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Molecular Therapy. Methods & Clinical Development

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https://www.readbyqxmd.com/read/28808666/lipidomic-evaluation-of-feline-neurologic-disease-after-aav-gene-therapy
#1
Heather L Gray-Edwards, Xuntian Jiang, Ashley N Randle, Amanda R Taylor, Taylor L Voss, Aime K Johnson, Victoria J McCurdy, Miguel Sena-Esteves, Daniel S Ory, Douglas R Martin
GM1 gangliosidosis is a fatal lysosomal disorder, for which there is no effective treatment. Adeno-associated virus (AAV) gene therapy in GM1 cats has resulted in a greater than 6-fold increase in lifespan, with many cats remaining alive at >5.7 years of age, with minimal clinical signs. Glycolipids are the principal storage product in GM1 gangliosidosis whose pathogenic mechanism is not completely understood. Targeted lipidomics analysis was performed to better define disease mechanisms and identify markers of disease progression for upcoming clinical trials in humans...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28791314/generation-of-a-vero-based-packaging-cell-line-to-produce-sv40-gene-delivery-vectors-for-use-in-clinical-gene-therapy-studies
#2
Miguel G Toscano, Jeroen van der Velden, Sybrand van der Werf, Machteld Odijk, Ana Roque, Rafael J Camacho-Garcia, Irene G Herrera-Gomez, Irene Mancini, Peter de Haan
Replication-defective (RD) recombinant simian virus 40 (SV40)-based gene delivery vectors hold a great potential for clinical applications because of their presumed non-immunogenicity and capacity to induce immune tolerance to the transgene products in humans. However, the clinical use of SV40 vectors has been hampered by the lack of a packaging cell line that produces replication-competent (RC) free SV40 particles in the vector production process. To solve this problem, we have adapted the current SV40 vector genome used for the production of vector particles and generated a novel Vero-based packaging cell line named SuperVero that exclusively expresses the SV40 large T antigen...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28765827/traceless-targeting-and-isolation-of-gene-edited-immortalized-keratinocytes-from-epidermolysis-bullosa-simplex-patients
#3
Magomet Aushev, Ulrich Koller, Claudio Mussolino, Toni Cathomen, Julia Reichelt
Epidermolysis bullosa simplex (EBS) is a blistering skin disease caused by dominant-negative mutations in either KRT5 or KRT14, resulting in impairment of keratin filament structure and epidermal fragility. Currently, nearly 200 mutations distributed across the entire length of these genes are known to cause EBS. Genome editing using programmable nucleases enables the development of ex vivo gene therapies for dominant-negative genetic diseases. A clinically feasible strategy involves the disruption of the mutant allele while leaving the wild-type allele unaffected...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28725658/mesenchymal-stem-cells-overexpressing-interleukin-10-promote-neuroprotection-in-experimental-acute-ischemic-stroke
#4
Masataka Nakajima, Chikako Nito, Kota Sowa, Satoshi Suda, Yasuhiro Nishiyama, Aki Nakamura-Takahashi, Yuko Nitahara-Kasahara, Kiwamu Imagawa, Tohru Hirato, Masayuki Ueda, Kazumi Kimura, Takashi Okada
Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10) at 0 or 3 hr after ischemia reperfusion...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28702476/regulatable-transgene-expression-for-prevention-of-chemotherapy-induced-peripheral-neuropathy
#5
Daisuke Kawata, Zetang Wu
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication associated with drug treatment of cancer for which there are no effective strategies of prevention or treatment. In this study, we examined the effect of intermittent expression of neurotophin-3 (NT-3) or interleukin-10 (IL-10) from replication-defective herpes simplex virus (HSV)-based regulatable vectors delivered by subcutaneous inoculation to the dorsal root ganglion (DRG) on the development of paclitaxel-induced peripheral neuropathy...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28702475/deletion-of-the-virion-host-shut-off-gene-enhances-neuronal-selective-transgene-expression-from-an-hsv-vector-lacking-functional-ie-genes
