6,056 results match your criteria Molecular Therapy [Journal]


Circulating lncRNA BC030099 Increases in Preeclampsia Patients.

Mol Ther Nucleic Acids 2019 Feb 1;14:562-566. Epub 2019 Feb 1.

Department of Gynecology and Obstetrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address:

Long noncoding RNAs (lncRNAs) have increasingly been shown to be important biological regulators involved in numerous diseases. Further, increasing evidence demonstrates that circulating lncRNAs can be used as diagnostic biomarkers. Therefore, the purpose of this study was to evaluate the potential for circulating lncRNAs as novel biomarkers for the diagnosis of preeclampsia. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.01.011DOI Listing
February 2019

Protease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue.

Mol Ther 2019 Jan 29. Epub 2019 Jan 29.

Department of Bioengineering, Rice University, 6100 Main St., Houston, TX 77005, USA. Electronic address:

Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, its adoption as a safe and effective delivery vector for certain diseases relies on altering its tropism to deliver transgenes to desired cell populations. To this end, we have developed a protease-activatable AAV vector, named provector, that responds to elevated extracellular protease activity commonly found in diseased tissue microenvironments. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.015DOI Listing
January 2019

TFAP2C-Activated MALAT1 Modulates the Chemoresistance of Docetaxel-Resistant Lung Adenocarcinoma Cells.

Mol Ther Nucleic Acids 2019 Jan 18;14:567-582. Epub 2019 Jan 18.

Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China. Electronic address:

Chemoresistance remains a great obstacle in effective lung adenocarcinoma (LUAD) treatment. Previously, we verified the role of microRNA-200b (miR-200b) in the formation of docetaxel (DTX)-resistant LUAD cells. This study aims to investigate the mechanism underlying the low level of miR-200b in DTX-resistant LUAD cells. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.01.005DOI Listing
January 2019

ERK Inhibitor Enhances Everolimus Efficacy through the Attenuation of dNTP Pools in Renal Cell Carcinoma.

Mol Ther Nucleic Acids 2019 Jan 10;14:550-561. Epub 2019 Jan 10.

Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China. Electronic address:

The clinical efficiency of everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is palliative as sequential or second-line therapy for renal cell carcinoma (RCC). However, the limited response of everolimus in RCC remains uncertain. In the present study, everolimus-resistant RCC models were established to understand the mechanisms and to seek combination approaches. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.01.001DOI Listing
January 2019

Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice.

Mol Ther 2019 Jan 7. Epub 2019 Jan 7.

GSK, Rockville, MD 20850, USA. Electronic address:

Venezuelan equine encephalitis virus (VEEV) is a known biological defense threat. A live-attenuated investigational vaccine, TC-83, is available, but it has a high non-response rate and can also cause severe reactogenicity. We generated two novel VEE vaccine candidates using self-amplifying mRNA (SAM). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15250016193000
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http://dx.doi.org/10.1016/j.ymthe.2018.12.013DOI Listing
January 2019
1 Read

MicroRNA-672-5p Identified during Weaning Reverses Osteopenia and Sarcopenia in Ovariectomized Mice.

Mol Ther Nucleic Acids 2019 Jan 10;14:536-549. Epub 2019 Jan 10.

Division of Endocrinology, CSIR-CDRI (Council of Scientific and Industrial Research-Central Drug Research Institute), Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India. Electronic address:

Post-menopausal condition augments the biological aging process, characterized by multiple metabolic disorders in which bone loss is the most prevalent outcome and usually coupled with sarcopenia. Coexistence of such associated pathogenesis have much worse health outcomes, compared to individuals with osteoporosis only. Pre- and post-natal bone development demands calcium from mother to fetus during pregnancy and lactation leading to a significant maternal skeletal loss. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.01.002DOI Listing
January 2019

Novel Chimeric Gene Therapy Vectors Based on Adeno-Associated Virus and Four Different Mammalian Bocaviruses.

Mol Ther Methods Clin Dev 2019 Mar 18;12:202-222. Epub 2019 Jan 18.

Department of Infectious Diseases/Virology, Heidelberg University Hospital, Heidelberg, Germany.

