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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.


  • Polymorphisms in the Glucocorticoid Receptor Gene and Associations with Glucocorticoid-Induced Avascular Osteonecrosis of the Femoral Head.
    Polymorphisms in the Glucocorticoid Receptor Gene and Associations with Glucocorticoid-Induced Avascular Osteonecrosis of the Femoral Head. [Journal Article]Genet Test Mol Biomarkers 2017 Mar 27.GTZhao Z, Xue Y, Hong D, et al. Most of these common SNPs in the NR3C1 gene likely do not play critical roles in the susceptibility of GANFH. However, the G allele at the SNP Bcll, irrespective of dosage, may increase risk for the de...Individual sensitivity to glucocorticoid (GC) therapy might play a pivotal role in the development of GC-induced avascular necrosis of the femoral head (GANFH). In a growing number of studies, common polymorphisms of the glucocorticoid receptor gene (nuclear receptor subfamily 3 group C member 1 [NR3C1]) have been associated with variability in the individual sensitivity to GCs. However, whether the NR3C1 gene polymorphisms actually influence the susceptibility of GANFH remains unknown.In this study, we report the findings of a case-control study to investigate the role of the NR3C1 gene single-nucleotide polymorphisms (SNPs) in GANFH susceptibility among 78 GANFH patients (GCs sensitive) and 115 GC-resistant controls.Our results found no significant associations between the SNPs N363S, Tth111I, BclI, ER22/23EK, and A3669G with GANFH susceptibility. The G allele in homozygous or heterozygous of SNP BclI was significantly different between control and GANFH combined with osteopenia subgroups (odds ratios [OR] = 1.81; 95% confidence intervals [CI] = 1.05-3.10; OR = 2.04; 95% CI = 1.03-4.07, respectively).Most of these common SNPs in the NR3C1 gene likely do not play critical roles in the susceptibility of GANFH. However, the G allele at the SNP Bcll, irrespective of dosage, may increase risk for the development of GANFH combined with osteopenia in the Chinese population.

  • Effects of IFN-γon the cell growth and the expression of ADAM33 gene in human embryonic lung Mrc-5 fibroblasts in vitro.
    Effects of IFN-γon the cell growth and the expression of ADAM33 gene in human embryonic lung Mrc-5 fibroblasts in vitro. [Journal Article]J Asthma 2017 Mar 27.:0.JALi W, Liang R, Huang H, et al. Derf1-induced Mrc-5 cells successfully imitated the in vivo conditions observed in patients with asthma. IFN-γ inhibited the proliferation and viability of Mrc-5 cells, and Derf1-induced Mrc-5 cells we...Publisher Full TextTo investigate the effects of interferon-γ (IFN-γ) on the proliferation and viability of human embryonic lung Mrc-5 fibroblasts in vitro and the expression of the A Disintegrin and Metalloprotease 33 (ADAM33) gene and to explore the mechanism of airway remodeling.Mrc-5 fibroblasts were sensitized with Dermatophagoides farinae 1 (Derf1) in vitro to mimic in vivo conditions observed in bronchial asthma. An inverted fluorescence microscope was used to observe changes in cell morphology before and after treatment. The viability of Mrc-5 cells was tested using the Cell Counting kit-8 (CCK8). Expression of the ADAM33 gene and protein in Mrc-5 cells was assessed using qPCR and Western blotting, respectively.Different concentrations of Derf1 increased cell growth and the expression of the ADAM33 gene in Mrc-5 cells, and these changes were most obvious in the 10 μg/ml group. In contrast, IFN-γ decreased cell growth and the expression of the ADAM33 gene in both Mrc-5 cells and Derf1-induced Mrc-5 cells, and these changes were most obvious in the 10 ng/ml group. The negative effects of 10 ng/ml IFN-γ were the most significant at 32 h.Derf1-induced Mrc-5 cells successfully imitated the in vivo conditions observed in patients with asthma. IFN-γ inhibited the proliferation and viability of Mrc-5 cells, and Derf1-induced Mrc-5 cells were more sensitive to IFN-γ treatment. IFN-γ treatment significantly downregulated the expression of the ADAM33 gene in a concentration- and time-dependent manner. IFN-γ may participate in airway remodeling in asthma by regulating the expression of the ADAM33 gene.