#6
Yoshitaka Miyagawa, Gianluca Verlengia, Bonnie Reinhart, Fang Han, Hiroaki Uchida, Silvia Zucchini, William F Goins, Michele Simonato, Justus B Cohen, Joseph C Glorioso
The ability of herpes simplex virus (HSV) to establish lifelong latency in neurons suggests that HSV-derived vectors hold promise for gene delivery to the nervous system. However, vector toxicity and transgene silencing have created significant barriers to vector applications to the brain. Recently, we described a vector defective for all immediate-early gene expression and deleted for the joint region between the two unique genome segments that proved capable of extended transgene expression in non-neuronal cells...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28702474/targeting-visceral-fat-by-intraperitoneal-delivery-of-novel-aav-serotype-vector-restricting-off-target-transduction-in-liver
#7
Wei Huang, Xianglan Liu, Nicholas J Queen, Lei Cao
It is challenging to genetically manipulate fat in adults. We demonstrate that intraperitoneal (i.p.) injection of an engineered adeno-associated virus (AAV) serotype Rec2 leads to high transduction of multiple visceral fat depots at a dose of 1 to 2 orders lower than commonly used doses for systemic gene delivery. To target adipose tissue, we develop a single AAV vector harboring two expression cassettes: one using the CBA promoter to drive transgene expression and one using the liver-specific albumin promoter to drive a microRNA-targeting WPRE sequence that only exists in this AAV vector...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28695155/in-silico-restriction-enzyme-digests-to-minimize-mapping-bias-in-genomic-sequencing
#8
REVIEW
Jason Roszik, György Fenyőfalvi, László Halász, Zsolt Karányi, Lóránt Székvölgyi
No abstract text is available yet for this article.
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28664166/lentiviral-fluorescent-genetic-barcoding-for-multiplex-fate-tracking-of-leukemic-cells
#9
Tobias Maetzig, Jens Ruschmann, Lea Sanchez Milde, Courteney K Lai, Niklas von Krosigk, R Keith Humphries
Tracking the behavior of leukemic samples both in vitro and in vivo plays an increasingly large role in efforts to better understand the leukemogenic processes and the effects of potential new therapies. Such work can be accelerated and made more efficient by methodologies enabling the characterization of leukemia samples in multiplex assays. We recently developed three sets of lentiviral fluorescent genetic barcoding (FGB) vectors that create 26, 14, and 6 unique immunophenotyping-compatible color codes from GFP-, yellow fluorescent protein (YFP)-, and monomeric kusabira orange 2 (mKO2)-derived fluorescent proteins...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28664165/clearance-of-heparan-sulfate-and-attenuation-of-cns-pathology-by-intracerebroventricular-bmn-250-in-sanfilippo-type-b-mice
#10
Mika Aoyagi-Scharber, Danielle Crippen-Harmon, Roger Lawrence, Jon Vincelette, Gouri Yogalingam, Heather Prill, Bryan K Yip, Brian Baridon, Catherine Vitelli, Amanda Lee, Olivia Gorostiza, Evan G Adintori, Wesley C Minto, Jeremy L Van Vleet, Bridget Yates, Sara Rigney, Terri M Christianson, Pascale M N Tiger, Melanie J Lo, John Holtzinger, Paul A Fitzpatrick, Jonathan H LeBowitz, Sherry Bullens, Brett E Crawford, Stuart Bunting
Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with no approved treatment. Intracerebroventricular (ICV) delivery of a modified recombinant NAGLU, consisting of human NAGLU fused with insulin-like growth factor 2 (IGF2) for enhanced lysosomal targeting, was previously shown to result in marked enzyme uptake and clearance of HS storage in the Naglu(-/-) mouse brain...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28664164/public-attitudes-toward-gene-therapy-in-china
#11
REVIEW
Jiang-Hui Wang, Rong Wang, Jia Hui Lee, Tiara W U Iao, Xiao Hu, Yu-Meng Wang, Lei-Lei Tu, Yi Mou, Wen-Li Zhu, Ai-Yong He, Shen-Yu Zhu, Di Cao, Lei Yang, Xiao-Bo Tan, Qing Zhang, Guan-Lu Liang, Shu-Min Tang, Ye-Di Zhou, Li-Jun Feng, Li-Jun Zhan, Nan-Nan Tian, Ming-Jie Tang, Ya-Ping Yang, Moeen Riaz, Peter van Wijngaarden, Gregory J Dusting, Guei-Sheung Liu, Yan He
No abstract text is available yet for this article.
