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Molecular Therapy. Methods & Clinical Development

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https://www.readbyqxmd.com/read/29766032/serum-free-erythroid-differentiation-for-efficient-genetic-modification-and-high-level-adult-hemoglobin-production
#1
Naoya Uchida, Selami Demirci, Juan J Haro-Mora, Atsushi Fujita, Lydia N Raines, Matthew M Hsieh, John F Tisdale
In vitro erythroid differentiation from primary human cells is valuable to develop genetic strategies for hemoglobin disorders. However, current erythroid differentiation methods are encumbered by modest transduction rates and high baseline fetal hemoglobin production. In this study, we sought to improve both genetic modification and hemoglobin production among human erythroid cells in vitro . To model therapeutic strategies, we transduced human CD34+ cells and peripheral blood mononuclear cells (PBMCs) with lentiviral vectors and compared erythropoietin-based erythroid differentiation using fetal-bovine-serum-containing media and serum-free media...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766031/a-rationally-engineered-capsid-variant-of-aav9-for-systemic-cns-directed-and-peripheral-tissue-detargeted-gene-delivery-in-neonates
#2
Dan Wang, Shaoyong Li, Dominic J Gessler, Jun Xie, Li Zhong, Jia Li, Karen Tran, Kim Van Vliet, Lingzhi Ren, Qin Su, Ran He, Jason E Goetzmann, Terence R Flotte, Mavis Agbandje-McKenna, Guangping Gao
Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766030/cre-recombinase-mediates-the-removal-of-bacterial-backbone-to-efficiently-generate-rsv40
#3
Xiaoxia Shi, Matthew Ryan Ykema, Jaco Hazenoot, Lysbeth Ten Bloemendaal, Irene Mancini, Machteld Odijk, Peter de Haan, Piter J Bosma
Gene therapy has been shown to be a feasible approach to treat inherited disorders in vivo . Among the currently used viral vector systems, adeno-associated virus (AAV) vectors are the most advanced and have been applied in patients successfully. An important drawback of non-integrating AAV vectors is their loss of expression upon cell division, while repeating systemic administration lacks efficacy due to the induction of neutralizing antibodies. In addition, a significant percentage of the general population is not eligible for AAV-mediated gene therapy due to pre-existing immunity...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766029/seizure-suppressant-and-neuroprotective-effects-of-encapsulated-bdnf-producing-cells-in-a-rat-model-of-temporal-lobe-epilepsy
#4
Chiara Falcicchia, Giovanna Paolone, Dwaine F Emerich, Francesca Lovisari, William J Bell, Tracie Fradet, Lars U Wahlberg, Michele Simonato
Brain-derived neurotrophic factor (BDNF) may represent a therapeutic for chronic epilepsy, but evaluating its potential is complicated by difficulties in its delivery to the brain. Here, we describe the effects on epileptic seizures of encapsulated cell biodelivery (ECB) devices filled with genetically modified human cells engineered to release BDNF. These devices, implanted into the hippocampus of pilocarpine-treated rats, highly decreased the frequency of spontaneous seizures by more than 80%. These benefits were associated with improved cognitive performance, as epileptic rats treated with BDNF performed significantly better on a novel object recognition test...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766028/a-non-integrating-lentiviral-approach-overcomes-cas9-induced-immune-rejection-to-establish-an-immunocompetent-metastatic-renal-cancer-model
#5
Junhui Hu, Shiruyeh Schokrpur, Maani Archang, Kip Hermann, Allison C Sharrow, Prateek Khanna, Jesse Novak, Sabina Signoretti, Rupal S Bhatt, Beatrice S Knudsen, Hua Xu, Lily Wu
The CRISPR-based technology has revolutionized genome editing in recent years. This technique allows for gene knockout and evaluation of function in cell lines in a manner that is far easier and more accessible than anything previously available. Unfortunately, the ability to extend these studies to in vivo syngeneic murine cell line implantation is limited by an immune response against cells transduced to stably express Cas9. In this study, we demonstrate that a non-integrating lentiviral vector approach can overcome this immune rejection and allow for the growth of transduced cells in an immunocompetent host...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766027/efficacy-and-safety-of-glycosidic-enzymes-for-improved-gene-delivery-to-the-retina-following-intravitreal-injection-in-mice
