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Molecular Therapy. Nucleic Acids

Anna M L Coenen-Stass, Helena Sork, Sole Gatto, Caroline Godfrey, Amarjit Bhomra, Kaarel Krjutškov, Jonathan R Hart, Jakub O Westholm, Liz O'Donovan, Andreas Roos, Hanns Lochmüller, Pier Lorenzo Puri, Samir El Andaloussi, Matthew J A Wood, Thomas C Roberts
Extracellular small RNAs (sRNAs), including microRNAs (miRNAs), are promising biomarkers for diseases such as Duchenne muscular dystrophy (DMD), although their biological relevance is largely unknown. To investigate the relationship between intracellular and extracellular sRNA levels on a global scale, we performed sRNA sequencing in four muscle types and serum from wild-type, dystrophic mdx, and mdx mice in which dystrophin protein expression was restored by exon skipping. Differentially abundant sRNAs were identified in serum (mapping to miRNA, small nuclear RNA [snRNA], and PIWI-interacting RNA [piRNA] loci)...
August 17, 2018: Molecular Therapy. Nucleic Acids
Carsten T Charlesworth, Joab Camarena, M Kyle Cromer, Sriram Vaidyanathan, Rasmus O Bak, Jason M Carte, Jason Potter, Daniel P Dever, Matthew H Porteus
Engineered nuclease-mediated gene targeting through homologous recombination (HR) in hematopoietic stem and progenitor cells (HSPCs) has the potential to treat a variety of genetic hematologic and immunologic disorders. Here, we identify critical parameters to reproducibly achieve high frequencies of RNA-guided (single-guide RNA [sgRNA]; CRISPR)-Cas9 nuclease (Cas9/sgRNA) and rAAV6-mediated HR at the β-globin (HBB) locus in HSPCs. We identified that by transducing HSPCs with rAAV6 post-electroporation, there was a greater than 2-fold electroporation-aided transduction (EAT) of rAAV6 endocytosis with roughly 70% of the cell population having undergone transduction within 2 hr...
September 7, 2018: Molecular Therapy. Nucleic Acids
Tommaso Iannitti, Joseph M Scarrott, Shibi Likhite, Ian R P Coldicott, Katherine E Lewis, Paul R Heath, Adrian Higginbottom, Monika A Myszczynska, Marta Milo, Guillaume M Hautbergue, Kathrin Meyer, Brian K Kaspar, Laura Ferraiuolo, Pamela J Shaw, Mimoun Azzouz
Of familial amyotrophic lateral sclerosis (fALS) cases, 20% are caused by mutations in the gene encoding human cytosolic Cu/Zn superoxide dismutase (hSOD1). Efficient translation of the therapeutic potential of RNAi for the treatment of SOD1-ALS patients requires the development of vectors that are free of significant off-target effects and with reliable biomarkers to discern sufficient target engagement and correct dosing. Using adeno-associated virus serotype 9 to deliver RNAi against hSOD1 in the SOD1G93A mouse model, we found that intrathecal injection of the therapeutic vector via the cisterna magna delayed onset of disease, decreased motor neuron death at end stage by up to 88%, and prolonged the median survival of SOD1G93A mice by up to 42%...
September 7, 2018: Molecular Therapy. Nucleic Acids
Haiyan Ji, Panpan Lu, Baochi Liu, Xiying Qu, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, He Yang, Hanyu Pan, Lin Zhao, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu
Highly active anti-retroviral therapy (HAART) cannot clear infected cells harboring HIV-1 proviral DNA from HIV-1-infected patients. We previously demonstrated that zinc-finger nucleases (ZFNs) can specifically and efficiently excise HIV-1 proviral DNA from latently infected human T cells by targeting long terminal repeats (LTRs), a novel and alternative antiretroviral strategy for eradicating HIV-1 infection. To prevent unwanted off-target effects from constantly expressed ZFNs, in this study, we engineered the expression of ZFNs under the control of HIV-1 LTR, by which ZFN expression can be activated by the HIV-1 (Trans-Activator of Transcription) Tat protein...