Parvoviruses are highly attractive templates for the engineering of safe, efficient, and specific gene therapy vectors, as best exemplified by adeno-associated virus (AAV). Another candidate that currently garners increasing attention is human bocavirus 1 (HBoV1). Notably, HBoV1 capsids can cross-package recombinant (r)AAV2 genomes, yielding rAAV2/HBoV1 chimeras that specifically transduce polarized human airway epithelia (pHAEs). Read More

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http://dx.doi.org/10.1016/j.omtm.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360332PMC

miR-221/222-Mediated Inhibition of Autophagy Promotes Dexamethasone Resistance in Multiple Myeloma.

Mol Ther 2019 Jan 24. Epub 2019 Jan 24.

Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan 430022, China. Electronic address:

Inherent or acquired resistance to chemotherapeutic drugs is still an obstacle for the treatment of multiple myeloma (MM). MicroRNA dysregulation is related to the development of chemoresistance in cancers. However, its role in chemoresistance of MM is largely unknown. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.012DOI Listing
January 2019

Micro-dystrophin Genes Bring Hope of an Effective Therapy for Duchenne Muscular Dystrophy.

Mol Ther 2019 Feb 12. Epub 2019 Feb 12.

MDUK Oxford Neuromuscular Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.

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http://dx.doi.org/10.1016/j.ymthe.2019.01.019DOI Listing
February 2019

Cartilage-Targeted IGF-1 Treatment to Promote Longitudinal Bone Growth.

Mol Ther 2019 Feb 1. Epub 2019 Feb 1.

Section on Growth and Development, National Institute of Child Health and Development, NIH, Bethesda, MD 20892, USA.

Recombinant human growth hormone (GH) is commonly used to treat short stature in children. However, GH treatment has limited efficacy, particularly in severe, non-GH-deficient conditions such as chondrodysplasias, and potential off-target effects. Because short stature results from decreased growth plate chondrogenesis, we developed a cartilage-targeting single-chain human antibody fragment (CaAb) aiming to deliver therapeutic molecules to the growth plate, thereby increasing treatment efficacy while minimizing adverse effects on other tissues. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.017DOI Listing
February 2019
6.227 Impact Factor

Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury.

Mol Ther 2019 Jan 24. Epub 2019 Jan 24.

Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, 90220 Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland.

Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.013DOI Listing
January 2019

Scavenger Receptor Class A1 Mediates Uptake of Morpholino Antisense Oligonucleotide into Dystrophic Skeletal Muscle.

Mol Ther Nucleic Acids 2019 Jan 25;14:520-535. Epub 2019 Jan 25.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan. Electronic address:

Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) is a promising treatment strategy for Duchenne muscular dystrophy (DMD). The most significant limitation of these clinically used compounds is their lack of delivery systems that target muscles; thus, cell-penetrating peptides are being developed to enhance uptake into muscles. Recently, we reported that uptake of peptide-conjugated PMOs into myofibers was mediated by scavenger receptor class A (SR-A), which binds negatively charged ligands. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.01.008DOI Listing
January 2019

The Downregulation of MicroRNA hsa-miR-340-5p in IAV-Infected A549 Cells Suppresses Viral Replication by Targeting RIG-I and OAS2.

Mol Ther Nucleic Acids 2019 Jan 10;14:509-519. Epub 2019 Jan 10.

State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Wuhan 430070, Hubei Province, China. Electronic address:

The influenza A virus poses serious public health challenges worldwide. Strikingly, small noncoding microRNAs (miRNAs) that modulate gene expression are closely involved in antiviral responses, although the underlying mechanisms are essentially unknown. We now report that microRNA-340 (miR340) is downregulated following influenza A and other RNA virus infections, implying that host cells deplete miR340 as an antiviral defense mechanism. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531193000
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http://dx.doi.org/10.1016/j.omtn.2018.12.014DOI Listing
January 2019
1 Read

Bioengineered Let-7c Inhibits Orthotopic Hepatocellular Carcinoma and Improves Overall Survival with Minimal Immunogenicity.