#6
Jasmina Cehajic-Kapetanovic, Nina Milosavljevic, Robert A Bedford, Robert J Lucas, Paul N Bishop
Viral gene delivery is showing great promise for treating retinal disease. Although subretinal vector delivery has mainly been used to date, intravitreal delivery has potential advantages if low retinal transduction efficiency can be overcome. To this end, we investigated the effects of co-injection of glycosaminoglycan-degrading enzymes, singly or in combination, with AAV2 as a method of increasing retinal transduction. Experiments using healthy mice demonstrated that these enzymes enhance retinal transduction...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766026/development-of-intrathecal-aav9-gene-therapy-for-giant-axonal-neuropathy
#7
Rachel M Bailey, Diane Armao, Sahana Nagabhushan Kalburgi, Steven J Gray
An NIH-sponsored phase I clinical trial is underway to test a potential treatment for giant axonal neuropathy (GAN) using viral-mediated GAN gene replacement (https://clinicaltrials.gov/ct2/show/NCT02362438). This trial marks the first instance of intrathecal (IT) adeno-associated viral (AAV) gene transfer in humans. GAN is a rare pediatric neurodegenerative disorder caused by autosomal recessive loss-of-function mutations in the GAN gene, which encodes the gigaxonin protein. Gigaxonin is involved in the regulation, turnover, and degradation of intermediate filaments (IFs)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766025/isoliquiritigenin-inhibits-il-1%C3%AE-induced-production-of-matrix-metalloproteinase-in-articular-chondrocytes
#8
Lei Zhang, Shiyun Ma, Hang Su, Jiaxiang Cheng
Osteoarthritis (OA) is a major joint disease in which inflammatory cytokine interleukin-1β (IL-1β) and matrix metalloproteinases (MMPs) play a pivotal role. Isoliquiritigenin has been reported to have anti-inflammation activity. In this study, the effect of isoliquiritigenin on IL-1β-induced production of matrix metalloproteinase and nuclear factor κB (NF-κB) activation was analyzed. We treated primary cultured articular chondrocytes with isoliquiritigenin and the expressions of MMPs were analyzed on mRNA and protein level...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766024/integrating-hdad5-35-vectors-as-a-new-platform-for-hsc-gene-therapy-of-hemoglobinopathies
#9
Chang Li, Nikoletta Psatha, Hongjie Wang, Manvendra Singh, Himanshu Bhusan Samal, Wenli Zhang, Anja Ehrhardt, Zsuzsanna Izsvák, Thalia Papayannopoulou, André Lieber
We generated an integrating, CD46-targeted, helper-dependent adenovirus HDAd5/35++ vector system for hematopoietic stem cell (HSC) gene therapy. The ∼12-kb transgene cassette included a β-globin locus control region (LCR)/promoter driven human γ-globin gene and an elongation factor alpha-1 (EF1α)-mgmtP140K expression cassette, which allows for drug-controlled increase of γ-globin-expressing erythrocytes. We transduced bone marrow lineage-depleted cells from human CD46-transgenic mice and transplanted them into lethally irradiated recipients...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766023/adeno-associated-virus-genome-population-sequencing-achieves-full-vector-genome-resolution-and-reveals-human-vector-chimeras
#10
Phillip W L Tai, Jun Xie, Kaiyuen Fong, Matthew Seetin, Cheryl Heiner, Qin Su, Michael Weiand, Daniella Wilmot, Maria L Zapp, Guangping Gao
Recombinant adeno-associated virus (rAAV)-based gene therapy has entered a phase of clinical translation and commercialization. Despite this progress, vector integrity following production is often overlooked. Compromised vectors may negatively impact therapeutic efficacy and safety. Using single molecule, real-time (SMRT) sequencing, we can comprehensively profile packaged genomes as a single intact molecule and directly assess vector integrity without extensive preparation. We have exploited this methodology to profile all heterogeneic populations of self-complementary AAV genomes via bioinformatics pipelines and have coined this approach AAV-genome population sequencing (AAV-GPseq)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766022/influence-of-pre-existing-anti-capsid-neutralizing-and-binding-antibodies-on-aav-vector-transduction