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28649578/anti-high-mobility-group-box-1-antibody-ameliorates-albuminuria-in-mrl-lpr-lupus-prone-mice
#12
Haruki Watanabe, Katsue S Watanabe, Keyue Liu, Sumie Hiramatsu, Sonia Zeggar, Eri Katsuyama, Noriko Tatebe, Akiya Akahoshi, Fumiaki Takenaka, Takahisa Hanada, Masaru Akehi, Takanori Sasaki, Ken-Ei Sada, Eiji Matsuura, Masahiro Nishibori, Jun Wada
We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4-15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2'-deoxy-2'-[(18)F]fluoro-β-D-arabinofuranosyl)cytosine ([(18)F]FAC) positron emission tomography/computed tomography (PET/CT) at 12 weeks...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28649577/in%C3%A2-vivo-murine-matured-human-cd3-cells-as-a-preclinical-model-for-t-cell-based-immunotherapies
#13
Kevin G Haworth, Christina Ironside, Zachary K Norgaard, Willimark M Obenza, Jennifer E Adair, Hans-Peter Kiem
Adoptive cellular immunotherapy is a promising and powerful method for the treatment of a broad range of malignant and infectious diseases. Although the concept of cellular immunotherapy was originally proposed in the 1990s, it has not seen successful clinical application until recent years. Despite significant progress in creating engineered receptors against both malignant and viral epitopes, no efficient preclinical animal models exist for rapidly testing and directly comparing these engineered receptors...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28626778/single-cell-based-vector-tracing-in-patients-with-ada-scid-treated-with-stem-cell-gene-therapy
#14
Yuka Igarashi, Toru Uchiyama, Tomoko Minegishi, Sirirat Takahashi, Nobuyuki Watanabe, Toshinao Kawai, Masafumi Yamada, Tadashi Ariga, Masafumi Onodera
Clinical improvement in stem cell gene therapy (SCGT) for primary immunodeficiencies depends on the engraftment levels of genetically corrected cells, and tracing the transgene in each hematopoietic lineage is therefore extremely important in evaluating the efficacy of SCGT. We established a single cell-based droplet digital PCR (sc-ddPCR) method consisting of the encapsulation of a single cell into each droplet, followed by emulsion PCR with primers and probes specific for the transgene. A fluorescent signal in a droplet indicates the presence of a single cell carrying the target gene in its genome, and this system can clearly determine the ratio of transgene-positive cells in the entire population at the genomic level...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28626777/long-term-efficacy-and-safety-of-insulin-and-glucokinase-gene-therapy-for-diabetes-8-year-follow-up-in-dogs
#15
Maria Luisa Jaén, Laia Vilà, Ivet Elias, Veronica Jimenez, Jordi Rodó, Luca Maggioni, Rafael Ruiz-de Gopegui, Miguel Garcia, Sergio Muñoz, David Callejas, Eduard Ayuso, Tura Ferré, Iris Grifoll, Anna Andaluz, Jesus Ruberte, Virginia Haurigot, Fatima Bosch
Diabetes is a complex metabolic disease that exposes patients to the deleterious effects of hyperglycemia on various organs. Achievement of normoglycemia with exogenous insulin treatment requires the use of high doses of hormone, which increases the risk of life-threatening hypoglycemic episodes. We developed a gene therapy approach to control diabetic hyperglycemia based on co-expression of the insulin and glucokinase genes in skeletal muscle. Previous studies proved the feasibility of gene delivery to large diabetic animals with adeno-associated viral (AAV) vectors...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28603746/preclinical-evaluation-of-a-lentiviral-vector-for-huntingtin-silencing
#16
Karine Cambon, Virginie Zimmer, Sylvain Martineau, Marie-Claude Gaillard, Margot Jarrige, Aurore Bugi, Jana Miniarikova, Maria Rey, Raymonde Hassig, Noelle Dufour, Gwenaelle Auregan, Philippe Hantraye, Anselme L Perrier, Nicole Déglon