Mol Ther Nucleic Acids 2019 Jan 24;14:498-508. Epub 2019 Jan 24.

Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA. Electronic address:

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths, warranting better therapies. Restoration of tumor-suppressive microRNAs depleted in hepatocellular carcinoma represents a new therapeutic strategy. Herein, we sought to identify a potent microRNA (miRNA) agent that could alleviate HCC tumor burden and improve survival. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.01.007DOI Listing
January 2019
1 Read

Exosomal Transmission of MicroRNA from HCV Replicating Cells Stimulates Transdifferentiation in Hepatic Stellate Cells.

Mol Ther Nucleic Acids 2019 Jan 18;14:483-497. Epub 2019 Jan 18.

Department of Integrated Life Sciences, Research Institute of Advanced Omics, Dankook University, 152, Jukjeon-ro, Suji-gu, Yongin 16890, Republic of Korea. Electronic address:

The mechanism by which hepatitis C virus (HCV) causes fibrosis and other chronic liver diseases remains poorly understood. Previously, we observed that HCV infection induces microRNA-192 (miR-192) expression, which in turn upregulates transforming growth factor β1 (TGF-β1) in hepatocytes. In this study, we aimed to determine the roles and mechanisms of HCV-induced miR-192 expression during chronic liver injury and fibrosis and to identify potential target of the liver disease. Read More

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http://dx.doi.org/10.1016/j.omtn.2019.01.006DOI Listing
January 2019
1 Read

Knockdown of USF1 Inhibits the Vasculogenic Mimicry of Glioma Cells via Stimulating SNHG16/miR-212-3p and linc00667/miR-429 Axis.

Mol Ther Nucleic Acids 2019 Jan 15;14:465-482. Epub 2019 Jan 15.

Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China. Electronic address:

The anti-angiogenic treatment of malignant glioma cells is an effective method to treat high-grade gliomas. However, due to the presence of vasculogenic mimicry (VM), the anti-angiogenic treatment of gliomas is not significantly effective in improving overall patient median survival. Therefore, this study investigated the mechanism of mimic formation of angiogenesis in gliomas. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.017DOI Listing
January 2019
1 Read

Hypermethylation of miR-205-5p by IR Governs Aggressiveness and Metastasis via Regulating Bcl-w and Src.

Mol Ther Nucleic Acids 2018 Dec 31;14:450-464. Epub 2018 Dec 31.

Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea. Electronic address:

Although radiotherapy has been successfully applied to treat many cancer types, surviving cancer cells often acquire therapeutic resistance, leading to increased risk of local recurrence and distant metastases via modification of the tumor microenvironment. Previously, we reported that high expression of Bcl-w in cancer patients is significantly correlated with poor survival as well as malignant activity. However, the relationship between ionizing radiation (IR)-induced resistance and Bcl-w expression in cancer cells is currently unclear. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.013DOI Listing
December 2018

Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury.

Mol Ther Nucleic Acids 2019 Jan 10;14:438-449. Epub 2019 Jan 10.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Republic of Korea; Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City 404-834, Republic of Korea. Electronic address:

Recent studies have shown that several upstream signaling elements of apoptosis and necroptosis are closely associated with acute injury in the heart. In our study, we observed that miR-105 was notably dysregulated in rat hearts with myocardial infarction (MI). Thus, the purpose of this study was to test the hypothesis that miR-105 participates in the regulation of RIP3/p-MLKL- and BNIP3-dependent necroptosis/apoptosis in H9c2 cells and MI rat hearts. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.015DOI Listing
January 2019
1 Read

Expansion of Anti-viral T Cells from Cord Blood by Accelerated Co-cultured Dendritic Cells.

Mol Ther Methods Clin Dev 2019 Jun 31;13:112-120. Epub 2018 Dec 31.

INSERM, U1016, Cochin Institute, Paris 75014, France.

