6,163 results match your criteria Molecular Therapy [Journal]


Improved CoChR Variants Restore Visual Acuity and Contrast Sensitivity in a Mouse Model of Blindness under Ambient Light Conditions.

Mol Ther 2019 Apr 9. Epub 2019 Apr 9.

Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address:

Severe photoreceptor cell death in retinal degenerative diseases leads to partial or complete blindness. Optogenetics is a promising strategy to treat blindness. The feasibility of this strategy has been demonstrated through the ectopic expression of microbial channelrhodopsins (ChRs) and other genetically encoded light sensors in surviving retinal neurons in animal models. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.04.002DOI Listing

Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Breast Cancer.

Mol Ther 2019 Apr 6. Epub 2019 Apr 6.

Department of Occupational and Environmental Health, School of Health Sciences, Wuhan University, Wuhan 430071, Hubei, China. Electronic address:

E2F transcription factors (E2Fs), a group of genes that encode a family of transcription factors, have been identified as being involved in the tumor progression of various cancer types. Increasing experimental evidence indicates that E2Fs are implicated in breast cancer tumorigenesis. However, the diverse expression patterns and prognostic values of eight E2Fs have yet to be analyzed. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15250016193015
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http://dx.doi.org/10.1016/j.ymthe.2019.03.019DOI Listing
April 2019
3 Reads

Gene and Cell Therapy: Success Stories and Future Challenges.

Mol Ther 2019 Apr 19. Epub 2019 Apr 19.

A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address:

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http://dx.doi.org/10.1016/j.ymthe.2019.04.012DOI Listing

miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma.

Mol Ther Nucleic Acids 2019 Mar 13;16:391-406. Epub 2019 Mar 13.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy; IRGS, Biogem, Molecular and Precision Oncology Laboratory, Via Camporeale, 83031 Ariano Irpino, Italy. Electronic address:

miR-125b, ubiquitously expressed and frequently dysregulated in several tumors, has gained special interest in the field of cancer research, displaying either oncogenic or oncosuppressor potential based on tumor type. We have previously demonstrated its tumor-suppressive role in multiple myeloma (MM), but the analysis of molecular mechanisms needs additional investigation. The purpose of this study was to explore the effects of miR-125b and its chemically modified analogs in modulating cell viability and cancer-associated molecular pathways, also focusing on the functional aspects of stress adaptation (autophagy and senescence), as well as programmed cell death (apoptosis). Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.023DOI Listing

Epigenetic Inhibition Puts Target Antigen in the Crosshairs of CAR T Cells.

Mol Ther 2019 Apr 18. Epub 2019 Apr 18.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA. Electronic address:

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https://linkinghub.elsevier.com/retrieve/pii/S15250016193017
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http://dx.doi.org/10.1016/j.ymthe.2019.04.007DOI Listing
April 2019
1 Read

Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea.

Mol Ther 2019 Apr 2. Epub 2019 Apr 2.

CNRS UMR 7260, Aix-Marseille Université, Marseille, France; Laboratory of Bioengineering and Nanoscience, LBN, University of Montpellier, Montpellier, France. Electronic address:

Most cases of sensorineural deafness are caused by degeneration of hair cells. Although stem/progenitor cell therapy is becoming a promising treatment strategy in a variety of organ systems, cell engraftment in the adult mammalian cochlea has not yet been demonstrated. In this study, we generated human otic progenitor cells (hOPCs) from induced pluripotent stem cells (iPSCs) in vitro and identified these cells by the expression of known otic markers. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15250016193011
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http://dx.doi.org/10.1016/j.ymthe.2019.03.018DOI Listing
April 2019
1 Read

Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma.

Mol Ther 2019 Apr 8. Epub 2019 Apr 8.

Allogene Therapeutics, Inc., 210 E. Grand Avenue, South San Francisco, CA 94080, USA. Electronic address:

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.04.001DOI Listing
April 2019
1 Read

Co-assembled Ca Alginate-Sulfate Nanoparticles for Intracellular Plasmid DNA Delivery.

Mol Ther Nucleic Acids 2019 Mar 28;16:378-390. Epub 2019 Mar 28.

Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; The Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel. Electronic address:

Successful gene therapy requires the development of suitable carriers for the selective and efficient delivery of genes to specific target cells, with minimal toxicity. In this work, we present a non-viral vector for gene delivery composed of biocompatible materials, CaCl, plasmid DNA and the semi-synthetic anionic biopolymer alginate sulfate (AlgS), which spontaneously co-assembled to form nanoparticles (NPs). The NPs were characterized with a slightly anionic surface charge (Zeta potential [ζ] = -14 mV), an average size of 270 nm, and their suspension was stable for several days with no aggregation. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193006
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http://dx.doi.org/10.1016/j.omtn.2019.03.006DOI Listing
March 2019
2 Reads

AAV Engineering Identifies a Species Barrier That Highlights a Portal to the Brain.

Mol Ther 2019 Apr 16. Epub 2019 Apr 16.

Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Mass Eye and Ear, Boston, MA, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; The Broad Institute of Harvard and MIT, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address:

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https://linkinghub.elsevier.com/retrieve/pii/S15250016193017
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http://dx.doi.org/10.1016/j.ymthe.2019.04.006DOI Listing
April 2019
1 Read

Highly Efficient and Selective CAR-Gene Transfer Using CD4- and CD8-Targeted Lentiviral Vectors.

Mol Ther Methods Clin Dev 2019 Jun 16;13:371-379. Epub 2019 Mar 16.

Division of Molecular Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany.

Chimeric antigen receptor (CAR)-modified T cells have revealed promising results in the treatment of cancer, but they still need to overcome various hurdles, including a complicated manufacturing process. Receptor-targeted lentiviral vectors (LVs) delivering genes selectively to T cell subtypes may facilitate and improve CAR T cell generation, but so far they have resulted in lower gene delivery rates than conventional LVs (vesicular stomatitis virus [VSV]-LV). To overcome this limitation, we studied the effect of the transduction enhancer Vectofusin-1 on gene delivery to human T cells with CD4- and CD8-targeted LVs, respectively, encoding a second-generation CD19-CAR in conjunction with a truncated version of the low-affinity nerve growth factor receptor (ΔLNGFR) as reporter. Read More

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http://dx.doi.org/10.1016/j.omtm.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453803PMC

Inducing Fat to Feed a Natural Killer of Malignancy.

Mol Ther 2019 Apr 13. Epub 2019 Apr 13.

Division of Transplant and Cellular Therapies, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ymthe.2019.04.005DOI Listing

Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2.

Mol Ther Nucleic Acids 2019 Mar 23;16:367-377. Epub 2019 Mar 23.

Sirna Therapeutics a former subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address:

Drug combinations can improve the control of diseases involving redundant and highly regulated pathways. Validating a multi-target therapy early in drug development remains difficult. Small interfering RNAs (siRNAs) are routinely used to selectively silence a target of interest. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463220PMC

Advancements and Obstacles of CRISPR-Cas9 Technology in Translational Research.

Mol Ther Methods Clin Dev 2019 Jun 15;13:359-370. Epub 2019 Mar 15.

Department of Thoracic Cancer, Cancer Center, West China Hospital, West China School of Medicine, Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, China.

The expanding CRISPR-Cas9 technology is an easily accessible, programmable, and precise gene-editing tool with numerous applications, most notably in biomedical research. Together with advancements in genome and transcriptome sequencing in the era of metadata, genomic engineering with CRISPR-Cas9 meets the developmental requirements of precision medicine, and clinical tests using CRISPR-Cas9 are now possible. This review summarizes developments and established preclinical applications of CRISPR-Cas9 technology, along with its current challenges, and highlights future applications in translational research. Read More

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http://dx.doi.org/10.1016/j.omtm.2019.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447755PMC

Preclinical Testing in Translational Animal Models of Prader-Willi Syndrome: Overview and Gap Analysis.

Mol Ther Methods Clin Dev 2019 Jun 14;13:344-358. Epub 2019 Mar 14.

Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing endocrine, musculoskeletal, and neurological dysfunction. PWS is caused by the inactivation of contiguous genes, complicating the development of targeted therapeutics. Clinical trials are now underway in PWS, with more trials to be implemented in the next few years. Read More

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http://dx.doi.org/10.1016/j.omtm.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447752PMC
June 2019
1 Read

Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels.

