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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.


  • Natural History of Infantile-Onset Spinal Muscular Atrophy.
    Natural History of Infantile-Onset Spinal Muscular Atrophy. [Journal Article]Ann Neurol 2017 Nov 17.ANKolb SJ, Coffey CS, Yankey JW, et al. These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real world", prospective natural hi...Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed.Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17).These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real world", prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. This article is protected by copyright. All rights reserved.

  • The Intrinsic Genetic and Epigenetic Regulator Factors as Therapeutic Targets, and the Effect on Fetal Globin Gene Expression.
    The Intrinsic Genetic and Epigenetic Regulator Factors as Therapeutic Targets, and the Effect on Fetal Globin Gene Expression. [Journal Article]Expert Rev Hematol 2017 Nov 17.ERAdelvand P, Hamid M, Sardari S Introduction The effort to induce fetal globin or Hb F gene expression as an alternative therapy for blood transfusion has been ongoing for few decades, with promising results evident in patients with ...Introduction The effort to induce fetal globin or Hb F gene expression as an alternative therapy for blood transfusion has been ongoing for few decades, with promising results evident in patients with hemoglobinopathies. Although the clinical outcomes have been satisfactory and significant, there are still concerns about the safety of Hb F inducers in the long-term. There are potent inducers which lose their potency and safety over the course of therapy. Area Covered: In this work, efforts have been made to review the latest findings on intrinsic genetic and epigenetic factors which are able to induce the gene expression of fetal globin in adult patients with beta (β)-thalassemia Major, Intermedia and sickle cell disease (SCD). Expert Commentary: To meet a satisfying therapeutic outcome in patients with hemoglobinopathies, in addition to adopting a potent Hb F inducer, a continuous level of gamma (γ)-globin gene over the course of therapy in safety condition also needs to be considered. Therefore, to reach this aim, it is suggested that the experiment designers consider the safety and long-term characteristics of the inducers simultaneously, by examining their synergistic effects.

  • Role of TCTP for Cellular Differentiation and Cancer Therapy.
    Role of TCTP for Cellular Differentiation and Cancer Therapy. [Journal Article]Results Probl Cell Differ 2017.:263-281.RPSeo EJ, Fischer N, Efferth T The translationally controlled tumor protein (TCTP) is a highly conserved protein that is regulated due to a high number of extracellular stimuli. TCTP has an important role for cell cycle and normal d...The translationally controlled tumor protein (TCTP) is a highly conserved protein that is regulated due to a high number of extracellular stimuli. TCTP has an important role for cell cycle and normal development. On the other side, tumor reversion and malignant transformation have been associated with TCTP. TCTP has been found among the 12 genes that are differentially expressed during mouse oocyte maturation, and an overexpression of this gene was reported in a wide variety of different cancer types. Its antiapoptotic effect is indicated by the interaction with several proapoptotic proteins of the Bcl-2 family and the p53 tumor suppressor protein. In this article, we draw attention to the role of TCTP in cancer, especially, focusing on cell differentiation and tumor reversion, a biological process by which highly tumorigenic cells lose their malignant phenotype. This protein has been shown to be the most strongly downregulated protein in revertant cells compared to the parental cancer cells. Decreased expression of TCTP results either in the reprogramming of cancer cells into reversion or apoptosis. As conventional chemotherapy is frequently associated with the development of drug resistance and high toxicity, the urge for the development of new or additional scientific approaches falls into place. Differentiation therapy aims at reinducing differentiation backward to the nonmalignant cellular state. Here, different approaches have been reported such as the induction of retinoid pathways and the use of histone deacetylase inhibitors. Also, PPARγ agonists and the activation of the vitamin D receptor have been reported as potential targets in differentiation therapy. As TCTP is known as the histamine-releasing factor, antihistaminic drugs have been shown to target this protein. Antihistaminic compounds, hydroxyzine and promethazine, inhibited cell growth of cancer cells and decreased TCTP expression of breast cancer and leukemia cells. Recently, we found that two antihistaminics, levomepromazine and buclizine, inhibited cancer cell growth by direct binding to TCTP and induction of cell differentiation. These data confirmed that TCTP is an exquisite target for anticancer differentiation therapy and antihistaminics have potential to be lead compounds for the direct interaction with TCTP as new inhibitors of human TCTP and tumor growth.

