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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.


  • Host factors that promote retrotransposon integration are similar in distantly related eukaryotes.
    Host factors that promote retrotransposon integration are similar in distantly related eukaryotes. [Journal Article]PLoS Genet 2017 Dec 12; 13(12):e1006775.PGRai SK, Sangesland M, Lee M, et al. Retroviruses and Long Terminal Repeat (LTR)-retrotransposons have distinct patterns of integration sites. The oncogenic potential of retrovirus-based vectors used in gene therapy is dependent on the se...Publisher Full TextRetroviruses and Long Terminal Repeat (LTR)-retrotransposons have distinct patterns of integration sites. The oncogenic potential of retrovirus-based vectors used in gene therapy is dependent on the selection of integration sites associated with promoters. The LTR-retrotransposon Tf1 of Schizosaccharomyces pombe is studied as a model for oncogenic retroviruses because it integrates into the promoters of stress response genes. Although integrases (INs) encoded by retroviruses and LTR-retrotransposons are responsible for catalyzing the insertion of cDNA into the host genome, it is thought that distinct host factors are required for the efficiency and specificity of integration. We tested this hypothesis with a genome-wide screen of host factors that promote Tf1 integration. By combining an assay for transposition with a genetic assay that measures cDNA recombination we could identify factors that contribute differentially to integration. We utilized this assay to test a collection of 3,004 S. pombe strains with single gene deletions. Using these screens and immunoblot measures of Tf1 proteins, we identified a total of 61 genes that promote integration. The candidate integration factors participate in a range of processes including nuclear transport, transcription, mRNA processing, vesicle transport, chromatin structure and DNA repair. Two candidates, Rhp18 and the NineTeen complex were tested in two-hybrid assays and were found to interact with Tf1 IN. Surprisingly, a number of pathways we identified were found previously to promote integration of the LTR-retrotransposons Ty1 and Ty3 in Saccharomyces cerevisiae, indicating the contribution of host factors to integration are common in distantly related organisms. The DNA repair factors are of particular interest because they may identify the pathways that repair the single stranded gaps flanking the sites of strand transfer following integration of LTR retroelements.

  • Genomic form of rhodopsin DNA nanoparticles rescued autosomal dominant Retinitis pigmentosa in the P23H knock-in mouse model.
    Genomic form of rhodopsin DNA nanoparticles rescued autosomal dominant Retinitis pigmentosa in the P23H knock-in mouse model. [Journal Article]Biomaterials 2017 Dec 05.:26-39.BMitra RN, Zheng M, Weiss ER, et al. Retinitis pigmentosa (RP) is a group of inherited retinal degenerative conditions and a leading cause of irreversible blindness. 25%-30% of RP cases are caused by inherited autosomal dominant (ad) muta...Publisher Full TextRetinitis pigmentosa (RP) is a group of inherited retinal degenerative conditions and a leading cause of irreversible blindness. 25%-30% of RP cases are caused by inherited autosomal dominant (ad) mutations in the rhodopsin (Rho) protein of the retina, which impose a barrier for developing therapeutic treatments for this genetically heterogeneous disorder, as simple gene replacement is not sufficient to overcome dominant disease alleles. Previously, we have explored using the genomic short-form of Rho (sgRho) for gene augmentation therapy of RP in a Rho knockout mouse model. We have shown improved gene expression and fewer epigenetic modifications compared with the use of a Rho cDNA expression construct. In the current study, we altered our strategy by delivering a codon-optimized genomic form of Rho (co-sgRho) (for gene replacement) in combination with an RNAi-based inactivation of endogenous Rho alleles (gene suppression of both mutant Rho alleles, but mismatched with the co-sgRho) into a homozygous RhoP23H/P23H knock-in (KI) RP mouse model, which has a severe phenotype of adRP. In addition, we have conjugated a cell penetrating TAT peptide sequence to our previously established CK30PEG10 diblock co-polymer. The DNAs were compacted with CK30PEG10-TAT diblock co-polymer to form DNA nanoparticles (NPs). These NPs were injected into the sub-retinal space of the KI mouse eyes. As a proof of concept, we demonstrated the efficiency of this strategy in the partial improvement of visual function in the RhoP23H/P23H KI mouse model.