September 7, 2018: Molecular Therapy. Nucleic Acids
Hui Li, Jiameng Yang, Rui Jiang, Xuefeng Wei, Chengchuang Song, Yongzhen Huang, Xianyong Lan, Chuzhao Lei, Yun Ma, Linyong Hu, Hong Chen
Muscle development is regulated by a series of complicate processes, and non-coding RNAs (ncRNAs) such as lncRNA have been reported to play important roles in regulating skeletal myogenesis and diseases. Here we profile the expression of lncRNA in cattle skeletal muscle tissue from fetus and adult developmental stages and detect 13,580 lncRNA candidates. Many of these lncRNAs are differentially expressed between two developmental stages. We further characterize one abundant lncRNA with the highest expression level of all downregulated lncRNAs, which we named muscle differentiation-associated lncRNA (MDNCR)...
September 7, 2018: Molecular Therapy. Nucleic Acids
Fu-Ju Tian, Xiao-Ying He, Jie Wang, Xiao Li, Xiao-Ling Ma, Fan Wu, Jing Zhang, Xiao-Rui Liu, Xiao-Li Qin, Yan Zhang, Wei-Hong Zeng, Yi Lin
Tristetraprolin (TTP) regulates the stability of multiple targets that have important biological roles. However, the role of TTP in trophoblasts at the maternal-fetal interface remains poorly understood. We demonstrated that TTP was upregulated in placental trophoblasts from patients with recurrent miscarriages (RMs). Immunofluorescence and immunoblotting analyses indicated that TTP was redistributed from the nucleus to the cytoplasm in trophoblasts from patients with RMs. Trophoblast invasion and proliferation was repressed by TTP overexpression and was enhanced by TTP knockdown...
September 7, 2018: Molecular Therapy. Nucleic Acids
Hee Ho Park, Robinson Triboulet, Martin Bentler, Swaroopa Guda, Peng Du, Haiming Xu, Richard I Gregory, Christian Brendel, David A Williams
RNAi-based gene therapy using miRNA-adapted short hairpin RNAs (shRNAmiR ) is a powerful approach to modulate gene expression. However, we have observed low viral titers with shRNAmiR -containing recombinant vectors and hypothesized that this could be due to cleavage of viral genomic RNA by the endogenous microprocessor complex during virus assembly. To test this hypothesis, we targeted DROSHA, the core component of the microprocessor complex, and successfully generated monoallelic and biallelic DROSHA knockout (KO) HEK293T cells for vector production...
September 7, 2018: Molecular Therapy. Nucleic Acids
Yun-Chao Xu, Xu Liu, Min Li, Yan Li, Chun-Yan Li, Ying Lu, Jaceline Sanches, Lu Wang, Yue Du, Li-Min Mao, Si-Bo Zuo, Hui-Ting Liu, Jie Shen, Bo Wang, Li Hou, Lian-Hong Li, Jian-Wu Tang, Jing-Fang Ju, Hong-Wei Guan, Bo Song
Doxorubicin is a widely used anthracycline-based anti-tumor agent for both solid and liquid tumors. Mounting evidence has demonstrated that microRNAs (miRNAs) are involved in chemoresistance and tumorigenesis. However, the roles of microRNA-501-5p (miR-501) in doxorubicin resistance and gastric cancer cell proliferation and invasion are still not fully understood. In this study, we identified that BLID (BH3-like motif-containing protein, cell death inducer) was directly regulated by miR-501 at the post-transcriptional level in multiple gastric cancer cell lines...
September 7, 2018: Molecular Therapy. Nucleic Acids
Kai You, Song-Yang Li, Jiao Gong, Jian-Hong Fang, Chong Zhang, Min Zhang, Yunfei Yuan, Jine Yang, Shi-Mei Zhuang
miR-125b is frequently dysregulated in different diseases. Activation of hepatic stellate cells (HSCs) is a critical event during liver fibrogenesis. However, the function and its underlying mechanism of miR-125b in HSC activation and liver fibrosis are still unknown. Here, we showed that miR-125b was upregulated in HSCs, but not in hepatocytes, during hepatic fibrogenesis in vivo and upon culture activation in vitro. Inhibition of miR-125b suppressed the expression of profibrogenic genes in culture-activated primary HSCs and reduced the basal and transforming growth factor β (TGF-β)-induced alpha-smooth muscle actin (α-SMA) expression and cell contraction of the immortalized HSC cell line...
