eXTReMe Tracker
Gene Therapy Net RSS feed Follow Gene Therapy Net on Twitter LinkedIn - Gene Therapy Net discussion group Facebook - Gene Therapy Net

Latest Articles on Gene Therapy

Overview of latest articles and publications on gene therapy in PubMed, including Human Gene Therapy, Journal of Molecular Medicine and Journal of Gene Medicine. PubMed is a service of the US National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals.


  • Knockdown of MALAT1 expression inhibits HUVEC proliferation by upregulation of miR-320a and downregulation of FOXM1 expression.
    Knockdown of MALAT1 expression inhibits HUVEC proliferation by upregulation of miR-320a and downregulation of FOXM1 expression. [Journal Article]Oncotarget 2017 Jun 16.OSun JY, Zhao ZW, Li WM, et al. Regulation of cancer angiogenesis could be a useful strategy in cancer therapy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), and can induce cancer ...Publisher Full TextRegulation of cancer angiogenesis could be a useful strategy in cancer therapy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), and can induce cancer cell proliferation, while lncRNAs, generally are able to act as microRNA (miRNA) sponges. The latter is a type of competitive endogenous RNA (ceRNA) that regulates expression of the targeting miRNAs and protein-coding genes. This study investigated the proliferative role of MALAT1 in human umbilical vein endothelial cells (HUVECs) and the underlying molecular events. The data showed that knockdown of MALAT1 expression using MALAT1 siRNA inhibited HUVEC proliferation and also significantly decreased levels of FOXM1 mRNA and protein in vitro, while knockdown of FOXM1 expression reduced HUVEC proliferation. Annotation of HUVEC microarray data revealed that seven miRNAs, including miR-320a, were upregulated after knockdown of MALAT1 expression in HUVECs. MALAT1 was shown to reciprocally interact with miR-320a, i.e., expression of one negatively regulated levels of the other, whereas knockdown of MALAT1 expression promoted miR-320a levels. Furthermore, miR-320a could directly target and inhibit FOXM1 expression in HUVECs. Knockdown of MALAT1 expression enhanced miR-320a expression but reduced FOXM1 expression resulting in downregulation of HUVEC proliferation. However, such an effect was inhibited by miR-320a depletion. In conclusion, this study demonstrates that miR-320a plays an important role in mediating the effects of MALAT1 on HUVEC proliferation by suppression of FOXM1 expression. Thus, targeting of this gene pathway could be a novel strategy in cancer therapy.

  • Intrinsic remote conditioning of the myocardium as a comprehensive cardiac response to ischemia and reperfusion.
    Intrinsic remote conditioning of the myocardium as a comprehensive cardiac response to ischemia and reperfusion. [Journal Article]Oncotarget 2017 Jun 12.OPavo N, Lukovic D, Zlabinger K, et al. We have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling. Her...Publisher Full TextWe have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling. Here we investigated the molecular signals of the ischemia non-affected remote lateral and posterior regions and present gene expression profiles of the entire left ventricle by using our novel and straightforward method of 2D and 3D image reconstruction. Five or 24h after repetitive 10min ischemia/reperfusion without subsequent infarction, pig hearts were explanted and myocardial samples from 52 equally distributed locations of the left ventricle were collected. Expressional changes of seven genes of interest (HIF-1α; caspase-3, transcription factor GATA4; myocyte enhancer factor 2C /MEF2c/; hexokinase 2 /HK2/; clusterin /CLU/ and excision repair cross-complementation group 4 /ERCC4/) were measured by qPCR. 2D and 3D gene expression maps were constructed by projecting the fold changes on the NOGA anatomical mapping coordinates. Caspase-3, GATA4, HK2, CLU, and ERCC4 were up-regulated region-specifically in the ischemic zone at 5 h post ischemia/reperfusion injury. Overexpression of GATA4, clusterin and ERCC4 persisted after 24 h. HK2 showed strong up-regulation in the ischemic zone and down-regulation in remote areas at 5 h, and was severely reduced in all heart regions at 24 h. These results indicate a quick onset of regulation of apoptosis-related genes, which is partially reversed in the late phase of ischemia/reperfusion cardioprotection, and highlight variations between ischemic and unaffected myocardium over time. The NOGA 2D and 3D construction system is an attractive method to visualize expressional variations in the myocardium.