  • Prior systemic treatment increased the incidence of somatic mutations in metastatic breast cancer.
    Prior systemic treatment increased the incidence of somatic mutations in metastatic breast cancer. [Journal Article]Eur J Cancer 2017 Dec 09.:64-71.EJFujii T, Matsuda N, Kono M, et al. Systemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutati...Publisher Full TextUnderstanding the biology of breast cancer is important for guiding treatment strategies and revealing resistance mechanisms. Our objectives were to investigate the relationship between previous systemic therapy exposure and mutational spectrum in metastatic breast cancer and to identify clinicopathological factors associated with identified frequent somatic mutations.Archival tissues of patients with metastatic breast cancer were subjected to hotspot molecular testing by next-generation sequencing. The variables that significantly differed (P < 0.05) in univariate analysis were selected to fit multivariate models. Logistic models were fit to estimate the association between mutation status and clinical variables of interest. Five-fold cross-validation was performed to estimate the prediction error of each model.A total of 922 patients were included in the analysis. In multivariate analysis, previous systemic treatment before molecular testing (N = 186) was associated with a significantly higher rate of TP53 and PIK3CA mutations compared with the lack of systemic treatment (P < 0.001 for both).Systemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutations. It is worth testing the gene profile when tumours become resistant to systemic treatments.

  • MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma.
    MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. [Journal Article]Cancer Cell 2017 Dec 11; 32(6):840-855.e8.CCHuang T, Kim CK, Alvarez AA, et al. ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphor...ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy.

  • [Systemic treatment of early breast cancer - current state of knowledge after the conference St Gallen 2017].
    [Systemic treatment of early breast cancer - current state of knowledge after the conference St Gallen 2017]. [English Abstract, Journal Article, Review]Pol Merkur Lekarski 2017 Nov 23; 43(257):232-236.PMSarosiek T Breast cancer is the most commonly diagnosed malignancy in women around the globe. It is also the world's first cause of female deaths from cancer. With the introduction of screening programs in most d...Publisher Full TextBreast cancer is the most commonly diagnosed malignancy in women around the globe. It is also the world's first cause of female deaths from cancer. With the introduction of screening programs in most developed countries, more and more cases of this cancer are diagnosed at local or localized stages, enabling radical treatment to be successful. At the same time, systemic treatment of early breast cancer is one of the most complex issues in clinical oncology. Because of the many prognostic factors that need to be taken into account when considering eligibility for treatment such as age, reproductive status (before or after menopause), type of cancer and severity of the disease, it is impossible to establish clear standards of conduct for many clinical situations. The international biennial St Gallen conference, the world's most prominent breast cancer specialists, who are struggling to address major clinical problems in the treatment of early breast cancer. St Gallen's recommendations address all issues related to the treatment of early breast cancer (in particular surgery, radiotherapy, and systemic treatment) and are set by a group of 52 experts by voting. This method allows us to establish consensus on issues that can not be clearly identified in the results of randomized clinical trials. In this way, more than 200 clinical issues were answered. The most important changes in day-to-day practice are the duration of ajuvant hormone therapy (10 instead of 5 years), the possibility of using aromatase inhibitors (in combination with ovarian function suppresion) in premenopausal women with high risk of recurrence and the timing of sentinel node biopsy after neo-adjuvant chemotherapy. There are also recommendations, which patients should undergo genetic testing to assess the risk of recurrence of breast cancer.