  • Cabergoline-related impulse control disorder in an adolescent with a giant prolactinoma.
    Cabergoline-related impulse control disorder in an adolescent with a giant prolactinoma. [Case Reports]Clin Endocrinol (Oxf) 2017 Mar 27.CEBulwer C, Conn R, Shankar A, et al. Giant prolactinomas, rare in children, can have devastating endocrine, neurological and visual sequelae. Dopamine agonists (DA) are effective first-line therapy with few side-effects at doses usually u...Publisher Full TextGiant prolactinomas, rare in children, can have devastating endocrine, neurological and visual sequelae. Dopamine agonists (DA) are effective first-line therapy with few side-effects at doses usually used for prolactinoma treatment(1) , but higher-dose therapy for Parkinson's disease has well-recognized associations with impulse control disorders (ICD) including pathological gambling, impulsive eating, compulsive shopping and hypersexuality. Such associations are not well recognized with prolactinomas; to our knowledge this is the first reported case of hypersexuality in an adolescent receiving cabergoline for a giant prolactinoma. This article is protected by copyright. All rights reserved.

  • CAR T-cell therapy for pancreatic cancer.
    CAR T-cell therapy for pancreatic cancer. [Journal Article, Review]J Surg Oncol 2017 Mar 27.JSDeSelm CJ, Tano ZE, Varghese AM, et al. Chimeric antigen receptor (CAR) T-cell therapy utilizes genetic engineering to redirect a patient's own T cells to target cancer cells. The remarkable results in hematological malignancies prompted inv...Publisher Full TextChimeric antigen receptor (CAR) T-cell therapy utilizes genetic engineering to redirect a patient's own T cells to target cancer cells. The remarkable results in hematological malignancies prompted investigating this approach in solid tumors such as pancreatic cancer. The complex tumor microenvironment, stromal hindrance in limiting immune response, and expression of checkpoint blockade on T cells pose hurdles. Herein, we summarize the opportunities, challenges, and state of knowledge in targeting pancreatic cancer with CAR T-cell therapy.

  • Detailed comparison of retroviral vectors and promoter configurations for stable and high transgene expression in human induced pluripotent stem cells.
    Detailed comparison of retroviral vectors and promoter configurations for stable and high transgene expression in human induced pluripotent stem cells. [Journal Article]Gene Ther 2017 Mar 27.GTHoffmann D, Schott JW, Geis FK, et al. Correction of patient-specific induced pluripotent stem cells (iPSC) upon gene delivery through retroviral vectors offers new treatment perspectives for monogenetic diseases. Gene-modified iPSC clones ...Publisher Full TextCorrection of patient-specific induced pluripotent stem cells (iPSC) upon gene delivery through retroviral vectors offers new treatment perspectives for monogenetic diseases. Gene-modified iPSC clones can be screened for safe integration sites and differentiated into transplantable cells of interest. However, the current bottleneck is epigenetic vector silencing. In order to identify the most suitable retroviral expression system in iPSC, we systematically compared vectors from different retroviral genera, different promoters and their combination with ubiquitous chromatin opening elements (UCOE), and several envelope pseudotypes. Lentiviral vectors (LV) pseudotyped with VSV-G were superior to gammaretroviral and alpharetroviral vectors and other envelopes tested. The elongation factor 1α short (EFS) promoter mediated the most robust expression, while expression levels were lower from the potent but more silencing-prone spleen focus forming virus (SFFV) promoter. Both full length (A2UCOE) and minimal (CBX3) UCOE juxtaposed to two physiological and one viral promoter reduced transgene silencing with equal efficiency. However, a promoter-specific decline in expression levels was not entirely prevented. Upon differentiation of transgene-positive iPSC into endothelial cells, A2UCOE.EFS and CBX3.EFS vectors maintained highest transgene expression in a larger fraction of cells as compared to all other constructs tested here. The function of UCOE diminished but did not fully counteract vector silencing and possibilities for improvements remain. Nevertheless, the CBX3.EFS in a LV background exhibited the most promising promoter and vector configuration for both high titer production and long-term genetic modification of human iPSC and their progeny.Gene Therapy accepted article preview online, 27 March 2017. doi:10.1038/gt.2017.20.