#11
Zachary Fitzpatrick, Christian Leborgne, Elena Barbon, Elisa Masat, Giuseppe Ronzitti, Laetitia van Wittenberghe, Alban Vignaud, Fanny Collaud, Séverine Charles, Marcelo Simon Sola, Fabienne Jouen, Olivier Boyer, Federico Mingozzi
Pre-existing immunity to adeno-associated virus (AAV) is highly prevalent in humans and can profoundly impact transduction efficiency. Despite the relevance to AAV-mediated gene transfer, relatively little is known about the fate of AAV vectors in the presence of neutralizing antibodies (NAbs). Similarly, the effect of binding antibodies (BAbs), with no detectable neutralizing activity, on AAV transduction is ill defined. Here, we delivered AAV8 vectors to mice carrying NAbs and demonstrated that AAV particles are taken up by both liver parenchymal and non-parenchymal cells; viral particles are then rapidly cleared, without resulting in transgene expression...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766021/transduction-patterns-of-adeno-associated-viral-vectors-in-a-laser-induced-choroidal-neovascularization-mouse-model
#12
Si Hyung Lee, Ye Seul Kim, Seung Kwan Nah, Hee Jong Kim, Ha Yan Park, Jin Young Yang, Keerang Park, Tae Kwann Park
Adeno-associated virus (AAV) vector is a promising platform technology for ocular gene therapy. Recently clinical successes to treat choroidal neovascularization (CNV) in wet type age-related macular degeneration have been reported. However, because pathologic conditions of the retina may alter the tropism of viral vectors, it is necessary to evaluate the transduction efficiency of different serotypes of AAV vectors in the retinas with CNVs. Here, we show the patterns and efficacy of transduction of AAV2, -5, and -8 vectors in a laser-induced CNV mouse model...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766020/amelioration-of-muscle-and-nerve-pathology-in-lama2-muscular-dystrophy-by-aav9-mini-agrin
#13
Chunping Qiao, Yi Dai, Viktoriya D Nikolova, Quan Jin, Jianbin Li, Bin Xiao, Juan Li, Sheryl S Moy, Xiao Xiao
LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin α2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno-associated viral (AAV) vector carrying the mini-agrin, which is a non-homologous functional substitute for the mutated laminin α2. A significant therapeutic effect in skeletal muscle was observed in our previous study using AAV serotype 1 (AAV1)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29707603/the-biological-activity-of-aav-vectors-for-choroideremia-gene-therapy-can-be-measured-by-in-vitro-prenylation-of-rab6a
#14
Maria I Patrício, Alun R Barnard, Christopher I Cox, Clare Blue, Robert E MacLaren
Choroideremia (CHM) is a rare, X-linked recessive retinal dystrophy caused by mutations in the CHM gene. CHM is ubiquitously expressed in human cells and encodes Rab escort protein 1 (REP1). REP1 plays a key role in intracellular trafficking through the prenylation of Rab GTPases, a reaction that can be reproduced in vitro . With recent advances in adeno-associated virus (AAV) gene therapy for CHM showing gene replacement to be a promising approach, an assay to assess the biological activity of the vectors is of the uttermost importance...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29707602/enhanced-production-of-exosome-associated-aav-by-overexpression-of-the-tetraspanin-cd9
#15
Lara Timantra Schiller, Nicolás Lemus-Diaz, Rafael Rinaldi Ferreira, Kai Oliver Böker, Jens Gruber
Research on cell-free vesicles revealed a multitude of characteristics, in particular of microvesicles and exosomes, that range from their potential as biomarkers to a function in horizontal transfer of genetic information from cell to cell and also include supportive functions in viral infection. Exosome-associated adeno-associated viruses (exo-AAVs) are of particular interest for the past couple of years, because they introduced a new source of highly potent recombinant AAVs with improved features, including accelerated transduction rates and more efficient immune escape...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29707601/an-assay-that-predicts-in-vivo-efficacy-for-dna-aptamers-that-stimulate-remyelination-in-a-mouse-model-of-multiple-sclerosis
