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Molecular Therapy. Nucleic Acids

Loren L Flynn, Chalermchai Mitrpant, Ianthe L Pitout, Sue Fletcher, Steve D Wilton
The severe childhood disease spinal muscular atrophy (SMA) arises from the homozygous loss of the survival motor neuron 1 gene (SMN1). A homologous gene potentially encoding an identical protein, SMN2 can partially compensate for the loss of SMN1; however, the exclusion of a critical exon in the coding region during mRNA maturation results in insufficient levels of functional protein. The rate of transcription is known to influence the alternative splicing of gene transcripts, with a fast transcription rate correlating to an increase in alternative splicing...
June 1, 2018: Molecular Therapy. Nucleic Acids
Anna-Elisa Roser, Lucas Caldi Gomes, Rashi Halder, Gaurav Jain, Fabian Maass, Lars Tönges, Lars Tatenhorst, Mathias Bähr, André Fischer, Paul Lingor
Parkinson's disease (PD) is the second-most-frequent neurodegenerative disorder worldwide. One major hallmark of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra. Glial cell line-derived neurotrophic factor (GDNF) potently increases DA neuron survival in models of PD; however, the underlying mechanisms are incompletely understood. MicroRNAs (miRNAs) are small, non-coding RNAs that are important for post-transcriptional regulation of gene expression. Using small RNA sequencing, we show that GDNF specifically increases the expression of miR-182-5p and miR-183-5p in primary midbrain neurons (PMNs)...
June 1, 2018: Molecular Therapy. Nucleic Acids
Masashi Fukuoka, Masaki Takahashi, Hiromi Fujita, Tomoko Chiyo, H Akiko Popiel, Shoko Watanabe, Hirokazu Furuya, Miho Murata, Keiji Wada, Takashi Okada, Yoshitaka Nagai, Hirohiko Hohjoh
Huntington's disease (HD) is an intractable neurodegenerative disorder caused by mutant Huntingtin (HTT) proteins that adversely affect various biomolecules and genes. MicroRNAs (miRNAs), which are functional small non-coding RNAs, are also affected by mutant HTT proteins. Here, we show amelioration in motor function and lifespan of HD-model mice, R6/2 mice, by supplying miR-132 to HD brains using a recombinant adeno-associated virus (rAAV) miRNA expression system. miR-132 is an miRNA related to neuronal maturation and function, but the level of miR-132 in the brain of R6/2 mice was significantly lower than that of wild-type mice...
June 1, 2018: Molecular Therapy. Nucleic Acids
Ángeles Mencía, Cristina Chamorro, Jose Bonafont, Blanca Duarte, Almudena Holguin, Nuria Illera, Sara G Llames, Maria José Escámez, Ingrid Hausser, Marcela Del Río, Fernando Larcher, Rodolfo Murillas
Recessive dystrophic epidermolysis bullosa is a severe skin fragility disease caused by loss of functional type VII collagen at the dermal-epidermal junction. A frameshift mutation in exon 80 of COL7A1 gene, c.6527insC, is highly prevalent in the Spanish patient population. We have implemented gene-editing strategies for COL7A1 frame restoration by NHEJ-induced indels in epidermal stem cells from patients carrying this mutation. TALEN nucleases designed to cut within the COL7A1 exon 80 sequence were delivered to primary patient keratinocyte cultures by non-integrating viral vectors...
June 1, 2018: Molecular Therapy. Nucleic Acids
Marie Pastor, Sandra Johnen, Nina Harmening, Mickäel Quiviger, Julie Pailloux, Martina Kropp, Peter Walter, Zoltán Ivics, Zsuzsanna Izsvák, Gabriele Thumann, Daniel Scherman, Corinne Marie
The anti-angiogenic and neurogenic pigment epithelium-derived factor (PEDF) demonstrated a potency to control choroidal neovascularization in age-related macular degeneration (AMD) patients. The goal of the present study was the development of an efficient and safe technique to integrate, ex vivo, the PEDF gene into retinal pigment epithelial (RPE) cells for later transplantation to the subretinal space of AMD patients to allow continuous PEDF secretion in the vicinity of the affected macula. Because successful gene therapy approaches require efficient gene delivery and stable gene expression, we used the antibiotic-free pFAR4 mini-plasmid vector to deliver the hyperactive Sleeping Beauty transposon system, which mediates transgene integration into the genome of host cells...