  • AAV9-mediated engineering of autotransplanted kidney of non-human primates.
    AAV9-mediated engineering of autotransplanted kidney of non-human primates. [Journal Article]Gene Ther 2017 Mar 27.GTTomasoni S, Trionfini P, Azzollini N, et al. Ex vivo gene transfer to the graft before transplantation is an attractive option for circumventing systemic side effects of chronic anti-rejection therapy. Gene delivery of the immunomodulatory protei...Publisher Full TextEx vivo gene transfer to the graft before transplantation is an attractive option for circumventing systemic side effects of chronic anti-rejection therapy. Gene delivery of the immunomodulatory protein CTLA4-Ig prevented chronic kidney rejection in a rat model of allotransplantation without the need for systemic immunosuppression. Here, we generated AAV2 and AAV9 vectors encoding for LEA29Y, an optimized version of CTLA4-Ig. Both LEA29Y vectors were equally efficient for reducing T-cell proliferation in vitro. Serotype 9 was chosen for in vivo experiments due to a lower frequency of preformed antibodies against the AAV9 capsid in 16 non-human primate tested sera. AAV9-LEA29Y was able to transduce the kidney of non-human primates in an auto-transplantation model. Expression of LEA29Y mRNA by renal cells translated into the production of the corresponding protein, which was confined to the graft but not detected in serum. Results in non-human primates represent a step forward in maintaining the portability of this strategy into clinics.Gene Therapy accepted article preview online, 27 March 2017. doi:10.1038/gt.2017.21.

  • Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract.
    Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract. [Journal Article]Gene Ther 2017 Mar 27.GTKurosaki F, Uchibori R, Mato N, et al. An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters, and routes of administration potentially influencing the efficiency...Publisher Full TextAn efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters, and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter. Regarding delivery routes, intratracheal administration resulted in strong transgene expression in the lung, whereas the intravenous and intranasal administration routes yielded negligible expression. The combination of the AAV6 capsid and CAG promoter resulted in sustained expression, and the intratracheally administered AAV6-CAG vector transduced bronchial cells and pericytes in the lung. These results suggest that AAV6-CAG vectors are more promising than the previously preferred AAV2 vectors for airway transduction, particularly when administered into the trachea. The present study offers an optimized strategy for AAV-mediated gene therapy for lung diseases, such as cystic fibrosis and pulmonary fibrosis.Gene Therapy accepted article preview online, 27 March 2017. doi:10.1038/gt.2017.19.

  • Multifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy.
    Multifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy. [Journal Article, Review]Mar Drugs 2017 Mar 27; 15(4)MDBabu A, Ramesh R Chitosan is a versatile polysaccharide of biological origin. Due to the biocompatible and biodegradable nature of chitosan, it is intensively utilized in biomedical applications in scaffold engineering...Publisher Full TextChitosan is a versatile polysaccharide of biological origin. Due to the biocompatible and biodegradable nature of chitosan, it is intensively utilized in biomedical applications in scaffold engineering as an absorption enhancer, and for bioactive and controlled drug release. In cancer therapy, chitosan has multifaceted applications, such as assisting in gene delivery and chemotherapeutic delivery, and as an immunoadjuvant for vaccines. The present review highlights the recent applications of chitosan and chitosan derivatives in cancer therapy.

  • Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production.
    Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production. [Journal Article]Int J Mol Sci 2017 Mar 26; 18(4)IJBanning A, König JF, Gray SJ, et al. Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU),...Publisher Full TextAspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing. Therefore, Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. Furthermore, we have here produced codon-optimized versions of these two variants and show that they are expressed at significantly higher levels than AGA with the natural codon-usage. Since optimal AGA expression is of vital importance for both gene therapy and enzyme replacement, our data suggest that use of codon-optimized AGA may be beneficial for these therapy options.

  • Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency.
    Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. [Journal Article]J Clin Invest 2017 Mar 27.JCIShaw KL, Garabedian E, Mishra S, et al. These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.Publisher Full TextAutologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study.Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution.With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant.These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.ClinicalTrials.gov NCT00794508.Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.

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