  • KIR content genotypes associate with carriage of hepatitis B surface antigen, e antigen and HBV viral load in Gambians.
    KIR content genotypes associate with carriage of hepatitis B surface antigen, e antigen and HBV viral load in Gambians. [Journal Article]PLoS One 2017; 12(11):e0188307.PlosYindom LM, Mendy M, Bodimeade C, et al. Certain KIR profiles may promote clearance of hepatitis B surface antigen whilst others predispose to e antigen carriage and high viral load. Larger studies are necessary to quantify the effects of ind...Hepatocellular carcinoma (HCC) causes over 800,000 deaths worldwide annually, mainly in low income countries, and incidence is rising rapidly in the developed world with the spread of hepatitis B (HBV) and C (HCV) viruses. Natural Killer (NK) cells protect against viral infections and tumours by killing abnormal cells recognised by Killer-cell Immunoglobulin-like Receptors (KIR). Thus genes and haplotypes encoding these receptors may be important in determining both outcome of initial hepatitis infection and subsequent chronic liver disease and tumour formation. HBV is highly prevalent in The Gambia and the commonest cause of liver disease. The Gambia Liver Cancer Study was a matched case-control study conducted between September 1997 and January 2001 where cases with liver disease were identified in three tertiary referral hospitals and matched with out-patient controls with no clinical evidence of liver disease.We typed 15 KIR genes using the polymerase chain reaction with sequence specific primers (PCR-SSP) in 279 adult Gambians, 136 with liver disease (HCC or Cirrhosis) and 143 matched controls. We investigated effects of KIR genotypes and haplotypes on HBV infection and associations with cirrhosis and HCC.Homozygosity for KIR group A gene-content haplotype was associated with HBsAg carriage (OR 3.7, 95% CI 1.4-10.0) whilst telomeric A genotype (t-AA) was associated with reduced risk of e antigenaemia (OR 0.2, 95% CI 0.0-0.6) and lower viral loads (mean log viral load 5.2 vs. 6.9, pc = 0.022). One novel telomeric B genotype (t-ABx2) containing KIR3DS1 (which is rare in West Africa) was also linked to e antigenaemia (OR 8.8, 95% CI 1.3-60.5). There were no associations with cirrhosis or HCC.Certain KIR profiles may promote clearance of hepatitis B surface antigen whilst others predispose to e antigen carriage and high viral load. Larger studies are necessary to quantify the effects of individual KIR genes, haplotypes and KIR/HLA combinations on long-term viral carriage and risk of liver cancer. KIR status could potentially inform antiviral therapy and identify those at increased risk of complications for enhanced surveillance.

  • Human hepatocyte transplantation for liver disease: Current status and future perspectives.
    Human hepatocyte transplantation for liver disease: Current status and future perspectives. [Journal Article, Review]Pediatr Res 2017 Nov 14.PRIansante V, Mitry RR, Filippi C, et al. Liver transplantation is the accepted treatment for patients with acute liver failure and liver-based metabolic disorders. However, donor organ shortage and lifelong need for immunosuppression are the ...Liver transplantation is the accepted treatment for patients with acute liver failure and liver-based metabolic disorders. However, donor organ shortage and lifelong need for immunosuppression are the main limitations to liver transplantation. In addition, loss of the native liver as target organ for future gene therapy for metabolic disorders limits the futuristic treatment options, resulting in the need for alternative therapeutic strategies. A potential alternative to liver transplantation is allogeneic hepatocyte transplantation. Over the last two decades hepatocyte transplantation has made the transition from bench to bedside. Standardized techniques have been established for isolation, culture, and cryopreservation of human hepatocytes. Clinical hepatocyte transplantation safety and short-term efficacy have been proven, however some major hurdles-mainly concerning shortage of donor organs, low cell engraftment and lack of long-lasting effect-need to be overcome to widen its clinical applications. Current research is aimed at addressing these problems, with the ultimate goal of increasing hepatocyte transplantation efficacy in clinical applications.Pediatric Research accepted article preview online, 14 November 2017. doi:10.1038/pr.2017.284.

  • How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?
    How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? [Journal Article, Review]Cell Death Differ 2017 Nov 17.CDAubrey BJ, Kelly GL, Janic A, et al. The tumour suppressor gene TP53 is mutated in ~50% of human cancers. In addition to its function in tumour suppression, p53 also plays a major role in the response of malignant as well as nontransforme...The tumour suppressor gene TP53 is mutated in ~50% of human cancers. In addition to its function in tumour suppression, p53 also plays a major role in the response of malignant as well as nontransformed cells to many anticancer therapeutics, particularly those that cause DNA damage. P53 forms a homotetrameric transcription factor that is reported to directly regulate ~500 target genes, thereby controlling a broad range of cellular processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death. For a long time, induction of apoptotic death in nascent neoplastic cells was regarded as the principal mechanism by which p53 prevents tumour development. This concept has, however, recently been challenged by the findings that in striking contrast to Trp53-deficient mice, gene-targeted mice that lack the critical effectors of p53-induced apoptosis do not develop tumours spontaneously. Remarkably, even mice lacking all mediators critical for p53-induced apoptosis, G1/S boundary cell cycle arrest and cell senescence do not develop any tumours spontaneously. In this review we discuss current understanding of the mechanisms by which p53 induces cell death and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy.Cell Death and Differentiation advance online publication, 17 November 2017; doi:10.1038/cdd.2017.169.

  • The role of microRNAs in chronic respiratory disease: recent insights.
    The role of microRNAs in chronic respiratory disease: recent insights. [Journal Article]Biol Chem 2017 Nov 27.BCStolzenburg LR, Harris A Chronic respiratory diseases encompass a group of diverse conditions affecting the airways, which all impair lung function over time. They include cystic fibrosis, idiopathic pulmonary fibrosis, chroni...Chronic respiratory diseases encompass a group of diverse conditions affecting the airways, which all impair lung function over time. They include cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma, which together affect hundreds of millions of people worldwide. MicroRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional gene repression, are now recognized as major regulators in the development and progression of chronic lung disease. Alterations in miRNA abundance occur in lung tissue, inflammatory cells, and freely circulating in blood and are thought to function both as drivers and modifiers of disease. Their importance in lung pathology has prompted the development of miRNA-based therapies and biomarker tools. Here, we review current literature on miRNA expression and function in chronic respiratory disease and highlight further research that is needed to propel miRNA treatments for lung disorders towards the clinic.