Mol Ther 2019 Mar 30. Epub 2019 Mar 30.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

Endothelial surface and circulating glycoprotein von Willebrand factor (vWF) regulates platelet adhesion and is associated with thrombotic diseases, including ischemic stroke, myocardial infarction, and peripheral vascular disease. Thrombosis, as manifested in these diseases, is the leading cause of disability and death in the western world. Current parenteral antithrombotic and thrombolytic agents used to treat these conditions are limited by a short therapeutic window, irreversibility, and major risk of hemorrhage. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.016DOI Listing
March 2019
2 Reads

Delivery of Cell-Specific Aptamers to the Arterial Wall with an Occlusion Perfusion Catheter.

Mol Ther Nucleic Acids 2019 Mar 23;16:360-366. Epub 2019 Mar 23.

Mechanical Engineering Department, University of South Alabama, Mobile, AL, USA. Electronic address:

Current strategies to prevent restenosis following endovascular treatment include the local delivery of anti-proliferative agents to inhibit vascular smooth muscle cell (VSMC) proliferation and migration. These agents, not specific to VSMCs, are deposited on the luminal surface and therefore target endothelial cells and delay vascular healing. Cell-targeted therapies, (e. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193006
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http://dx.doi.org/10.1016/j.omtn.2019.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462795PMC
March 2019
1 Read

Rapidly Neutralizable and Highly Anticoagulant Thrombin-Binding DNA Aptamer Discovered by MACE SELEX.

Mol Ther Nucleic Acids 2019 Mar 22;16:348-359. Epub 2019 Mar 22.

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo 153-8902, Japan; JST, PRESTO, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo 153-8902, Japan. Electronic address:

We present a rapidly neutralizable and highly anticoagulant thrombin-binding aptamer with a short toehold sequence, originally discovered by systematic evolution of ligands by exponential enrichment (SELEX) with microbead-assisted capillary electrophoresis (MACE). MACE is a novel CE-partitioning method for SELEX and able to separate aptamers from a library of unbound nucleic acids, where the aptamer and target complexes can be detected reliably and partitioned with high purity even in the first selection cycle. Three selection rounds of MACE-SELEX discovered several TBAs with a nanomolar affinity (K = 4. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193006
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http://dx.doi.org/10.1016/j.omtn.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462803PMC
March 2019
5 Reads

AAV5-miHTT Gene Therapy Demonstrates Sustained Huntingtin Lowering and Functional Improvement in Huntington Disease Mouse Models.

Mol Ther Methods Clin Dev 2019 Jun 16;13:334-343. Epub 2019 Mar 16.

Department of Research and Development, uniQure biopharma B.V., Amsterdam, the Netherlands.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an autosomal dominant CAG repeat expansion in the () gene. The translated expanded polyglutamine repeat in the HTT protein is known to cause toxic gain of function. We showed previously that strong HTT lowering prevented neuronal dysfunction in HD rodents and minipigs after single intracranial injection of adeno-associated viral vector serotype 5 expressing a microRNA targeting human (AAV5-miHTT). Read More

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http://dx.doi.org/10.1016/j.omtm.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446047PMC

Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration.

Mol Ther 2019 Mar 30. Epub 2019 Mar 30.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada; Department of Otolaryngology - Head & Neck Surgery, University of Toronto, Toronto, ON M5G 2C4, Canada. Electronic address:

Hearing loss is one of the most prevalent sensory deficits worldwide and can result from the death of mechanosensory hair cells that transduce auditory signals in the cochlea. The mammalian cochlea lacks the capacity to regenerate these hair cells once damaged, and currently there are no biological therapies for hearing loss. Understanding the signaling pathways responsible for hair cell development can inform regenerative strategies and identify targets for treating hearing loss. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.017DOI Listing
March 2019
1 Read

MicroRNA-145 Regulates Pathological Retinal Angiogenesis by Suppression of TMOD3.

Mol Ther Nucleic Acids 2019 Mar 21;16:335-347. Epub 2019 Mar 21.

Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. Electronic address:

Pathological angiogenesis is a hallmark of various vascular diseases, including vascular eye disorders. Dysregulation of microRNAs (miRNAs), a group of small regulatory RNAs, has been implicated in the regulation of ocular neovascularization. This study investigated the specific role of microRNA-145 (miR-145) in regulating vascular endothelial cell (EC) function and pathological ocular angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193005
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http://dx.doi.org/10.1016/j.omtn.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460252PMC
March 2019
4 Reads

Strategies for the Induction of Immune Tolerance to Enzyme Replacement Therapy in Mucopolysaccharidosis Type I.