Hematopoietic stem cell transplantation (HSCT) using unrelated cord blood (CB) donors is a suitable approach when an HLA-matched donor is not available. However, one important drawback is the risk of life-threatening viral infections prior to immune reconstitution, particularly from adenoviruses (AdVs). Although adoptive therapy with expanded virus-reactive donor T cells has proven effective to treat these infections in HSCT recipients, the manufacturing process is complex and requires large numbers of cells, which is incompatible with CB donor units. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357851PMC
June 2019
1 Read

Utilization of HEPES for Enhancing Protein Transfection into Mammalian Cells.

Mol Ther Methods Clin Dev 2019 Jun 20;13:99-111. Epub 2018 Dec 20.

Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.

The delivery of active proteins into cells (protein transfection) for biological purposes offers considerable potential for clinical applications. Herein we demonstrate that, with a readily available, inexpensive organic agent, the 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) method can be used for simple and efficient protein transfection. By mixing proteins with a pure HEPES solution before they are applied to live cells, proteins with various molecular weights (including antibodies, recombinant proteins, and peptides) were successfully delivered into the cytoplasm of different cell types. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357789PMC

AntagomiR-103 and -107 Treatment Affects Cardiac Function and Metabolism.

Mol Ther Nucleic Acids 2018 Dec 22;14:424-437. Epub 2018 Dec 22.

CARIM School for Cardiovascular Diseases, Department of Cardiology, Maastricht University, 6229 ER Maastricht, the Netherlands. Electronic address:

MicroRNA-103/107 regulate systemic glucose metabolism and insulin sensitivity. For this reason, inhibitory strategies for these microRNAs are currently being tested in clinical trials. Given the high metabolic demands of the heart and the abundant cardiac expression of miR-103/107, we questioned whether antagomiR-mediated inhibition of miR-103/107 in C57BL/6J mice impacts on cardiac function. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365487PMC
December 2018

Human Novel MicroRNA Seq-915_x4024 in Keratinocytes Contributes to Skin Regeneration by Suppressing Scar Formation.

Mol Ther Nucleic Acids 2019 Jan 10;14:410-423. Epub 2019 Jan 10.

Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China; Shenyang Amnion Bioengineering and Technology R & D Center, 155-5 Chuangxin Street, Hunnan District, Shenyang City 110015, Liaoning Province, China. Electronic address:

Early in gestation, wounds in fetal skin heal by regeneration, in which microRNAs play key roles. Seq-915_x4024 is a novel microRNA candidate confirmed by deep sequencing and mirTools 2.0. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365370PMC
January 2019
3 Reads

miR-10a-5p Promotes Chondrocyte Apoptosis in Osteoarthritis by Targeting HOXA1.

Mol Ther Nucleic Acids 2018 Dec 25;14:398-409. Epub 2018 Dec 25.

Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang Province 310016, China. Electronic address:

Osteoarthritis (OA) is a common joint disease characterized by degradation of the articular cartilage and joint inflammation. Studies have revealed the importance of microRNAs in the regulation of chondrocyte apoptosis. MicroRNA deep sequencing of control and osteoarthritic cartilage has revealed that miR-10a-5p is significantly upregulated in osteoarthritic tissues. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365368PMC
December 2018
2 Reads

Generation of Genetically Stable Human Direct-Conversion-Derived Neural Stem Cells Using Quantity Control of Proto-oncogene Expression.

Mol Ther Nucleic Acids 2018 Dec 20;14:388-397. Epub 2018 Dec 20.

Stem Cells and Regenerative Bioengineering Institute in Kangstem Biotech, Biomedical Science Building, #81 Seoul National University, Seoul 08826, South Korea; Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea. Electronic address:

As the human lifespan has increased due to developments in medical technology, the number of patients with neurological diseases has rapidly increased. Therefore, studies on effective treatments for neurological diseases are becoming increasingly important. To perform these studies, it is essential to obtain a large number of patient-derived neural cells. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365637PMC
December 2018
1 Read

AAV2/8 Anti-angiogenic Gene Therapy Using Single-Chain Antibodies Inhibits Murine Choroidal Neovascularization.

Mol Ther Methods Clin Dev 2019 Jun 22;13:86-98. Epub 2018 Nov 22.

Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK.