  • Relationship between the TERT, TNIP1 and OBFC1 genetic polymorphisms and susceptibility to colorectal cancer in Chinese Han population.
    Relationship between the TERT, TNIP1 and OBFC1 genetic polymorphisms and susceptibility to colorectal cancer in Chinese Han population. [Journal Article]Oncotarget 2017 Jun 06.OLi C, Zhao Z, Zhou J, et al. Colorectal cancer (CRC) is one of the most common diseases worldwide, and telomere length has been reported correlate with CRC. This study aimed to investigate whether polymorphisms of telomere length ...Publisher Full TextColorectal cancer (CRC) is one of the most common diseases worldwide, and telomere length has been reported correlate with CRC. This study aimed to investigate whether polymorphisms of telomere length related genes are associated with susceptibility to CRC in Chinese Han population. 11 SNPs from TERT, TNIP1 and OBFC1 genes were selected and genotyped, in addition odds ratio (OR) and 95% confidence intervals (CI) were used to evaluate association between the SNPs and CRC risk in 247 patients clinically and 300 controls in a Chinese Han population. Our results showed that minor allele "G" of rs7708392 and minor allele "C" of rs10036748 in TNIP1 gene were significantly associated with an increased the CRC risk in genotype model, dominant model and additive model after Bonferroni's multiple adjusted (P<0.0011). Moreover, the two SNPs rs7708392 and rs10036748 were in strong linkage disequilibrium. We observed that the haplotype "G-C" was more frequent among CRC patients and associated with a 1.58-fold increased CRC risk (95%CI=1.17-2.13, P=0.003). Contrarily, haplotype "C-T" was associated with a 0.63-fold reduced CRC risk (95%CI=0.47-0.86, P=0.003). Additionally, SNPs in this study except rs7708392 and rs10036748 were found a modest connection with CRC risk. In conclusion, our study firstly provides evidence for a novel association between polymorphisms of telomere length related TNIP1 gene and CRC susceptibility in Chinese Han population, and the results need a further identification in a large sample size and other populations.

  • Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer.
    Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer. [Journal Article]Br J Cancer 2017 Jun 27.BJOddo D, Siravegna G, Gloghini A, et al. We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.British Journal of Cancer advance online publication, 27 June 2017; doi:...Publisher Full TextCombined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF(V600E) and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.British Journal of Cancer advance online publication, 27 June 2017; doi:10.1038/bjc.2017.196 www.bjcancer.com.

  • Natural History, Pathogenesis, and Treatment of Evans Syndrome in Children.
    Natural History, Pathogenesis, and Treatment of Evans Syndrome in Children. [Journal Article]J Pediatr Hematol Oncol 2017 Jun 26.JPMantadakis E, Farmaki E Primary Evans syndrome (ES) is defined by the concurrent or sequential occurrence of immune thrombocytopenia and autoimmune hemolytic anemia in the absence of an underlying etiology. The syndrome is ch...Publisher Full TextPrimary Evans syndrome (ES) is defined by the concurrent or sequential occurrence of immune thrombocytopenia and autoimmune hemolytic anemia in the absence of an underlying etiology. The syndrome is characterized by a chronic, relapsing, and potentially fatal course requiring long-term immunosuppressive therapy. Treatment of ES is hardly evidence-based. Corticosteroids are the mainstay of therapy. Rituximab has emerged as the most widely used second-line treatment, as it can safely achieve high response rates and postpone splenectomy. An increasing number of new genetic defects involving critical pathways of immune regulation identify specific disorders, which explain cases of ES previously reported as "idiopathic".

  • Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?
    Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet? [Journal Article]Pharmacotherapy 2017 Jun 27.PChung C, Ma H Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not shown significant changes over the last few decades. In this review...Publisher Full TextDespite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not shown significant changes over the last few decades. In this review, we present a nonexhaustive key summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies, which depart significantly from conventional chemotherapy, the current mainstay for treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia (ALL) and PML-RARα for acute promyelocytic leukemia. There is evidence that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors (TKIs) can extend its use from relapsed disease to upfront induction therapy. Core-binding factor (CBF)-AML in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer. This article is protected by copyright. All rights reserved.

  • Serotonin transporter gene polymorphisms and SSRI tolerability: review of pharmacogenetic evidence.
    Serotonin transporter gene polymorphisms and SSRI tolerability: review of pharmacogenetic evidence. [Journal Article]Pharmacotherapy 2017 Jun 27.PZhu J, Klein-Fedyshin M, Stevenson JM The S allele of 5-HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body...Publisher Full TextSelective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy for mood and anxiety disorders. The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene SLC6A4, two polymorphic sites termed 5-HTTLPR and STin2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of SSRI efficacy and tolerability studies.This review summarizes approximately 15 years of study of these polymorphisms as they relate to SSRI tolerability phenotypes.Four online databases (PubMed, Cochrane CENTRAL, PsycINFO, and PharmGKB were searched for articles on polymorphisms of SLC6A4 including 5-HTTLPR and STin2 utilizing a systematic approach. Specific and general psychopharmacology terms, along with adverse effect and tolerability concepts, added to the search strategy. The Human Gene Mutation Database was checked for additional references.Forty studies met the inclusion criteria. While null and occasionally opposite associations are reported, the low expression 5-HTTLPR S allele is generally associated with greater adverse drug reaction burden during SSRI therapy. The most convincing evidence is in studies of antidepressant-induced mania and gastrointestinal adverse events. Studies of STin2 are sparse and have conflicting findings.The S allele of 5-HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body of evidence including assay errors, dissimilar grouping of genotypes, the role of ethnicity in associations, and study methodological differences. The clinical utility of serotonin transporter genotypes is not yet delineated but will ultimately depend on genotypic effects on both tolerability and efficacy of SSRIs This article is protected by copyright. All rights reserved.