Mol Ther Methods Clin Dev 2019 Jun 2;13:321-333. Epub 2019 Mar 2.

Stem Cell and Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. Read More

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http://dx.doi.org/10.1016/j.omtm.2019.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441787PMC
June 2019
1 Read

Characterization of HIV-1 Nucleoside-Modified mRNA Vaccines in Rabbits and Rhesus Macaques.

Mol Ther Nucleic Acids 2019 Apr 21;15:36-47. Epub 2019 Mar 21.

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Despite the enormous effort in the development of effective vaccines against HIV-1, no vaccine candidate has elicited broadly neutralizing antibodies in humans. Thus, generation of more effective anti-HIV vaccines is critically needed. Here we characterize the immune responses induced by nucleoside-modified and purified mRNA-lipid nanoparticle (mRNA-LNP) vaccines encoding the clade C transmitted/founder HIV-1 envelope (Env) 1086C. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193006
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http://dx.doi.org/10.1016/j.omtn.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454128PMC
April 2019
4 Reads

Genome-Editing Technologies: Concept, Pros, and Cons of Various Genome-Editing Techniques and Bioethical Concerns for Clinical Application.

Mol Ther Nucleic Acids 2019 Apr 3;16:326-334. Epub 2019 Apr 3.

Department of Pathology, PNS HAFEEZ Hospital, Pathology E-8, Islamabad, Islamabad 44400, Pakistan. Electronic address:

The traditional healthcare system is at the doorstep for entering into the arena of molecular medicine. The enormous knowledge and ongoing research have now been able to demonstrate methodologies that can alter DNA coding. The techniques used to edit or change the genome evolved from the earlier attempts like nuclease technologies, homing endonucleases, and certain chemical methods. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193005
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http://dx.doi.org/10.1016/j.omtn.2019.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454098PMC
April 2019
8 Reads

Delivery of GalNAc-Conjugated Splice-Switching ASOs to Non-hepatic Cells through Ectopic Expression of Asialoglycoprotein Receptor.

Mol Ther Nucleic Acids 2019 Mar 13;16:313-325. Epub 2019 Mar 13.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. Electronic address:

Splice-switching antisense oligonucleotides (ASOs) are promising therapeutic tools to target various genetic diseases, including cancer. However, in vivo delivery of ASOs to orthotopic tumors in cancer mouse models or to certain target tissues remains challenging. A viable solution already in use is receptor-mediated uptake of ASOs via tissue-specific receptors. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453860PMC
March 2019
1 Read

In Vivo Delivery of a DNA-Encoded Monoclonal Antibody Protects Non-human Primates against Zika Virus.

Mol Ther 2019 Mar 28. Epub 2019 Mar 28.

Vaccine & Immunotherapy Center, The Wistar Institute of Anatomy & Biology, Philadelphia, PA, USA. Electronic address:

Zika virus (ZIKV) infection is endemic to several world regions, and many others are at high risk for seasonal outbreaks. Synthetic DNA-encoded monoclonal antibody (DMAb) is an approach that enables in vivo delivery of highly potent mAbs to control infections. We engineered DMAb-ZK190, encoding the mAb ZK190 neutralizing antibody, which targets the ZIKV E protein DIII domain. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.005DOI Listing

Adoptive Transfer of NKG2D CAR mRNA-Engineered Natural Killer Cells in Colorectal Cancer Patients.

Mol Ther 2019 Mar 20. Epub 2019 Mar 20.

Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China. Electronic address:

By fusing the extracellular domain of the natural killer (NK) cell receptor NKG2D to DAP12, we constructed a chimeric antigen receptor (CAR) to improve NK cell tumor responses. An RNA electroporation approach that provides transient expression of the CAR was adopted as a risk mitigation strategy. Expression of the NKG2D RNA CAR significantly augmented the cytolytic activity of NK cells against several solid tumor cell lines in vitro and provided a clear therapeutic benefit to mice with established solid tumors. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.011DOI Listing
March 2019
1 Read

A Novel Endogenous Damage Signal, CSF-2, Activates Multiple Beneficial Functions of Adipose Tissue-Derived Mesenchymal Stem Cells.

Mol Ther 2019 Mar 19. Epub 2019 Mar 19.

Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea. Electronic address:

The major challenges of current mesenchymal stem cell (MSC)-based therapeutics are their low differentiation potential into specialized cell types and their homing ability to sites of injury. Therefore, many researchers have directed their efforts toward finding a novel stimulatory factor that can significantly enhance the therapeutic effects of MSCs. Colony-stimulating factor 2 (CSF-2) is previously known as a hematopoietic growth factor involved in the differentiation of various myeloid cells from hematopoietic progenitor cells. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15250016193009
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http://dx.doi.org/10.1016/j.ymthe.2019.03.010DOI Listing
March 2019
1 Read

Lentiviral Vector-Based Dendritic Cell Vaccine Suppresses HIV Replication in Humanized Mice.

Mol Ther 2019 Mar 15. Epub 2019 Mar 15.

Department of Microbiology, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address:

HIV-1-infected individuals are treated with lifelong antiretroviral drugs to control the infection. A means to strengthen the antiviral T cell response might allow them to control viral loads without antiretroviral drugs. We report the development of a lentiviral vector-based dendritic cell (DC) vaccine in which HIV-1 antigen is co-expressed with CD40 ligand (CD40L) and a soluble, high-affinity programmed cell death 1 (PD-1) dimer. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.008DOI Listing
March 2019
1 Read

DNA Aptamers Targeting BACE1 Reduce Amyloid Levels and Rescue Neuronal Deficiency in Cultured Cells.

Mol Ther Nucleic Acids 2019 Mar 15;16:302-312. Epub 2019 Mar 15.

Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China. Electronic address:

β-amyloid (Aβ) plays an essential role in the pathogenesis of Alzheimer's disease (AD). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is indispensable for Aβ production, and knockout of BACE1 has no overt phenotypes in mouse. Thus, fine modulation of BACE1 may be a safe and effective treatment for AD patients. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453838PMC
March 2019
2 Reads

Antithrombotic Effect of shRNA Target F12 Mediated by Adeno-Associated Virus.

Mol Ther Nucleic Acids 2019 Mar 15;16:295-301. Epub 2019 Mar 15.

The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China. Electronic address:

Coagulation factor XII (FXII) plays a crucial role in thrombosis. Moreover, deficiencies in FXII are not associated with excessive bleeding, and its depletion exhibits satisfactory protective effect on thrombus formation. Several strategies targeting FXII have been applied to inhibit thrombosis formation. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454094PMC
March 2019
2 Reads

MicroRNA-134-5p Regulates Media Degeneration through Inhibiting VSMC Phenotypic Switch and Migration in Thoracic Aortic Dissection.

Mol Ther Nucleic Acids 2019 Feb 28;16:284-294. Epub 2019 Feb 28.

Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu, China. Electronic address:

Abnormal phenotypic switch, migration, and proliferation of vascular smooth muscle cells (VSMCs) are hallmarks for pathogenesis of thoracic aortic dissection (TAD). In the current study, we identified miR-134-5p as a critical regulator controlling human VSMC phenotypic switch and migration to investigate whether miR-134-5p affects human VSMC functions and development of TAD. Using miRNA microarray of aorta specimens from 12 TAD and 12 controls, we identified miR-134-5p, which was significantly downregulated in TAD tissues. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446055PMC
February 2019
2 Reads

miR-3687 Overexpression Promotes Bladder Cancer Cell Growth by Inhibiting the Negative Effect of FOXP1 on Cyclin E2 Transcription.

Mol Ther 2019 Mar 15. Epub 2019 Mar 15.

Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA. Electronic address:

Cyclin E2, a member of the cyclin family, is a key cell cycle-related protein. This protein plays essential roles in cancer progression, and, as such, an inhibitor of cyclin E2 has been approved to treat several types of cancers. Even so, mechanisms underlying how to regulate cyclin E2 expression in cancer remain largely unknown. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.006DOI Listing
March 2019
6.227 Impact Factor

Exploring the MIR143-UPAR Axis for the Inhibition of Human Prostate Cancer Cells In Vitro and In Vivo.

Mol Ther Nucleic Acids 2019 Feb 27;16:272-283. Epub 2019 Feb 27.

Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany.

MIR143 is pathologically downregulated and may function as a tumor suppressor in prostate cancer. Likewise, the urokinase plasminogen activator receptor (UPAR) is overexpressed in prostate carcinoma, representing a negative prognostic marker and putative therapeutic target gene. In this paper, we establish UPAR as a new direct target of MIR143. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444223PMC
February 2019
2 Reads

A Facile Method for the Removal of dsRNA Contaminant from In Vitro-Transcribed mRNA.