While anti-angiogenic therapies for wet age-related macular degeneration (AMD) are effective for many patients, they require multiple injections and are expensive and prone to complications. Gene therapy could be an elegant solution for this problem by providing a long-term source of anti-angiogenic proteins after a single administration. Another potential issue with current therapeutic proteins containing a fragment crystallizable (Fc) domain (such as whole antibodies like bevacizumab) is the induction of an unwanted immune response. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350388PMC

Trans-ocular Electric Current Enhances AAV-Mediated Retinal Gene Transduction after Intravitreal Vector Administration.

Mol Ther Methods Clin Dev 2019 Jun 21;13:77-85. Epub 2018 Dec 21.

Section for Translational Research on Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA.

Adeno-associated virus (AAV) vector-mediated gene delivery is a promising approach for therapy, but implementation in the eye currently is hampered by the need for delivering the vector underneath the retina, using surgical application into the subretinal space. This limits the extent of the retina that is treated and may cause surgical injury. Vector delivery into the vitreous cavity would be preferable because it is surgically less invasive and would reach more of the retina. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350231PMC

Macrophage Assay Predicts the Anti-inflammatory Potential of Exosomes from Human Mesenchymal Stromal Cells.

Mol Ther Methods Clin Dev 2019 Jun 15;13:67-76. Epub 2018 Dec 15.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77845, USA.

Extracellular vesicles (EVs) play key roles in cell biology and may provide new clinical diagnostics and therapies. However, it has proven difficult to develop protocols for their purification and characterization. One of the major barriers in the field has been a lack of convenient assays for their bioactivity. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350420PMC
June 2019
1 Read

Development of Novel Micro-dystrophins with Enhanced Functionality.

Mol Ther 2019 Jan 25. Epub 2019 Jan 25.

Molecular and Cellular Biology Program, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA; Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address:

Gene therapies using adeno-associated viral (AAV) vectors have advanced into clinical trials for several diseases, including Duchenne muscular dystrophy (DMD). A limitation of AAV is the carrying capacity (∼5 kb) available for genes and regulatory cassettes (RCs). These size constraints are problematic for the 2. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.002DOI Listing
January 2019
1 Read

Oral Gavage of Ginger Nanoparticle-Derived Lipid Vectors Carrying Dmt1 siRNA Blunts Iron Loading in Murine Hereditary Hemochromatosis.

Mol Ther 2019 Jan 12. Epub 2019 Jan 12.

Food Science & Human Nutrition Department, University of Florida, Gainesville, FL, USA. Electronic address:

Nanoparticles (NPs) have been utilized to deliver drugs to the intestinal epithelium in vivo. Moreover, NPs derived from edible plants are less toxic than synthetic NPs. Here, we utilized ginger NP-derived lipid vectors (GDLVs) in a proof-of-concept investigation to test the hypothesis that inhibiting expression of divalent metal-ion transporter 1 (Dmt1) would attenuate iron loading in a mouse model of hereditary hemochromatosis (HH). Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.003DOI Listing
January 2019
2 Reads

Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination.

Mol Ther 2019 Jan 22. Epub 2019 Jan 22.

Department of Internal Medicine I, Ulm University Hospital, Albert Einstein Allee 23, 89081 Ulm, Germany. Electronic address:

Hepatitis B virus (HBV) core (HBV-C) antigens with homologous or heterologous HIV-tat48-57-like (HBV-C149tat) cationic domains non-specifically bind cellular RNA in vector-transfected cells. Here, we investigated whether RNA-binding to cationic domains influences the immunogenicity of endogenously expressed antigens delivered by DNA vaccination. We initially evaluated induction of HBV-C (K/C93)-specific CD8 T cell responses in C57BL/6J (B6) and 1. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.011DOI Listing
January 2019
2 Reads

rAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart.

Mol Ther 2019 Jan 15. Epub 2019 Jan 15.

Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA; Department of Pediatrics, Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH 43210, USA. Electronic address:

Dilated cardiomyopathy is a common cause of death in patients with Duchenne muscular dystrophy (DMD). Gene therapies for DMD must, therefore, have a therapeutic impact in cardiac as well as skeletal muscles. Our previous studies have shown that GALGT2 overexpression in mdx skeletal muscles can prevent muscle damage. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.005DOI Listing
January 2019
1 Read

Exosome-Mediated miR-29 Transfer Reduces Muscle Atrophy and Kidney Fibrosis in Mice.