#16
Robin M Heider, John A Smestad, Hernan Nicolas Lemus, Brandon Wilbanks, Arthur E Warrington, Justin P Peters, Moses Rodriguez, L James Maher
Multiple sclerosis (MS) is a debilitating disease for which regenerative therapies are sought. We have previously described human antibodies and DNA aptamer-streptavidin conjugates that promote remyelination after systemic injection into mice infected by Theiler's murine encephalomyelitis virus. Here, we report an in vitro assay of myelin binding with results that correlate with remyelination outcome in vivo , as shown for data from a set of DNA aptamer complexes of different size and formulation. This in vitro assay will be valuable for future screening of MS regenerative therapies targeting remyelination...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29707600/preclinical-development-of-a-lentiviral-vector-for-gene-therapy-of-x-linked-severe-combined-immunodeficiency
#17
Valentina Poletti, Sabine Charrier, Guillaume Corre, Bernard Gjata, Alban Vignaud, Fang Zhang, Michael Rothe, Axel Schambach, H Bobby Gaspar, Adrian J Thrasher, Fulvio Mavilio
X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the interleukin-2 receptor γ chain gene (IL2RG), and it is characterized by profound defects in T, B, and natural killer (NK) cell functions. Transplantation of hematopoietic stem/progenitor cells (HSPCs) genetically corrected with early murine leukemia retrovirus (MLV)-derived gammaretroviral vectors showed restoration of T cell immunity in patients, but it resulted in vector-induced insertional oncogenesis. We developed a self-inactivating (SIN) lentiviral vector carrying a codon-optimized human IL2RG cDNA driven by the EF1α short promoter (EFS-IL2RG), and we tested its efficacy and safety in vivo by transplanting transduced Il2rg-deficient Lin- HSPCs in an Il2rg -/- / Rag2 -/- mouse model...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29601071/erratum-detection-of-replication-competent-lentivirus-using-a-qpcr-assay-for-vsv-g
#18
Lindsey M Skrdlant, Randall J Armstrong, Brett M Keidaisch, Mario F Lorente, David L DiGiusto
[This corrects the article DOI: 10.1016/j.omtm.2017.09.001.].
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29560384/neurturin-gene-therapy-protects-parasympathetic-function-to-prevent-irradiation-induced-murine-salivary-gland-hypofunction
#19
Joao N A Ferreira, Changyu Zheng, Isabelle M A Lombaert, Corinne M Goldsmith, Ana P Cotrim, Jennifer M Symonds, Vaishali N Patel, Matthew P Hoffman
Head and neck cancer patients treated with irradiation often present irreversible salivary gland hypofunction for which no conventional treatment exists. We recently showed that recombinant neurturin, a neurotrophic factor, improves epithelial regeneration of mouse salivary glands in ex vivo culture after irradiation by reducing apoptosis of parasympathetic neurons. Parasympathetic innervation is essential to maintain progenitor cells during gland development and for regeneration of adult glands. Here, we investigated whether a neurturin-expressing adenovirus could be used for gene therapy in vivo to protect parasympathetic neurons and prevent gland hypofunction after irradiation...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29556508/production-and-purification-of-high-titer-newcastle-disease-virus-for-use-in-preclinical-mouse-models-of-cancer
#20
Lisa A Santry, Thomas M McAusland, Leonardo Susta, Geoffrey A Wood, Pierre P Major, Jim J Petrik, Byram W Bridle, Sarah K Wootton
Newcastle disease virus (NDV) is a single-stranded, negative-sense RNA virus in the Paramyxoviridae family. Although primarily an avian pathogen, NDV is a potent oncolytic virus that has been shown to be safe and effective in a variety of preclinical cancer models and human clinical trials. To produce virus for oncolytic trials, NDV is commonly amplified in embryonated chicken eggs and purified from the allantoic fluid. Conventional methods for purifying virus from allantoic fluid often result in relatively low-titer preparations containing high levels of impurities, including immunogenic chicken host cell proteins from allantoic fluid...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
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