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) backbone and removing the original reporter genes...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28603745/lentivector-iterations-and-pre-clinical-scale-up-toxicity-testing-targeting-mobilized-cd34-cells-for-correction-of-fabry-disease
#17
Ju Huang, Aneal Khan, Bryan C Au, Dwayne L Barber, Lucía López-Vásquez, Nicole L Prokopishyn, Michel Boutin, Michael Rothe, Jack W Rip, Mona Abaoui, Murtaza S Nagree, Shaalee Dworski, Axel Schambach, Armand Keating, Michael L West, John Klassen, Patricia V Turner, Sandra Sirrs, C Anthony Rupar, Christiane Auray-Blais, Ronan Foley, Jeffrey A Medin
Fabry disease is a rare lysosomal storage disorder (LSD). We designed multiple recombinant lentivirus vectors (LVs) and tested their ability to engineer expression of human α-galactosidase A (α-gal A) in transduced Fabry patient CD34(+) hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28573152/cell-therapy-in-myology-dynamics-of-muscle-precursor-cell-death-after-intramuscular-administration-in-non-human-primates
#18
Daniel Skuk, Jacques P Tremblay
Cell therapy could be useful for the treatment of myopathies. A problem observed in mice, with different results and interpretations, is a significant death among the transplanted cells. We analyzed this problem in non-human primates, the animal model more similar to humans. Autologous or allogeneic myoblasts (with or without a reporter gene) were proliferated in vitro, labeled with [(14)C]thymidine, and intramuscularly injected in macaques. Some monkeys were immunosuppressed for long-term follow-up. Cell-grafted regions were biopsied at different intervals and analyzed by radiolabel quantification and histology...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28567432/effect-of-a-fusion-peptide-by-covalent-conjugation-of-a-mitochondrial-cell-penetrating-peptide-and-a-glutathione-analog-peptide
#19
Carmine Pasquale Cerrato, Ülo Langel
Previously, we designed and synthesized a library of mitochondrial antioxidative cell-penetrating peptides (mtCPPs) superior to the parent peptide, SS31, to protect mitochondria from oxidative damage. A library of antioxidative glutathione analogs called glutathione peptides (UPFs), exceptional in hydroxyl radical elimination compared with glutathione, were also designed and synthesized. Here, a follow-up study is described, investigating the effects of the most promising members from both libraries on reactive oxidative species scavenging ability...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28540323/neuroglobin-can-prevent-or-reverse-glaucomatous-progression-in-dba-2j-mice
#20
Hélène Cwerman-Thibault, Christophe Lechauve, Sébastien Augustin, Delphine Roussel, Élodie Reboussin, Ammara Mohammad, Julie Degardin-Chicaud, Manuel Simonutti, Hong Liang, Françoise Brignole-Baudouin, Anne Maron, Thomas Debeir, Marisol Corral-Debrinski
Mitochondrial dysfunction is responsible for hereditary optic neuropathies. We wished to determine whether preserving mitochondrial bioenergetics could prevent optic neuropathy in a reliable model of glaucoma. DBA/2J mice exhibit elevated intraocular pressure, progressive degeneration of their retinal ganglion cells, and optic neuropathy that resembles glaucoma. We established that glaucoma in these mice is directly associated with mitochondrial dysfunction: respiratory chain activity was compromised in optic nerves 5 months before neuronal loss began, and the amounts of some mitochondrial proteins were reduced in retinas of glaucomatous mice...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
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