Mol Ther 2019 Jan 18. Epub 2019 Jan 18.

Department of Medicine, Renal Division, Emory University, Atlanta, GA 30322, USA. Electronic address:

Our previous study showed that miR-29 attenuates muscle wasting in chronic kidney disease. Other studies found that miR-29 has anti-fibrosis activity. We hypothesized that intramuscular injection of exosome-encapsulated miR-29 would counteract unilateral ureteral obstruction (UUO)-induced muscle wasting and renal fibrosis. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.008DOI Listing
January 2019
1 Read

The Attenuation of Trophoblast Invasion Caused by the Downregulation of EZH2 Is Involved in the Pathogenesis of Human Recurrent Miscarriage.

Mol Ther Nucleic Acids 2018 Dec 22;14:377-387. Epub 2018 Dec 22.

Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China. Electronic address:

Recurrent miscarriage (RM) is currently defined as two or more losses of a clinically established intrauterine pregnancy. Despite years of research, RM continues to be a clinically frustrating challenge for patients and physicians, and its etiology remains poorly understood. Accumulating evidence has suggested that epigenetic modifications are involved in early embryogenesis, and defects in epigenetic patterning contribute to the development of RM. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356049PMC
December 2018

Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.

Mol Ther Methods Clin Dev 2019 Mar 31;12:184-201. Epub 2018 Dec 31.

The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Hemophilia A (HA) and hemophilia B (HB) are X-linked bleeding disorders due to inheritable deficiencies in either coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Recently, gene therapy clinical trials with adeno-associated virus (AAV) vectors and protein-engineered transgenes, B-domain deleted (BDD) FVIII and FIX-Padua, have reported near-phenotypic cures in subjects with HA and HB, respectively. Here, we review the biology and the clinical development of FVIII-BDD and FIX-Padua as transgenes. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349562PMC
March 2019
1 Read

TALEN-Mediated Gene Editing of in Human Hematopoietic Stem Cells Leads to Therapeutic Fetal Hemoglobin Induction.

Mol Ther Methods Clin Dev 2019 Mar 31;12:175-183. Epub 2018 Dec 31.

Center for Immunity and Immunotherapies and the Program for Cell and Gene Therapy, Seattle Children's Research Institute, Seattle, WA 98101, USA.

Elements within the γ-hemoglobin promoters ( and ) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous promoters to de-repress fetal hemoglobin. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348980PMC
March 2019
1 Read

Preclinical Development of an AAV8-hUGT1A1 Vector for the Treatment of Crigler-Najjar Syndrome.

Mol Ther Methods Clin Dev 2019 Mar 31;12:157-174. Epub 2018 Dec 31.

INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France.

Adeno-associated viruses (AAVs) are among the most efficient vectors for liver gene therapy. Results obtained in the first hemophilia clinical trials demonstrated the long-term efficacy of this approach in humans, showing efficient targeting of hepatocytes with both self-complementary (sc) and single-stranded (ss) AAV vectors. However, to support clinical development of AAV-based gene therapies, efficient and scalable production processes are needed. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348934PMC

Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies.

Mol Ther 2019 Jan 12. Epub 2019 Jan 12.

Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA.

Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.004DOI Listing
January 2019
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Analyzing the Interactions of mRNAs and ncRNAs to Predict Competing Endogenous RNA Networks in Osteosarcoma Chemo-Resistance.

Mol Ther 2019 Jan 7. Epub 2019 Jan 7.

Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, PR China; Institute of Bone Tumor, Tongji University, School of Medicine, Shanghai 200072, PR China.

Chemo-resistance is a huge obstacle encountered in the osteosarcoma (OS) treatment. Protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), including long ncRNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA), have been demonstrated to play an essential role in the regulation of cancer biology. However, the comprehensive expression profile and competing endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in the OS chemo-resistance still remain unclear. Read More

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http://dx.doi.org/10.1016/j.ymthe.2019.01.001DOI Listing
January 2019

circRNA.33186 Contributes to the Pathogenesis of Osteoarthritis by Sponging miR-127-5p.