June 1, 2018: Molecular Therapy. Nucleic Acids
Juan-Feng Zhao, Qiu Zhao, Hui Hu, Jia-Zhi Liao, Ju-Sheng Lin, Chao Xia, Ying Chang, Jing Liu, An-Yuan Guo, Xing-Xing He
Hepatocellular carcinoma (HCC) is a worldwide malignance, and the underlying mechanisms of this disease are not fully elucidated. In this study, the existence and function of achaete-scute homolog-1 (ASH1)-miR-375-YWHAZ signaling axis in HCC were determined. Our experiments and the Cancer Genome Atlas (TCGA) sequencing data analyses showed that ASH1 and miR-375 were significantly downregulated, whereas YWHAZ was significantly upregulated in HCC. Furthermore, we found that ASH1 positively regulates miR-375, and miR-375 directly downregulates its target YWHAZ...
June 1, 2018: Molecular Therapy. Nucleic Acids
Yaying Sun, Hui Wang, Yan Li, Shaohua Liu, Jiwu Chen, Hao Ying
Fibrosis is common after skeletal muscle injury, undermining tissue regeneration and function. The mechanism underlying skeletal muscle fibrosis remains unveiled. Transforming growth factor-β/Smad signaling pathway is supposed to play a pivotal role. However, how microRNAs interact with transforming growth factor-β/Smad-related muscle fibrosis remains unclear. We showed that microRNA (miR)-24-3p and miR-122-5p declined in skeletal muscle fibrosis, which was a consequence of transforming growth factor-β. Upregulating Smad4 suppressed two microRNAs, whereas inhibiting Smad4 elevated microRNAs...
June 1, 2018: Molecular Therapy. Nucleic Acids
Amy E Arnold, Elise Malek-Adamian, Phuong U Le, Anika Meng, Saúl Martínez-Montero, Kevin Petrecca, Masad J Damha, Molly S Shoichet
Glioblastoma stem cells (GSCs) are invasive, treatment-resistant brain cancer cells that express downregulated in renal cell carcinoma (DRR), also called FAM107A, a genetic driver of GSC invasion. We developed antibody-antisense oligonucleotide (AON) conjugates to target and reduce DRR/FAM107A expression. Specifically, we used antibodies against antigens expressed on the GSCs, such as CD44 and EphA2, conjugated to chemically modified AONs against DRR/FAM107A, which were designed as chimeras of DNA and 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA) for increased nuclease stability and mRNA affinity...
June 1, 2018: Molecular Therapy. Nucleic Acids
Jan Hoinka, Rolf Backofen, Teresa M Przytycka
No abstract text is available yet for this article.
June 1, 2018: Molecular Therapy. Nucleic Acids
Chao Chen, Dongxu Yue, Liangyu Lei, Hairong Wang, Jia Lu, Ya Zhou, Shiming Liu, Tao Ding, Mengmeng Guo, Lin Xu
The technique of targeted expression of interesting genes, including distinct delivery systems and specific gene promoter-operating expression, is an important strategy for gene therapy against cancers. Up to now, extensive literature documented the efficacy of distinct delivery systems, such as the liposome system, nano-particle system, polyetherimide (PEI) system, and so on, in cancer gene therapy. However, a related document on the potential value of using a specific gene promoter, such as a tumor suppressor, in cancer gene therapy was still scary...
June 1, 2018: Molecular Therapy. Nucleic Acids
Zhuojia Lin, Yanan Lu, Qiuyu Meng, Chen Wang, Xiaonan Li, Yuxin Yang, Xiaoru Xin, Qidi Zheng, Jie Xu, Xin Gui, Tianming Li, Hu Pu, Wujun Xiong, Jiao Li, Song Jia, Dongdong Lu
MicroRNAs are known to be involved in carcinogenesis. Recently, microRNA-372 (miR372) has been proven to play a substantial role in several human cancers, but its functions in liver cancer remain unclear. Herein, our results demonstrate that miR372 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR372 enhances expression of Y-box-binding protein 1 (YB-1) by targeting for phosphatase and tensin homolog (PTEN) directly and consequently promotes phosphorylation of YB-1 via HULC looping dependent on ERK1/2 and PTEN...