September 7, 2018: Molecular Therapy. Nucleic Acids
Wooshik Choi, Junghun Lee, Jaeman Lee, Kyeong Ryang Ko, Sunyoung Kim
Hepatocyte growth factor (HGF) has been well characterized for its roles in the migration of muscle progenitors during embryogenesis and the differentiation of muscle stem cells, but its function in adult neurogenic muscle atrophic conditions is poorly understood. Here we investigated whether HGF/c-met signaling has any effects on muscle-atrophic conditions. It was found that HGF expression was upregulated in skeletal muscle tissue following surgical denervation and in hSOD1-G93A transgenic mice showing severe muscle loss...
September 7, 2018: Molecular Therapy. Nucleic Acids
Araksya Izmiryan, Clarisse Ganier, Matteo Bovolenta, Alain Schmitt, Fulvio Mavilio, Alain Hovnanian
Recessive dystrophic epidermolysis bullosa is a rare and severe genetic skin disease resulting in blistering of the skin and mucosa. Recessive dystrophic epidermolysis bullosa (RDEB) is caused by a wide variety of mutations in COL7A1-encoding type VII collagen, which is essential for dermal-epidermal adhesion. Here we demonstrate the feasibility of ex vivo COL7A1 editing in primary RDEB cells and in grafted 3D skin equivalents through CRISPR/Cas9-mediated homology-directed repair. We designed five guide RNAs to correct a RDEB causative null mutation in exon 2 (c...
September 7, 2018: Molecular Therapy. Nucleic Acids
Jun Young Park, Ye Lim Cho, Ju Ri Chae, Sung Hwan Moon, Won Gil Cho, Yun Jung Choi, Soo Jin Lee, Won Jun Kang
Gemcitabine has been considered a first-line chemotherapy agent for the treatment of pancreatic cancer. However, the initial response rate of gemcitabine is low and chemoresistance occurs frequently. Aptamers can be effectively internalized into cancer cells via binding to target molecules with high affinity and specificity. In the current study, we constructed an aptamer-based gemcitabine delivery system, APTA-12, and assessed its therapeutic effects on pancreatic cancer cells in vitro and in vivo. APTA-12 was effective in vitro and in vivo in pancreatic cancer cells with high expression of nucleolin...
September 7, 2018: Molecular Therapy. Nucleic Acids
Sriram Vaidyanathan, Krist T Azizian, A K M Ashiqul Haque, Jordana M Henderson, Ayal Hendel, Sabrina Shore, Justin S Antony, Richard I Hogrefe, Michael S D Kormann, Matthew H Porteus, Anton P McCaffrey
The Cas9/guide RNA (Cas9/gRNA) system is commonly used for genome editing. mRNA expressing Cas9 can induce innate immune responses, reducing Cas9 expression. First-generation Cas9 mRNAs were modified with pseudouridine and 5-methylcytosine to reduce innate immune responses. We combined four approaches to produce more active, less immunogenic second-generation Cas9 mRNAs. First, we developed a novel co-transcriptional capping method yielding natural Cap 1. Second, we screened modified nucleotides in Cas9 mRNA to identify novel modifications that increase Cas9 activity...
September 7, 2018: Molecular Therapy. Nucleic Acids
Meng Zhou, Long Hu, Zicheng Zhang, Nan Wu, Jie Sun, Jianzhong Su
Patients with colon cancer are often faced a high risk of disease recurrence within 5 years of treatment that is the major cause of cancer mortality. Reliable molecular markers were required to improve the most effective personalized therapy. Here, we identified a recurrence-associated six-lncRNA (long non-coding RNA) signature (LINC0184, AC105243.1, LOC101928168, ILF3-AS1, MIR31HG, and AC006329.1) that can effectively distinguish between high and low risk of cancer recurrence from 389 patients of a discovery dataset, and validated its robust performance in four independent datasets comprising a total of 906 colon cancer patients...