Mol Ther Nucleic Acids 2019 Apr 27;15:26-35. Epub 2019 Feb 27.

BioNTech RNA Pharmaceuticals, 55131 Mainz, Germany.

The increasing importance of in vitro-transcribed (IVT) mRNA for synthesizing the encoded therapeutic protein in vivo demands the manufacturing of pure mRNA products. The major contaminant in the IVT mRNA is double-stranded RNA (dsRNA), a transcriptional by-product that can be removed only by burdensome procedure requiring special instrumentation and generating hazardous waste. Here we present an alternative simple, fast, and cost-effective method involving only standard laboratory techniques. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444222PMC
April 2019
3 Reads

Clinically Relevant Correction of Recessive Dystrophic Epidermolysis Bullosa by Dual sgRNA CRISPR/Cas9-Mediated Gene Editing.

Mol Ther 2019 Mar 15. Epub 2019 Mar 15.

Department of Biomedical Engineering, Carlos III University (UC3M), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) U714, Madrid, Spain; Fundación Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain; Epithelial Biomedicine Division, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain. Electronic address:

Gene editing constitutes a novel approach for precisely correcting disease-causing gene mutations. Frameshift mutations in COL7A1 causing recessive dystrophic epidermolysis bullosa are amenable to open reading frame restoration by non-homologous end joining repair-based approaches. Efficient targeted deletion of faulty COL7A1 exons in polyclonal patient keratinocytes would enable the translation of this therapeutic strategy to the clinic. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.007DOI Listing
March 2019
3 Reads

Synthetic miR-143 Exhibited an Anti-Cancer Effect via the Downregulation of K-RAS Networks of Renal Cell Cancer Cells In Vitro and In Vivo.

Mol Ther 2019 Mar 13. Epub 2019 Mar 13.

United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address:

To understand the role of RAS-signaling networks in the pathogenesis of renal cell carcisnoma, we clarified the relationship between miR-143 and RAS. The expression of miR-143 was extremely downregulated in tumor tissues from renal cell carcinoma patients compared with that in the adjacent normal tissues and Caki-1 cells. We developed a synthetic miR-143#12, and we found that the ectopic expression of it inhibited cell growth with autophagy in Caki-1 cells. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.004DOI Listing
March 2019
3 Reads
6.227 Impact Factor

lncRNA TUG1 Promotes Cisplatin Resistance by Regulating CCND2 via Epigenetically Silencing miR-194-5p in Bladder Cancer.

Mol Ther Nucleic Acids 2019 Feb 26;16:257-271. Epub 2019 Feb 26.

School of Health Sciences, Macao Polytechnic Institute, Macao, China. Electronic address:

Taurine-upregulated gene 1 (TUG1) has been involved in tumorigenesis of several human cancers, but its precise biological role in bladder cancer remains largely elusive. In this study, we found that TUG1 was upregulated in bladder cancer and the expression of TUG1 was positively and negatively correlated with CCND2 and miR-194-5p, respectively. MiR-194-5p expression was frequently decreased through promoter hypermethylation, while it was epigenetically increased following cisplatin and 5-aza-2'-deoxycytidine (5-Aza-DC) treatment. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439231PMC
February 2019

Allele-Specific CRISPR/Cas9 Correction of a Heterozygous DNM2 Mutation Rescues Centronuclear Myopathy Cell Phenotypes.

Mol Ther Nucleic Acids 2019 Feb 27;16:246-256. Epub 2019 Feb 27.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France; INSERM U1258, Illkirch 67404, France; CNRS UMR7104, Illkirch 67404, France; Strasbourg University, Illkirch 67404, France. Electronic address:

Genome editing with the CRISPR/Cas9 technology has emerged recently as a potential strategy for therapy in genetic diseases. For dominant mutations linked to gain-of-function effects, allele-specific correction may be the most suitable approach. In this study, we tested allele-specific inactivation or correction of a heterozygous mutation in the Dynamin 2 (DNM2) gene that causes the autosomal dominant form of centronuclear myopathies (CNMs), a rare muscle disorder belonging to the large group of congenital myopathies. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439232PMC
February 2019

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-126-3p Inhibits Pancreatic Cancer Development by Targeting ADAM9.

Mol Ther Nucleic Acids 2019 Mar 1;16:229-245. Epub 2019 Mar 1.

Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China. Electronic address:

Pancreatic cancer is a lethal malignancy with relatively few effective therapies. Recent investigations have highlighted the role of microRNAs (miRNAs) as crucial regulators in various tumor processes including tumor progression. Hence the current study aimed to investigate the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomal microRNA-126-3p (miR-126-3p) in pancreatic cancer. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439275PMC

Generate TALE/TALEN as Easily and Rapidly as Generating CRISPR.

Mol Ther Methods Clin Dev 2019 Jun 19;13:310-320. Epub 2019 Feb 19.

State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China.

TALE has always had potential as a gene-editing and regulatory tool. However, with the advent of CRISPR/Cas9, an easier to use tool with the same function, TALE has recently been abandoned because of the time-consuming and low-efficiency process required for its construction. The off-target activity of CRISPR/Cas9 has been a challenge to its application. Read More

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http://dx.doi.org/10.1016/j.omtm.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423989PMC

The Future: In Vivo CAR T Cell Gene Therapy.

Mol Ther 2019 Apr 23;27(4):707-709. Epub 2019 Mar 23.

Université Côte d'Azur, INSERM, C3M, Nice, France; CIRI - Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, INSERM, U1111, CNRS, UMR5308, ENS Lyon, 69007 Lyon, France. Electronic address:

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http://dx.doi.org/10.1016/j.ymthe.2019.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453545PMC

Safety of CD34 Hematopoietic Stem Cells and CD4 T Lymphocytes Transduced with LVsh5/C46 in HIV-1 Infected Patients with High-Risk Lymphoma.

Mol Ther Methods Clin Dev 2019 Jun 26;13:303-309. Epub 2019 Feb 26.

Paris Descartes, Sorbonne Paris Cité, France.

Although the risk of developing lymphoma has decreased in the highly active antiretroviral therapy era, this cancer remains the major cause of mortality in HIV-infected patients. Autologous hematopoietic stem cell transplantation (ASCT) outcome does not differ for HIV-infected versus HIV-uninfected patients. We propose to develop a new treatment for HIV-associated high-risk lymphoma based on autologous transplantation of two genetically modified products: CD4 T lymphocytes and CD34 hematopoietic stem cells (HSPCs). Read More

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http://dx.doi.org/10.1016/j.omtm.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416524PMC
June 2019
5 Reads

Anti-cancer Effects of a Chemically Modified miR-143 on Bladder Cancer by Either Systemic or Intravesical Treatment.

Mol Ther Methods Clin Dev 2019 Jun 20;13:290-302. Epub 2019 Feb 20.

United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.

We developed a novel chemically modified miR-143 (miR-143#12), and with it we investigated the contribution of miR-143 to the pathogenesis of bladder cancer (BC), in which miR-143 is extremely downregulated. Since miR-143 silenced K-RAS and RAS effector-signaling molecules Erk and Akt, we performed the ectopic expression of miR-143 in human BC 253J-BV cells, and we examined the growth inhibition and the mechanism of it and in orthotopic model mice. As a result, miR-143#12 induced a marked growth inhibition with apoptosis through impairing RAS-signaling networks, including SOS1, which exchanges guanosine diphosphate (GDP)/RAS for active guanosine triphosphate (GTP)/RAS. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S23290501193002
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http://dx.doi.org/10.1016/j.omtm.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416526PMC
June 2019
4 Reads

In vitro-Transcribed mRNA Therapeutics: Out of the Shadows and Into the Spotlight.

Authors:
Katalin Karikó

Mol Ther 2019 Apr 21;27(4):691-692. Epub 2019 Mar 21.

BioNTech RNA Pharmaceuticals, Mainz, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ymthe.2019.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453554PMC

Recent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases.

Mol Ther 2019 Apr 6;27(4):803-823. Epub 2019 Mar 6.

Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University Children's Hospital, University of Tuebingen, 72074 Tuebingen, Germany. Electronic address:

Protein supplementation therapy using in vitro-transcribed (IVT) mRNA for genetic diseases contains huge potential as a new class of therapy. From the early ages of synthetic mRNA discovery, a great number of studies showed the versatile use of IVT mRNA as a novel approach to supplement faulty or absent protein and also as a vaccine. Many modifications have been made to produce high expressions of mRNA causing less immunogenicity and more stability. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453549PMC
April 2019
4 Reads

Non-viral Delivery of Zinc Finger Nuclease mRNA Enables Highly Efficient In Vivo Genome Editing of Multiple Therapeutic Gene Targets.