June 1, 2018: Molecular Therapy. Nucleic Acids
Elisa Callegari, Lucilla D'Abundo, Paola Guerriero, Carolina Simioni, Bahaeldin K Elamin, Marta Russo, Alice Cani, Cristian Bassi, Barbara Zagatti, Luciano Giacomelli, Stella Blandamura, Farzaneh Moshiri, Simona Ultimo, Antonio Frassoldati, Giuseppe Altavilla, Laura Gramantieri, Luca Maria Neri, Silvia Sabbioni, Massimo Negrini
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Prognosis is poor, and therapeutic options are limited. MicroRNAs (miRNAs) have emerged as potential therapeutic molecules against cancer. Here, we investigated the therapeutic efficacy of miR-199a-3p, an miRNA highly expressed in normal liver and downregulated in virtually all HCCs. The therapeutic value of miR-199a-3p mimic molecules was assayed in the TG221 mouse, a transgenic model highly predisposed to the development of liver cancer...
June 1, 2018: Molecular Therapy. Nucleic Acids
Mario Lescan, Regine Mariette Perl, Sonia Golombek, Martin Pilz, Ludmilla Hann, Mahua Yasmin, Andreas Behring, Timea Keller, Andrea Nolte, Franziska Gruhn, Efrat Kochba, Yotam Levin, Christian Schlensak, Hans Peter Wendel, Meltem Avci-Adali
Elastin is one of the most important and abundant extracellular matrix (ECM) proteins that provide elasticity and resilience to tissues and organs, including vascular walls, ligaments, skin, and lung. Besides hereditary diseases, such as Williams-Beuren syndrome (WBS), which results in reduced elastin synthesis, injuries, aging, or acquired diseases can lead to the degradation of existing elastin fibers. Thus, the de novo synthesis of elastin is required in several medical conditions to restore the elasticity of affected tissues...
June 1, 2018: Molecular Therapy. Nucleic Acids
Wei Chen, Pengmian Feng, Hui Yang, Hui Ding, Hao Lin, Kuo-Chen Chou
RNA modifications are additions of chemical groups to nucleotides or their local structural changes. Knowledge about the occurrence sites of these modifications is essential for in-depth understanding of the biological functions and mechanisms and for treating some genomic diseases as well. With the avalanche of RNA sequences generated in the post-genomic age, many computational methods have been proposed for identifying various types of RNA modifications one by one. However, so far no method whatsoever has been developed for simultaneously identifying several different types of RNA modifications...
June 1, 2018: Molecular Therapy. Nucleic Acids
Duc-Hiep Bach, Donghwa Kim, Song Yi Bae, Won Kyung Kim, Ji-Young Hong, Hye-Jung Lee, Nirmal Rajasekaran, Soonbum Kwon, Yanhua Fan, Thi-Thu-Trang Luu, Young Kee Shin, Jeeyeon Lee, Sang Kook Lee
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used clinically as target therapies for lung cancer patients, but the occurrence of acquired drug resistance limits their efficacy. Nicotinamide N-methyltransferase (NNMT), a cancer-associated metabolic enzyme, is commonly overexpressed in various human tumors. Emerging evidence also suggests a crucial loss of function of microRNAs (miRNAs) in modulating tumor progression in response to standard therapies. However, their precise roles in regulating the development of drug-resistant tumorigenesis are still poorly understood...
June 1, 2018: Molecular Therapy. Nucleic Acids
Hassan Javanbakht, Henrik Mueller, Johanna Walther, Xue Zhou, Anaïs Lopez, Thushara Pattupara, Julie Blaising, Lykke Pedersen, Nanna Albæk, Malene Jackerott, Tianlai Shi, Corinne Ploix, Wouter Driessen, Robert Persson, Jacob Ravn, John A T Young, Søren Ottosen
Chronic hepatitis B infection (CHB) is an area of high unmet medical need. Current standard-of-care therapies only rarely lead to a functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss following treatment. The goal for next generation CHB therapies is to achieve a higher rate of functional cure with finite treatment duration. To address this urgent need, we are developing liver-targeted single-stranded oligonucleotide (SSO) therapeutics for CHB based on the locked nucleic acid (LNA) platform...
