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  • 1
    Language: English
    In: Journal of Controlled Release, 20 July 2012, Vol.161(2), pp.377-388
    Description: After over 20 years from the first application of gene transfer in humans, gene therapy is now a mature discipline, which has progressively overcome several of the hurdles that prevented clinical success in the early stages of application. So far, the vast majority of gene therapy clinical trials have exploited viral vectors as very efficient nucleic acid delivery vehicles both in vivo and ex vivo. Here we summarize the current status of viral gene transfer for clinical applications, with special emphasis on the molecular properties of the major classes of viral vectors and the information so far obtained from gene therapy clinical trials.
    Keywords: Adenovirus ; Adeno-Associated Virus ; Gene Therapy ; Retrovirus ; Viral Vectors ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0168-3659
    E-ISSN: 1873-4995
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 08 September 2015, Vol.112(36), pp.11276-81
    Description: Viral vectors based on the adeno-associated virus (AAV) hold great promise for in vivo gene transfer; several unknowns, however, still limit the vectors' broader and more efficient application. Here, we report the results of a high-throughput, whole-genome siRNA screening aimed at identifying cellular factors regulating AAV transduction. We identified 1,483 genes affecting vector efficiency more than 4-fold and up to 50-fold, either negatively or positively. Most of these factors have not previously been associated to AAV infection. The most effective siRNAs were independent from the virus serotype or analyzed cell type and were equally evident for single-stranded and self-complementary AAV vectors. A common characteristic of the most effective siRNAs was the induction of cellular DNA damage and activation of a cell cycle checkpoint. This information can be exploited for the development of more efficient AAV-based gene delivery procedures. Administration of the most effective siRNAs identified by the screening to the liver significantly improved in vivo AAV transduction efficiency.
    Keywords: DNA-Damage Response ; RNA Interference ; Adeno-Associated Virus ; High-Throughput Screening ; Self-Complementary Vectors ; RNA Interference ; Transduction, Genetic ; Dependovirus -- Genetics ; Genome, Human -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Journal of Molecular Biology, 13 February 2015, Vol.427(3), pp.688-694
    Description: Current antiretroviral therapies fail to cure HIV-1 ( uman mmunodeficiency irus type ) infection because HIV-1 persists as a transcriptionally inactive provirus in resting memory CD4 T cells. Multiple molecular events are known to regulate HIV-1 gene expression, yet the mechanisms governing the establishment and maintenance of latency remain incompletely understood. Here we summarize different molecular aspects of viral latency, from its establishment in resting CD4 T cells to the mechanisms involved in the reactivation of latent viral reservoirs. We focus on the relevance of chromatin structure and nuclear architecture in determining the transcriptional fate of integrated HIV-1 genomes, in light of recent findings indicating that proximity to specific subnuclear neighborhoods regulates HIV-1 gene expression.
    Keywords: HIV-1 ; Latency ; Chromatin ; Nuclear Architecture ; Gene Expression ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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  • 4
    In: Nature, 2012, Vol.492(7429), p.376
    Description: In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high- content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.
    Keywords: Microrna -- Research ; Microrna -- Physiological Aspects ; Cell Proliferation -- Research ; Cell Proliferation -- Physiological Aspects ; Gene Expression -- Research ; Gene Expression -- Physiological Aspects ; Cell Regulation -- Research ; Cell Regulation -- Physiological Aspects;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
    Article
    Article
    Language: English
    In: Cell Host & Microbe, 14 December 2016, Vol.20(6), pp.700-702
    Description: Combination therapy for HIV infection is effective at controlling disease but fails to eradicate the virus because a persistent reservoir of cells harbors latent HIV DNA. In this issue of , show that the mTOR kinase is essential to reactivate HIV from latency. Combination therapy for HIV infection is effective at controlling disease but fails to eradicate the virus because a persistent reservoir of cells harbors latent HIV DNA. In this issue of , Besnard et al. (2016) show that the mTOR kinase is essential to reactivate HIV from latency.
    Keywords: HIV ; Latency ; Mtor ; Therapy ; Biology
    ISSN: 1931-3128
    E-ISSN: 1934-6069
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(11), p.e111781
    Description: Somatic gene therapy is a promising tool for the treatment of severe diseases. Because of its abuse potential for performance enhancement in sports, the World Anti-Doping Agency (WADA) included the term 'gene doping' in the official list of banned substances and methods in 2004. Several nested...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    In: Nature, 2015
    Description: Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome. However, the reason why the virus selects only certain genes among all transcriptionally active regions in a target cell remains largely unknown. Here we show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore. This region contains a series of cellular genes, which are preferentially targeted by the virus, and characterized by the presence of active transcription chromatin marks before viral infection. In contrast, the virus strongly disfavours the heterochromatic regions in the nuclear lamin-associated domains and other transcriptionally active regions located centrally in the nucleus. Functional viral integrase and the presence of the cellular Nup153 and LEDGF/p75 integration cofactors are indispensable for the peripheral integration of the virus. Once integrated at the nuclear pore, the HIV-1 DNA makes contact with various nucleoporins; this association takes part in the transcriptional regulation of the viral genome. These results indicate that nuclear topography is an essential determinant of the HIV-1 life cycle.
