putnam
Recombinant, Escherichia coli-derived outer membrane vesicles (rOMVs), which display heterologous protein subunits, have potential as a vaccine adjuvant platform. One drawback to rOMVs is their lipopolysaccharide (LPS) content, limiting their translatability to the clinic due to potential adverse effects. Here, we explore a unique rOMV construct with structurally remodeled lipids containing only the lipid IVa portion of LPS, which does not stimulate human TLR4. The rOMVs are derived from a genetically engineered B strain of E...
February 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28214253/long-noncoding-rna-linc00673-is-activated-by-sp1-and-exerts-oncogenic-properties-by-interacting-with-lsd1-and-ezh2-in-gastric-cancer
#12
Mingde Huang, Jiakai Hou, Yunfei Wang, Min Xie, Chenchen Wei, Fengqi Nie, Zhaoxia Wang, Ming Sun
Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the biological function of these molecules and the mechanisms responsible for their alteration in gastric cancer (GC) are not fully understood. In this study, we found that lncRNA LINC00673 is significantly upregulated in gastric cancer. Knockdown of LINC00673 inhibited cell proliferation and invasion and induced cell apoptosis, whereas LINC00673 overexpression had the opposite effect...
February 14, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28202391/the-efficacy-of-cardiac-anti-mir-208a-therapy-is-stress-dependent
#13
Joep E C Eding, Charlotte J Demkes, Joshua M Lynch, Anita G Seto, Rusty L Montgomery, Hillary M Semus, Aimee L Jackson, Marc Isabelle, Stefano Chimenti, Eva van Rooij
MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inhibits the cardiomyocyte-specific miR-208a...
February 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28202390/systemic-injection-of-rpe65-programmed-bone-marrow-derived-cells-prevents-progression-of-chronic-retinal-degeneration
#14
Xiaoping Qi, S Louise Pay, Yuanqing Yan, James Thomas, Alfred S Lewin, Lung-Ji Chang, Maria B Grant, Michael E Boulton
Bone marrow stem and progenitor cells can differentiate into a range of non-hematopoietic cell types, including retinal pigment epithelium (RPE)-like cells. In this study, we programmed bone marrow-derived cells (BMDCs) ex vivo by inserting a stable RPE65 transgene using a lentiviral vector. We tested the efficacy of systemically administered RPE65-programmed BMDCs to prevent visual loss in the superoxide dismutase 2 knockdown (Sod2 KD) mouse model of age-related macular degeneration. Here, we present evidence that these RPE65-programmed BMDCs are recruited to the subretinal space, where they repopulate the RPE layer, preserve the photoreceptor layer, retain the thickness of the neural retina, reduce lipofuscin granule formation, and suppress microgliosis...
February 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28202389/targeting-the-hdac2-hnf-4a-mir-101b-ampk-pathway-rescues-tauopathy-and-dendritic-abnormalities-in-alzheimer-s-disease
#15
Dan Liu, Hui Tang, Xin-Yan Li, Man-Fei Deng, Na Wei, Xiong Wang, Ya-Fan Zhou, Ding-Qi Wang, Peng Fu, Jian-Zhi Wang, Sébastien S Hébert, Jian-Guo Chen, Youming Lu, Ling-Qiang Zhu
Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer's disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Aβ overproduction in AD; however, its involvement in tau pathology and other memory-related functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD...
February 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28202388/viral-vector-reprogramming-of-adult-resident-striatal-oligodendrocytes-into-functional-neurons
#16
Marc S Weinberg, Hugh E Criswell, Sara K Powell, Aadra P Bhatt, Thomas J McCown
Recent advances suggest that in vivo reprogramming of endogenous cell populations provides a viable alternative for neuron replacement. Astrocytes and oligodendrocyte precursor cells can be induced to transdifferentiate into neurons in the CNS, but, in these instances, reprogramming requires either transgenic mice or retroviral-mediated gene expression. We developed a microRNA (miRNA)-GFP construct that in vitro significantly reduced the expression of polypyrimidine tract-binding protein, and, subsequently, we packaged this construct in a novel oligodendrocyte preferring adeno-associated virus vector...
February 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28190779/lentiviral-transfer-of-%C3%AE-globin-with-fusion-gene-nup98-hoxa10hd-expands-hematopoietic-stem-cells-and-ameliorates-murine-%C3%AE-thalassemia
#17
Hui Fen Zhao, Allistair Abraham, Yoon-Sang Kim, Yong-Dong Wang, Tamara Pestina, Jun Zhan, Keith Humphries, Arthur W Nienhuis, Derek A Persons
Recently, an engineered Homeobox-nucleoporin fusion gene, NUP98-HOXA10HD or NA10HD, was reported to expand and maintain murine hematopoietic stem cells (HSCs). We postulated that NA10HD would increase the number of human γ-globin-expressing cells to therapeutic levels. We developed a double gene lentiviral vector encoding both human γ-globin and NA10HD, which was used to transduce human peripheral blood CD34(+) cells and increased engraftment 2- to 2.5-fold at 15 weeks post-transplantation in immunodeficient mice...
February 9, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28190778/genome-editing-for-sickle-cell-disease-a-little-bcl11a-goes-a-long-way
#18
EDITORIAL
Mir A Hossain, Jörg Bungert
No abstract text is available yet for this article.
February 9, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28189492/hiv-receives-a-one-two-knockout-punch
#19
Conrad Russell Cruz, Catherine M Bollard
No abstract text is available yet for this article.
February 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28187947/partial-restoration-of-cftr-function-in-cftr-null-mice-following-targeted-cell-replacement-therapy
#20
Pascal Duchesneau, Rickvinder Besla, Mathieu F Derouet, Li Guo, Golnaz Karoubi, Amanda Silberberg, Amy P Wong, Thomas K Waddell
Cystic fibrosis (CF) is a fatal recessive genetic disorder caused by a mutation in the gene encoding CF transmembrane conductance regulator (CFTR) protein. Alteration in CFTR leads to thick airway mucus and bacterial infection. Cell therapy has been proposed for CFTR restoration, but efficacy has been limited by low engraftment levels. In our previous studies, we have shown that using a pre-conditioning regimen in combination with optimization of cell number and time of delivery, we could obtain greater bone marrow cell (BMC) retention in the lung...
February 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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