September 7, 2018: Molecular Therapy. Nucleic Acids
Joan K Ho, Paul J White, Colin W Pouton
Delivery of plasmids for gene expression in vivo is an inefficient process that requires improvement and optimization to unlock the clinical potential of DNA vaccines. With ease of manufacture and biocompatibility in mind, we explored condensation of DNA in aqueous solution with a self-crosslinking, endosome-escaping lipopeptide (LP), stearoyl-Cys-His-His-Lys-Lys-Lys-amide (stearoyl-CH2 K3 ), to produce cationic LP/DNA complexes. To test whether poly(ethylene glycol) (PEG)-ylation of these cationic complexes to neutralize the surface charge would improve the distribution, gene expression, and immune responses poly(ethylene glycol), these LP/DNA complexes were combined with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000 )...
September 7, 2018: Molecular Therapy. Nucleic Acids
Vinod Kumar, Virender Kumar, Amit Kumar Chaudhary, Donald W Coulter, Timothy McGuire, Ram I Mahato
Medulloblastoma (MB) is a clinically challenging, childhood brain tumor with a diverse genetic makeup and differential miRNA profile. Aiming to identify deregulated miRNAs in MB, the miRNA expression profile of human MB samples was compared to that of normal cerebellar tissues. As a result, 8 upregulated and 64 downregulated miRNAs were identified in MB samples. Although various algorithms have been developed to predict the interaction between miRNA-mRNA pairs, the complexity and fidelity of miRNA-mRNA remain a concern...
September 7, 2018: Molecular Therapy. Nucleic Acids
Gang Han, Caorui Lin, Hanhan Ning, Xianjun Gao, HaiFang Yin
Approval of antisense oligonucleotide eteplirsen highlights the promise of exon-skipping therapeutics for Duchenne muscular dystrophy patients. However, the limited efficacy of eteplirsen underscores the importance to improve systemic delivery and efficacy. Recently, we demonstrated that a glucose and fructose (GF) delivery formulation effectively potentiates phosphorodiamidate morpholino oligomer (PMO). Considering the clinical potential of GF, it is important to determine the long-term compatibility and efficacy with PMO in mdx mice prior to clinical translation...
September 7, 2018: Molecular Therapy. Nucleic Acids
Javier López-Beas, Vivian Capilla-González, Yolanda Aguilera, Nuria Mellado, Christian C Lachaud, Franz Martín, Tarik Smani, Bernat Soria, Abdelkrim Hmadcha
Human pluripotent stem cells retain the extraordinary capacity to differentiate into pancreatic beta cells. For this particular lineage, more effort is still required to stress the importance of developing an efficient, reproducible, easy, and cost-effective differentiation protocol to obtain more mature, homogeneous, and functional insulin-secreting cells. In addition, microRNAs (miRNAs) have emerged as a class of small non-coding RNAs that regulate many cellular processes, including pancreatic differentiation...
September 7, 2018: Molecular Therapy. Nucleic Acids
Claudia Montagna, Gianluca Petris, Antonio Casini, Giulia Maule, Gian Marco Franceschini, Ilaria Zanella, Luciano Conti, Francesca Arnoldi, Oscar R Burrone, Lorena Zentilin, Serena Zacchigna, Mauro Giacca, Anna Cereseto
The method of delivery of CRISPR-Cas9 into target cells is a strong determinant of efficacy and specificity in genome editing. Even though high efficiency of Cas9 delivery is necessary for optimal editing, its long-term and high levels of expression correlate with increased off-target activity. We developed vesicles (VEsiCas) carrying CRISPR-SpCas9 ribonucleoprotein complexes (RNPs) that are efficiently delivered into target cells through the fusogenic glycoprotein of the vesicular stomatitis virus (VSV-G)...
September 7, 2018: Molecular Therapy. Nucleic Acids
Kinjal A Patel, Rajeev K Chaudhary, Ipsita Roy
Huntington's disease (HD) is associated with the misfolding and aggregation of mutant huntingtin harboring an elongated polyglutamine stretch at its N terminus. A distinguishing pathological hallmark of HD is mitochondrial dysfunction. Any strategy that can restore the integrity of the mitochondrial environment should have beneficial consequences for the disease. Specific RNA aptamers were selected that were able to inhibit aggregation of elongated polyglutamine stretch containing mutant huntingtin fragment (103Q-htt)...
September 7, 2018: Molecular Therapy. Nucleic Acids
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