    Keywords: Cell Nucleus -- Genetics ; Chromosome Positioning -- Genetics ; Genetic Loci -- Genetics ; HIV-1 -- Genetics ; Virus Integration -- Genetics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 8
    Language: English
    In: The Journal of biological chemistry, 11 March 2011, Vol.286(10), pp.8644-54
    Description: Proliferation of mammalian cardiomyocytes stops rapidly after birth and injured hearts do not regenerate adequately. High cyclin-dependent kinase inhibitor (CKI) levels have been observed in cardiomyocytes, but their role in maintaining cardiomyocytes in a post-mitotic state is still unknown. In this report, it was investigated whether CKI knockdown by RNA interference induced cardiomyocyte proliferation. We found that triple transfection with p21(Waf1), p27(Kip1), and p57(Kip2) siRNAs induced both neonatal and adult cardiomyocyte to enter S phase and increased the nuclei/cardiomyocyte ratio; furthermore, a subpopulation of cardiomyocytes progressed beyond karyokynesis, as assessed by the detection of mid-body structures and by straight cardiomyocyte counting. Intriguingly, cardiomyocyte proliferation occurred in the absence of overt DNA damage and aberrant mitotic figures. Finally, CKI knockdown and DNA synthesis reactivation correlated with a dramatic change in adult cardiomyocyte morphology that may be a prerequisite for cell division. In conclusion, CKI expression plays an active role in maintaining cardiomyocyte withdrawal from the cell cycle.
    Keywords: Cell Cycle -- Physiology ; Cyclin-Dependent Kinase Inhibitor Proteins -- Metabolism ; Muscle Proteins -- Metabolism ; Myocytes, Cardiac -- Metabolism
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 9
    Language: English
    In: Journal of molecular biology, 29 July 2011, Vol.410(5), pp.933-43
    Description: Signal transducers and activator of transcription (STAT) proteins are often constitutively activated in leukocytes of HIV-1(+) individuals, which frequently show a dominant expression of a C-terminally truncated isoform of STAT5 (STAT5Δ). STAT5Δ can act as a negative regulator of human immunodeficiency virus type 1 (HIV-1) expression in both CD8-depleted primary leukocytes and chronically infected promonocytic U1 cells stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF). Activated STAT5Δ can directly bind to two consensus sequences in the HIV-1 long terminal repeat (LTR) promoter; binding impairs recruitment of RNA polymerase II (Crotti, A., Lusic, M., Lupo, R., Lievens, P. M., Liboi, E., Della Chiara, G., et al. (2007). Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression. Blood, 109, 5380-5389). One of the STAT consensus sequences overlaps with one nuclear factor κB (NF-κB) binding site; interestingly, NF-κB1/p50 homodimers, frequently detected in monocytic cells, are negative regulators of HIV transcription. Here, we show that GM-CSF stimulation of U1 cells, while not inducing NF-κB activation, leads to STAT5Δ phosphorylation and binding to the NF-κB/STAT target sequence in the HIV LTR promoter, which already associates with p50 under unstimulated conditions. STAT5Δ was found to associate with p50, but not with RelA/p65, in both U1 cells expressing endogenous proteins and 293T cells overexpressing these factors. Furthermore, GM-CSF stimulation promoted concurrent binding of STAT5Δ and p50 at the HIV LTR promoter in U1 cells. Immunoprecipitation of chromatin from GM-CSF-stimulated U1 cells confirmed in vivo binding of p50 to the viral promoter together with STAT5Δ. Thus, cytokine-activated STAT5Δ/p50 complexes can contribute to the maintenance of HIV-1 latency in monocytic cells.
    Keywords: Protein Multimerization ; Transcription, Genetic ; HIV-1 -- Genetics ; Mutant Proteins -- Metabolism ; Nf-Kappa B P50 Subunit -- Metabolism ; Stat5 Transcription Factor -- Metabolism ; Sequence Deletion -- Genetics
    ISSN: 00222836
    E-ISSN: 1089-8638
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  • 10
    Language: English
    In: Molecular Therapy, June 2015, Vol.23(6), pp.984-986
    Description: Through an elegant combination of transgenic techniques, a study by Tian et al. recently published in Science Translational Medicine1 shows that a cluster of five microRNAs (miRNAs), miR-302/367, controls cardiac myocyte proliferation during embryonic and neonatal life. More notably, reactivation of these miRNAs following myocardial infarction promotes re-entry of adult cardiomyocytes into the cell cycle and induces cardiac regeneration. The authors found that these miRNAs interfere with the recently described Hippo pathway that regulates proliferation of various cell types, including cardiomyocytes. More specifically, miR-302/367 directly reduces the expression of three inhibitory proteins in this pathway, leading to the activation of the Yap1 transcription factor, a master regulator of cardiac proliferation.
    Keywords: Medicine ; Biology
    ISSN: 1525-0016
    E-ISSN: 1525-0024
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