  • Whole-exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets.
    Whole-exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets. [Journal Article]J Pathol 2017 Dec 12.JPLyu J, Song Z, Chen J, et al. Oral mucosal melanoma (OMM) is rare and aggressive subtype of melanoma with little known about its pathogenesis carcinogenesis. We therefore performed whole-exome sequencing (WES) on 19 matched OMM tum...Publisher Full TextOral mucosal melanoma (OMM) is rare and aggressive subtype of melanoma with little known about its pathogenesis carcinogenesis. We therefore performed whole-exome sequencing (WES) on 19 matched OMM tumor/normal pairs in order to gain insight on potential genetic drivers of tumor formation. For the first time we describe the comprehensive mutational profile of OMM. Our data suggests that the genetic background of OMM differs from those of other melanoma subtypes. We identified recurrent mutations involving KIT, POLE,PTPRD, PTCHD2 and DMXL2. Notably, copy number analysis revealed recurrently amplified regions of 12q14 (57.9%, containing CDK4) and 5p15 (47.4%, containing TERT). CNV analysis in a separate cohort of 15 samples validated the frequent CNV in CDK4 and TERT. We also observed that the melanocyte development and pigmentation signaling pathway is frequently altered in OMM. Furthermore, our data suggest several altered genes that may be amenable for targeted therapy. We identified one patient with metastatic OMM in our cohort who was identified to harbor a targetable KIT mutation using our WES results. This patient was able to achieve complete remission following implementation of KIT-targeted therapy. These findings provide further insight into the genetic underpinnings of OMM development and suggests that patients with OMM may benefit from WES analysis to identify potential targetable genetic mutations.

  • Potential Effects of Horizontal Gene Exchange in the Human Gut.
    Potential Effects of Horizontal Gene Exchange in the Human Gut. [Journal Article]Front Immunol 2017.:1630.FILerner A, Matthias T, Aminov R Many essential functions of the human body are dependent on the symbiotic microbiota, which is present at especially high numbers and diversity in the gut. This intricate host-microbe relationship is a...Many essential functions of the human body are dependent on the symbiotic microbiota, which is present at especially high numbers and diversity in the gut. This intricate host-microbe relationship is a result of the long-term coevolution between the two. While the inheritance of mutational changes in the host evolution is almost exclusively vertical, the main mechanism of bacterial evolution is horizontal gene exchange. The gut conditions, with stable temperature, continuous food supply, constant physicochemical conditions, extremely high concentration of microbial cells and phages, and plenty of opportunities for conjugation on the surfaces of food particles and host tissues, represent one of the most favorable ecological niches for horizontal gene exchange. Thus, the gut microbial system genetically is very dynamic and capable of rapid response, at the genetic level, to selection, for example, by antibiotics. There are many other factors to which the microbiota may dynamically respond including lifestyle, therapy, diet, refined food, food additives, consumption of pre- and probiotics, and many others. The impact of the changing selective pressures on gut microbiota, however, is poorly understood. Presumably, the gut microbiome responds to these changes by genetic restructuring of gut populations, driven mainly via horizontal gene exchange. Thus, our main goal is to reveal the role played by horizontal gene exchange in the changing landscape of the gastrointestinal microbiome and potential effect of these changes on human health in general and autoimmune diseases in particular.