  • Bidirectional Retroviral Integration Site PCR Methodology and Quantitative Data Analysis Workflow.
    Bidirectional Retroviral Integration Site PCR Methodology and Quantitative Data Analysis Workflow. [Journal Article]J Vis Exp 2017 Jun 14; (124)JVSuryawanshi GW, Xu S, Xie Y, et al. Integration Site (IS) assays are a critical component of the study of retroviral integration sites and their biological significance. In recent retroviral gene therapy studies, IS assays, in combinatio...Integration Site (IS) assays are a critical component of the study of retroviral integration sites and their biological significance. In recent retroviral gene therapy studies, IS assays, in combination with next-generation sequencing, have been used as a cell-tracking tool to characterize clonal stem cell populations sharing the same IS. For the accurate comparison of repopulating stem cell clones within and across different samples, the detection sensitivity, data reproducibility, and high-throughput capacity of the assay are among the most important assay qualities. This work provides a detailed protocol and data analysis workflow for bidirectional IS analysis. The bidirectional assay can simultaneously sequence both upstream and downstream vector-host junctions. Compared to conventional unidirectional IS sequencing approaches, the bidirectional approach significantly improves IS detection rates and the characterization of integration events at both ends of the target DNA. The data analysis pipeline described here accurately identifies and enumerates identical IS sequences through multiple steps of comparison that map IS sequences onto the reference genome and determine sequencing errors. Using an optimized assay procedure, we have recently published the detailed repopulation patterns of thousands of Hematopoietic Stem Cell (HSC) clones following transplant in rhesus macaques, demonstrating for the first time the precise time point of HSC repopulation and the functional heterogeneity of HSCs in the primate system. The following protocol describes the step-by-step experimental procedure and data analysis workflow that accurately identifies and quantifies identical IS sequences.

  • Analysis of the Gap Junction-dependent Transfer of miRNA with 3D-FRAP Microscopy.
    Analysis of the Gap Junction-dependent Transfer of miRNA with 3D-FRAP Microscopy. [Journal Article]J Vis Exp 2017 Jun 19; (124)JVLemcke H, Voronina N, Steinhoff G, et al. Small antisense RNAs, like miRNA and siRNA, play an important role in cellular physiology and pathology and, moreover, can be used as therapeutic agents in the treatment of several diseases. The develo...Small antisense RNAs, like miRNA and siRNA, play an important role in cellular physiology and pathology and, moreover, can be used as therapeutic agents in the treatment of several diseases. The development of new, innovative strategies for miRNA/siRNA therapy is based on an extensive knowledge of the underlying mechanisms. Recent data suggest that small RNAs are exchanged between cells in a gap junction-dependent manner, thereby inducing gene regulatory effects in the recipient cell. Molecular biological techniques and flow cytometric analysis are commonly used to study the intercellular exchange of miRNA. However, these methods do not provide high temporal resolution, which is necessary when studying the gap junctional flux of molecules. Therefore, to investigate the impact of miRNA/siRNA as intercellular signaling molecules, novel tools are needed that will allow for the analysis of these small RNAs at the cellular level. The present protocol describes the application of three-dimensional fluorescence recovery after photobleaching (3D-FRAP) microscopy to elucidating the gap junction-dependent exchange of miRNA molecules between cardiac cells. Importantly, this straightforward and non-invasive live-cell imaging approach allows for the visualization and quantification of the gap junctional shuttling of fluorescently labeled small RNAs in real time, with high spatio-temporal resolution. The data obtained by 3D-FRAP confirm a novel pathway of intercellular gene regulation, where small RNAs act as signaling molecules within the intercellular network.

  • A Unified Methodological Framework for Vestibular Schwannoma Research.
    A Unified Methodological Framework for Vestibular Schwannoma Research. [Journal Article]J Vis Exp 2017 Jun 20; (124)JVLandegger LD, Sagers JE, Dilwali S, et al. Vestibular schwannomas are the most common neoplasms of the cerebellopontine angle, making up 6-8% percent of all intracranial growths. Though these tumors cause sensorineural hearing loss in up to 95%...Vestibular schwannomas are the most common neoplasms of the cerebellopontine angle, making up 6-8% percent of all intracranial growths. Though these tumors cause sensorineural hearing loss in up to 95% of affected individuals, the molecular mechanisms underlying this hearing loss remain elusive. This article outlines the steps established in our laboratory to facilitate the collection and processing of various primary human tissue samples for downstream research applications integral to the study of vestibular schwannomas. Specifically, this work describes a unified methodological framework for the collection, processing, and culture of Schwann and schwannoma cells from surgical samples. This is integrated with parallel processing steps now considered essential for current research: the collection of tumor and nerve secretions, the preservation of RNA and the extraction of protein from collected tissues, the fixation of tissue for the preparation of sections, and the exposure of primary human cells to adeno-associated viruses for application to gene therapy. Additionally, this work highlights the translabyrinthine surgical approach to collect this tumor as a unique opportunity to obtain human sensory epithelium from the inner ear and perilymph. Tips to improve experimental quality are provided and common pitfalls highlighted.

Suggestions