Mol Ther 2019 Jan 15. Epub 2019 Jan 15.

Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. Electronic address:

Osteoarthritis (OA), the most prevalent age-related joint disorder, is characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral bone sclerosis. Accumulating evidences indicate that circular RNAs (circRNAs) play a critical role in various diseases, but the function of circRNAs in OA remains largely unknown. Here we showed that circRNA. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15250016193000
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http://dx.doi.org/10.1016/j.ymthe.2019.01.006DOI Listing
January 2019
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Viral Vector-Based Delivery of CRISPR/Cas9 and Donor DNA for Homology-Directed Repair in an In Vitro Model for Canine Hemophilia B.

Mol Ther Nucleic Acids 2018 Dec 20;14:364-376. Epub 2018 Dec 20.

Institute for Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany. Electronic address:

Gene therapy represents an attractive alternative to treat hemophilia B. Here we established three hepatocyte-derived cell lines based on Huh7, PLC/PRF/5, and Hep3B cells stably carrying a mutated canine FIX (cFIXmut) transgene containing a single point mutation in the catalytic domain. Based on these in vitro models resembling a commonly used canine large animal model, the tetracycline-controlled transcriptional activator (Tet-on)-inducible CRISPR/Cas9 system and an optimized donor were used to correct mutated cFIX gene through homology-directed repair (HDR). Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356096PMC
December 2018
1 Read

Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness.

Mol Ther 2019 Jan 7. Epub 2019 Jan 7.

Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. Read More

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http://dx.doi.org/10.1016/j.ymthe.2018.12.014DOI Listing
January 2019
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Adeno-Associated Viral Vector 2 and 9 Transduction Is Enhanced in Streptozotocin-Induced Diabetic Mouse Retina.

Mol Ther Methods Clin Dev 2019 Jun 1;13:55-66. Epub 2018 Dec 1.

Department of Ophthalmology, College of Medicine, Soonchunhyang University, Cheonan 31151, Republic of Korea.

Adeno-associated viruses (AAVs) are currently the most popular vector platform technology for ocular gene therapy. While transduction efficiency and tropism of intravitreally administered AAV has been fairly well established in various retinal conditions, its transduction pattern in diabetic retinas has not previously been characterized. Here, we describe the transduction efficiencies of four different AAV serotypes, AAV2, 5, 8, and 9, in streptozotocin (STZ)-induced diabetic mouse retinas after intravitreal injections, which differed according to the duration of diabetic induction. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330514PMC
June 2019
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Kinetics and MR-Based Monitoring of AAV9 Vector Delivery into Cerebrospinal Fluid of Nonhuman Primates.

Mol Ther Methods Clin Dev 2019 Jun 8;13:47-54. Epub 2018 Dec 8.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94103, USA.

Here we evaluated the utility of MRI to monitor intrathecal infusions in nonhuman primates. Adeno-associated virus (AAV) spiked with gadoteridol, a gadolinium-based MRI contrast agent, enabled real-time visualization of infusions delivered either via cerebromedullary cistern, lumbar, cerebromedullary and lumbar, or intracerebroventricular infusion. The kinetics of vector clearance from the cerebrospinal fluid (CSF) were analyzed. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S23290501183012
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http://dx.doi.org/10.1016/j.omtm.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330508PMC
June 2019
3 Reads

Engineering and Design of Chimeric Antigen Receptors.

Mol Ther Methods Clin Dev 2019 Mar 31;12:145-156. Epub 2018 Dec 31.

Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA.

T cells engineered with chimeric antigen receptors (CARs) have emerged as a potent new class of therapeutics for cancer, based on their remarkable potency in blood cancers. Since the first clinical reports of their efficacy emerged 7 years ago, investigators have focused on the mechanisms and properties that make CARs effective or toxic, and their effects on T cell biology. Novel CAR designs coupled with improvements in gene transfer technology, incorporating advances in gene editing, have the potential to increase access to engineered cell therapies, as well as improve their potency in solid tumors. Read More

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http://dx.doi.org/10.1016/j.omtm.2018.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330382PMC
March 2019
1 Read

The Future of the Molecular Therapy Journal Family: Change Is Inevitable. Growth Is Optional.