  • Ibalizumab Targeting CD4 Receptors, An Emerging Molecule in HIV Therapy.
    Ibalizumab Targeting CD4 Receptors, An Emerging Molecule in HIV Therapy. [Journal Article, Review]Front Microbiol 2017.:2323.FMIacob SA, Iacob DG The HIV infection is responsible for the most devastating global pandemic of the last century. More than 39 million people have died of HIV/AIDS since 1981. The development of the antiretroviral (ARV) ...The HIV infection is responsible for the most devastating global pandemic of the last century. More than 39 million people have died of HIV/AIDS since 1981. The development of the antiretroviral (ARV) treatment begins with the discovery of zidovudine a nucleoside reverse transcriptase inhibitor. This breakthrough was followed by other ARV drug classes and representatives. Presently, HIV treatment employs 27 ARV representatives belonging to five different classes. Despite the proven benefits of ARV treatment and its long-term control of the HIV infection, there is an increasing concern about the numerous adverse effects and resistance to current ARV drugs. Therefore, the new HIV treatment strategies focus on the development of new ARV agents with a high genetic barrier to resistance and low toxicity. Monoclonal antibodies (MAbs) belong to a new drug class with encouraging results in the treatment of cancer, autoimmune disorders and most recently against HIV infection. The advantages of using MAbs for HIV treatment are related to their antiviral effect, lack of toxicity, good resistance profile, additional synergy with other ARV drug classes and ability to restore CD4 T-cell responses. The current article is a short summary of ibalizumab, an anti-CD4 monoclonal antibody that interferes with HIV viral entry. Current studies on ibalizumab have underlined its antiviral potential, minimal adverse effects, and lack of crossed resistance with other ARV agents thus supporting its further therapeutic use in multidrug resistant HIV-infected patients.

  • Molecular Targets in Non-Small Cell Lung Cancer.
    Molecular Targets in Non-Small Cell Lung Cancer. [Journal Article, Review]Ochsner J 2017; 17(4):388-392.OJGriffin R, Ramirez RA Patients with advanced NSCLC should undergo mutational testing to evaluate for actionable mutations. If such a mutation is discovered, targeted therapy should be considered for first-line treatment.Lung cancer is the second most common cancer in the United States among men and women, and it is the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases. Historically, patients with metastatic NSCLC received similar cytotoxic chemotherapy regimens. Genotyping studies have revealed genetic/molecular abnormalities in lung cancer. These driver mutations render a cancer dependent on that specific mutation's biochemical pathway for its growth and survival. With the development of tyrosine kinase inhibitors and antibodies against specific driver mutations, the landscape of lung cancer treatment has changed from treatment based on histologic subtype to treatment based on molecularly defined subtypes.In this article, we review the current molecular-targeted therapies in lung cancer.We review landmark trials that have led to approval of molecular-targeted therapies against epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1. We also explore less common mutations/molecular abnormalities and review data on the use of targeted therapies against them. Finally, we offer a treatment algorithm for patients with metastatic NSCLC that harbors actionable mutations.Patients with advanced NSCLC should undergo mutational testing to evaluate for actionable mutations. If such a mutation is discovered, targeted therapy should be considered for first-line treatment.

  • Antifolate drug resistance: Novel mutations and haplotype distribution in dhps and dhfr from Northeast India.
    Antifolate drug resistance: Novel mutations and haplotype distribution in dhps and dhfr from Northeast India. [Journal Article]J Biosci 2017 Dec; 42(4):531-535.JBSarmah NP, Sarma K, Bhattacharyya DR, et al. Malaria is a major public health concern in Northeast India with a preponderance of drug-resistant strains. Until recently the partner drug for artemisinin combination therapy (ACT) was sulphadoxine py...Publisher Full TextMalaria is a major public health concern in Northeast India with a preponderance of drug-resistant strains. Until recently the partner drug for artemisinin combination therapy (ACT) was sulphadoxine pyrimethamine (SP). Antifolate drug resistance has been associated with the mutations at dihydropteroate synthase (dhps) and dihydrofolatereductase (dhfr) genes. This study investigated antifolate drug resistance at the molecular level. A total of 249 fever cases from Arunachal Pradesh, NE India, were screened for malaria, and of these, 75 were found to be positive for Plasmodium falciparum. Samples were sequenced and analysed with the help of BioEdit and ClustalW. Three novel point mutations were found in the dhps gene with 10 haplotypes along with the already reported mutations. A single haplotype having quadruple mutation was found in the dhfr gene. The study reports higher degree of antifolate drug resistance as evidenced by the presence of multiple point mutations in dhps and dhfr genes. The findings of this study strongly discourage the use SP as a partner drug in ACT.

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