  • Small molecule Photoregulin3 prevents retinal degeneration in the Rho(P23H) mouse model of retinitis pigmentosa.
    Small molecule Photoregulin3 prevents retinal degeneration in the Rho(P23H) mouse model of retinitis pigmentosa. [Journal Article]Elife 2017 Nov 17.ENakamura PA, Shimchuk AA, Tang S, et al. Regulation of rod gene expression has emerged as a potential therapeutic strategy to treat retinal degenerative diseases like retinitis pigmentosa (RP). We previously reported on a small molecule modul...Regulation of rod gene expression has emerged as a potential therapeutic strategy to treat retinal degenerative diseases like retinitis pigmentosa (RP). We previously reported on a small molecule modulator of the rod transcription factor Nr2e3, Photoregulin1 (PR1), that regulates the expression of photoreceptor-specific genes. Although PR1 slows the progression of retinal degeneration in models of RP in vitro, in vivo analyses were not possible with PR1. We now report a structurally unrelated compound, Photoregulin3 (PR3) that also inhibits rod photoreceptor gene expression, potentially though Nr2e3 modulation. To determine the effectiveness of PR3 as a potential therapy for RP, we treated Rho(P23H) mice with PR3 and assessed retinal structure and function. PR3-treated Rho(P23H) mice showed significant structural and functional photoreceptor rescue compared with vehicle-treated littermate control mice. These results provide further support that pharmacological modulation of rod gene expression provides a potential strategy for the treatment of RP.

  • The Frequency of Mutations in Quinolone Resistance-Determining Regions and Plasmid-Mediated Quinolone Resistance in Shigella Isolates Recovered from Pediatric Patients in Tehran, Iran: An Overlooked Problem.
    The Frequency of Mutations in Quinolone Resistance-Determining Regions and Plasmid-Mediated Quinolone Resistance in Shigella Isolates Recovered from Pediatric Patients in Tehran, Iran: An Overlooked Problem. [Journal Article]Microb Drug Resist 2017 Nov 17.MDYaghoubi S, Ranjbar R, Soltan Dallal MM, et al. Fluoroquinolone (FQ) resistance in clinical isolates of Shigella species has been increasing reported in recent years. This study was carried out to find the mutations within the quinolone resistance-d...Fluoroquinolone (FQ) resistance in clinical isolates of Shigella species has been increasing reported in recent years. This study was carried out to find the mutations within the quinolone resistance-determining regions (QRDRs) and the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants among the clinical isolates of Shigella sp. in Tehran, Iran. A total of 50 Shigella isolates were collected from five teaching therapeutic centers in Tehran, Iran and analyzed for antibiotic susceptibility over a period of 20 months from July 2015 to January 2017. The PCR and direct nucleotide sequencing were used for genetic alterations in the QRDRs. The PMQR genes were detected using PCR. The results revealed four types of mutations in the QRDR of gyrA: 20 (40%) had a S83L mutation, 1 (2%) had a S83A mutation, 2 (4%) had a D87G mutation, and 1 (2%) isolate had a D87Y mutation. Mutations were also found at codon N57D, D200N, and E210K in three isolates. Seven hospitalized children had qnrS determinants, and one isolates had the mutation S83A, while two isolates had double mutations at S83L and/or D87G (Ser83Leu and Asp-87Gly). The PMQR gene-positive isolates had the single replacement of serine with leucine. In hospitalized children, two isolates had two types of PMQR determinants (qnrS and qnrA) and (qnrS and qnrB) at once. The results of this study indicate that the emergence of strains with mutations in the QRDR regions and the capture of PMQR determinants in strains may lead to failure in therapy with FQ and the widespread emergence of strains with high-level FQ resistance.

  • ATAD2 in cancer: A pharmacologically challenging but tractable target.
    ATAD2 in cancer: A pharmacologically challenging but tractable target. [Journal Article]Expert Opin Ther Targets 2017 Nov 17.EOHussain M, Zhou Y, Song Y, et al. ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have...ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a "difficult to drug" or "least druggable" target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding. Areas covered: In this review, after shedding light on the multifaceted roles of ATAD2 in normal physiology as well as in cancer-etiology, we discuss technical challenges rendered by ATAD2's BRD active site and the recent drug discovery efforts to find small molecule inhibitors against it. Expert opinion: The identification of a novel low-nanomolar semi-permeable chemical probe against ATAD2's BRD by recent drug discovery campaign has demonstrated it to be a pharmacologically tractable target. Nevertheless, the development of high quality bioavailable inhibitors against ATAD2 is still a pending task. Moreover, ATAD2 may also potentially be utilized as a promising target for future development of RNAi-based therapy to treat cancers.

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