Mol Ther 2019 Feb 18;27(2):281-282. Epub 2019 Jan 18.

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http://dx.doi.org/10.1016/j.ymthe.2019.01.007DOI Listing
February 2019
6 Reads

Optimizing Synthetic miRNA Minigene Architecture for Efficient miRNA Hairpin Concatenation and Multi-target Gene Knockdown.

Mol Ther Nucleic Acids 2018 Dec 14;14:351-363. Epub 2018 Dec 14.

Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address:

Synthetic microRNA (miRNA) minigenes (SMIGs) have a major potential for molecular therapy; however, their optimal architecture still needs to be determined. We have previously optimized the stem structure of miRNA hairpins for efficient gene knockdown. Here, we investigate the overall architecture of SMIGs driven by polymerase II-dependent promoters. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350225PMC
December 2018
2 Reads

Nucleotide Modification Alters MicroRNA-Dependent Silencing of MicroRNA Switches.

Mol Ther Nucleic Acids 2018 Dec 18;14:339-350. Epub 2018 Dec 18.

Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA. Electronic address:

mRNA therapeutics hold great promise for the treatment of human diseases. While incorporating naturally occurring modified nucleotides during synthesis has greatly increased their potency and safety, challenges in selective expression have hindered clinical applications. MicroRNA (miRNA)-regulated in vitro-transcribed mRNAs, called miRNA switches, have been used to control the expression of exogenous mRNA in a cell-selective manner. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350232PMC
December 2018
2 Reads

Posttranscriptional Regulation of 14q32 MicroRNAs by the CIRBP and HADHB during Vascular Regeneration after Ischemia.

Mol Ther Nucleic Acids 2018 Dec 6;14:329-338. Epub 2018 Dec 6.

Department of Surgery, Leiden University Medical, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical, Leiden, the Netherlands; Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria. Electronic address:

After induction of ischemia in mice, 14q32 microRNAs are regulated in three distinct temporal patterns. These expression patterns, as well as basal expression levels, are independent of the microRNA genes' order in the 14q32 locus. This implies that posttranscriptional processing is a major determinant of 14q32 microRNA expression. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S21622531183031
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http://dx.doi.org/10.1016/j.omtn.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350214PMC
December 2018
3 Reads

DANCR Promotes Metastasis and Proliferation in Bladder Cancer Cells by Enhancing IL-11-STAT3 Signaling and CCND1 Expression.

Mol Ther 2019 Feb 9;27(2):326-341. Epub 2019 Jan 9.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address:

The prognosis for patients with bladder cancer (BCa) with lymph node (LN) metastasis is poor, and it is not improved by current treatments. Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumors, including BCa. However, the role of Differentiation antagonizing non-protein coding RNA (DANCR) in BCa LN metastasis remains unclear. Read More

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http://dx.doi.org/10.1016/j.ymthe.2018.12.015DOI Listing
February 2019
2 Reads

Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases.

Mol Ther 2018 Dec 22. Epub 2018 Dec 22.

Department of Pediatrics, Ludwig Maximilian University of Munich, 80337 Munich, Germany; Ethris GmbH, RNA Biology, 82152 Planegg, Germany. Electronic address:

Promising improvements in the field of transcript therapeutics have clearly enhanced the potential of mRNA as a new pillar for protein replacement therapies. Synthetic mRNAs are engineered to replace mutated mRNAs and to be immunologically inconspicuous and highly stable while maximizing protein expression. Approaches to deliver mRNA into the cellular cytoplasm safely and efficiently have been further developed so that two mRNA-based approaches replacing vascular endothelial growth factor (VEGF) and cystic fibrosis transmembrane conductance regulator (CFTR) have now made it into clinical trials. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15250016183061
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http://dx.doi.org/10.1016/j.ymthe.2018.12.012DOI Listing
December 2018
4 Reads