June 1, 2018: Molecular Therapy. Nucleic Acids
Bence György, Camilla Lööv, Mikołaj P Zaborowski, Shuko Takeda, Benjamin P Kleinstiver, Caitlin Commins, Ksenia Kastanenka, Dakai Mu, Adrienn Volak, Vilmantas Giedraitis, Lars Lannfelt, Casey A Maguire, J Keith Joung, Bradley T Hyman, Xandra O Breakefield, Martin Ingelsson
The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes dominantly inherited Alzheimer's disease (AD) as a result of increased β-secretase cleavage of the amyloid-β (Aβ) precursor protein. This leads to abnormally high Aβ levels, not only in brain but also in peripheral tissues of mutation carriers. Here, we selectively disrupted the human mutant APPSW allele using CRISPR. By applying CRISPR/Cas9 from Streptococcus pyogenes, we generated allele-specific deletions of either APPSW or APPWT ...
June 1, 2018: Molecular Therapy. Nucleic Acids
Baehyun Shin, Roy Jung, Hyejin Oh, Gwen E Owens, Hyeongseok Lee, Seung Kwak, Ramee Lee, Susan L Cotman, Jong-Min Lee, Marcy E MacDonald, Ji-Joon Song, Ravi Vijayvargia, Ihn Sik Seong
The CAG repeat expansion that elongates the polyglutamine tract in huntingtin is the root genetic cause of Huntington's disease (HD), a debilitating neurodegenerative disorder. This seemingly slight change to the primary amino acid sequence alters the physical structure of the mutant protein and alters its activity. We have identified a set of G-quadruplex-forming DNA aptamers (MS1, MS2, MS3, MS4) that bind mutant huntingtin proximal to lysines K2932/K2934 in the C-terminal CTD-II domain. Aptamer binding to mutant huntingtin abrogated the enhanced polycomb repressive complex 2 (PRC2) stimulatory activity conferred by the expanded polyglutamine tract...
June 1, 2018: Molecular Therapy. Nucleic Acids
Sushmita Poddar, Pei She Loh, Zi Hao Ooi, Farhana Osman, Joachim Eul, Volker Patzel
Spliceosome-mediated RNA trans-splicing enables correction or labeling of pre-mRNA, but therapeutic applications are hampered by issues related to the activity and target specificity of trans-splicing RNA (tsRNA). We employed computational RNA structure design to improve both on-target activity and specificity of tsRNA in a herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy approach targeting alpha fetoprotein (AFP), a marker of hepatocellular carcinoma (HCC) or human papillomavirus type 16 (HPV-16) pre-mRNA...
June 1, 2018: Molecular Therapy. Nucleic Acids
Mert Yanik, Surya Prakash Goud Ponnam, Tobias Wimmer, Lennart Trimborn, Carina Müller, Isabel Gambert, Johanna Ginsberg, Annabella Janise, Janina Domicke, Wolfgang Wende, Birgit Lorenz, Knut Stieger
Common genome-editing strategies are either based on non-homologous end joining (NHEJ) or, in the presence of a template DNA, based on homologous recombination with long (homology-directed repair [HDR]) or short (microhomology-mediated end joining [MMEJ]) homologous sequences. In the current study, we aim to develop a model system to test the activity of MMEJ after CRISPR/Cas9-mediated cleavage in cell culture. Following successful proof of concept in an episomally based reporter system, we tested template plasmids containing a promoter-less luciferase gene flanked by microhomologous sequences (mhs) of different length (5, 10, 15, 20, 30, and 50 bp) that are complementary to the mouse retinitis pigmentosa GTPase regulator (RPGR)-ORF15, which is under the control of a CMV promoter stably integrated into a HEK293 cell line...
June 1, 2018: Molecular Therapy. Nucleic Acids
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