Mol Ther 2019 Apr 7;27(4):866-877. Epub 2019 Mar 7.

Sangamo Therapeutics, 501 Canal Blvd., Suite A, Richmond, CA 94804, USA.

It has previously been shown that engineered zinc finger nucleases (ZFNs) can be packaged into adeno-associated viruses (AAVs) and delivered intravenously into mice, non-human primates, and most recently, humans to induce highly efficient therapeutic genome editing in the liver. Lipid nanoparticles (LNPs) are synthetic delivery vehicles that enable repeat administration and are not limited by the presence of preexisting neutralizing antibodies in patients. Here, we show that mRNA encoding ZFNs formulated into LNP can enable >90% knockout of gene expression in mice by targeting the TTR or PCSK9 gene, at mRNA doses 10-fold lower than has ever been reported. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453547PMC
April 2019
6.227 Impact Factor

A Small RNA Transforms the Multidrug Resistance of Pseudomonas aeruginosa to Drug Susceptibility.

Mol Ther Nucleic Acids 2019 Feb 22;16:218-228. Epub 2019 Feb 22.

Department of Biomedical Sciences, College of Veterinary Medicine and Life Science, City University of Hong Kong, Kowloon, Hong Kong Special Administrative Region, China. Electronic address:

Bacteria with multiple drug resistance (MDR) have become a global issue worldwide, and hundreds of thousands of people's lives are threatened every year. The emergence of novel MDR strains and insufficient development of new antimicrobial agents are the major reasons that limit the choice of antibiotics for the treatment of bacterial infection. Thus, preserving the clinical value of current antibiotics could be one of the effective approaches to resolve this problem. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193004
Publisher Site
http://dx.doi.org/10.1016/j.omtn.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429555PMC
February 2019
6 Reads

MicroRNA-26b-5p Inhibits Mouse Liver Fibrogenesis and Angiogenesis by Targeting PDGF Receptor-Beta.

Mol Ther Nucleic Acids 2019 Feb 26;16:206-217. Epub 2019 Feb 26.

Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China. Electronic address:

Here microRNAs (miRNAs) with potentially therapeutic effects were screened and explored during liver fibrogenesis and angiogenesis via targeting the important mediators. Chimera mice with EGFP bone marrow mesenchymal stromal cells (BMSCs) were fed with methionine-choline-deficient and high-fat (MCDHF) diet to induce liver injury. Increased expression of platelet-derived growth factor receptor-beta (PDGFR-β) was detected in MCDHF mice, with a positive correlation to fibrosis and angiogenesis markers. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426711PMC
February 2019
3 Reads

Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation.

Mol Ther Nucleic Acids 2019 Feb 26;16:194-205. Epub 2019 Feb 26.

Department of RNA Therapeutics, Merck & Co., Inc., West Point, PA 19486, USA; Department of Infectious Diseases and Vaccines, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address:

Clinical application of siRNA-based therapeutics outside of the liver has been hindered by the inefficient delivery of siRNA effector molecules into extra-hepatic organs and cells of interest. To understand the parameters that enable RNAi activity in vivo, it is necessary to develop a systematic approach to identify which cells within a tissue are permissive to oligonucleotide internalization and activity. In the present study, we evaluate the distribution and activity within the lung of chemically stabilized siRNA to characterize cell-type tropism and structure-activity relationship. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426712PMC
February 2019
3 Reads

Tetrafunctional Block Copolymers Promote Lung Gene Transfer in Newborn Piglets.

Mol Ther Nucleic Acids 2019 Feb 26;16:186-193. Epub 2019 Feb 26.

Université Côte d'Azur, INSERM, CNRS, IPMC, Valbonne, France; FHU-OncoAge, Nice, France. Electronic address:

Tetrafunctional block copolymers are molecules capable of complexing DNA. Although ineffective in vitro, studies in mice have shown that the tetrafunctional block copolymer 704 is a more efficient lung gene transfer agent than the cationic liposome GL67A, previously used in a phase II clinical trial in cystic fibrosis patients. In the present study, we compared the gene transfer capacity of the 704-DNA formulation and a cationic liposome-DNA formulation equivalent to GL67A in a larger-animal model, the newborn piglet. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426709PMC
February 2019
1 Read