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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.


  • IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development.
    Kavrochorianou N, Evangelidou M, Markogiannaki M, et al. IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development. [JOURNAL ARTICLE]J Leukoc Biol 2015 Jul 31.AbstractPublisher Full TextAlthough interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-β administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T-helper 17 responses, with a reduced fraction of CCR6(+) CD4(+) T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-γ-producing CD4(+) T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-γ-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis.

  • Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors.
    Zhou Q, Uhlig KM, Muth A, et al. Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors. [JOURNAL ARTICLE]J Immunol 2015 Jul 31.AbstractPublisher Full TextPlaying a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.

  • Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies.
    Depreeuw J, Hermans E, Schrauwen S, et al. Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies. [JOURNAL ARTICLE]Gynecol Oncol 2015 Jul 28.Endometrial carcinoma (EC) is the sixth most common cancer in women and therapies are limited for advanced and recurrent disease. Patient-derived tumor xenograft (PDTX) models are becoming popular tools in translational research because of their histological and genetic similarity to the original tumors and the ability to predict therapeutic response to treatments. Here, we established and characterized a panel of 24 EC PDTX models which includes the major histological and genetic subtypes observed in patients.Fresh tumor tissues collected from primary, metastatic and recurrent type I and type II EC patients were engrafted in immunocompromised mice. Histology, vimentin, and cytokeratin expression were evaluated, together with Microsatellite instability (MSI), mutation profiling by Whole Exome Sequencing and copy number profiling by Whole Genome Low Coverage Sequencing. The efficacy of both PI3K and MEK inhibitors was evaluated in a model of endometrioid carcinoma harboring PTEN, PIK3CA and KRAS mutations.We observed good similarity between primary tumors and the corresponding xenografts, at histological and genetic level. Among the engrafted endometrioid models, we found a significant enrichment of MSI and POLE mutated tumors, compared to non-engrafted samples. Combination treatment with NVP-BEZ235 and AZD6244 showed the possibility to stabilize the tumor growth in one model originated from a patient who already received several lines of chemotherapy.The established EC PDTX models, resembling the original human tumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups.

  • Polyelectrolyte complexes of hTERT siRNA and polyethyleneimine: Effect of degree of PEG grafting on biological and cellular activity.
    Safari F, Tamaddon AM, Zarghami N, et al. Polyelectrolyte complexes of hTERT siRNA and polyethyleneimine: Effect of degree of PEG grafting on biological and cellular activity. [JOURNAL ARTICLE]Artif Cells Nanomed Biotechnol 2015 Jul 31.:1-8.Gene silencing by siRNA (short interfering RNA)-targeted human telomerase reverse transcriptase (hTERT) is considered a successful strategy for cancer gene therapy. Polyelectrolyte complexes (PEC) of siRNA and cationic polymers such as polyethyleneimine (PEI) have been widely used for cellular transfection; however, they demonstrate some disadvantages such as cytotoxicity and extracellular matrix restrictions. PEG grafting technology was used in an attempt to improve the biocompatibility of PECs. Considering that this technology may compromise the cellular uptake of PECs, we aimed to study the effect of degree of PEI PEGylation on the carrier cytotoxicity, cellular association, and transfection efficiency of hTERT siRNA in the lung cancer cell line A549. Activated NHS ester of methoxy PEG-COOH 5 KDa was grafted to hyperbranched PEI 25 KDa in the molar ratios of 0.2 and 1. The copolymers were characterized by (1)H-NMR spectroscopy. PECs of PEI or PEG-g-PEI with siRNA, alone or co-incubated with heparin sulfate, were studied by the ethidium bromide exclusion assay. Cytotoxicity of the polymers (PEG-g-PEI vs PEI), alone and upon formation of PEC nanoparticles with hTERT siRNA, was determined by a validated MTT assay, in comparison to a scrambled control sequence, in A549 human lung carcinoma cells. The cellular uptake of the PECs of FITC-labeled siRNA was investigated by flow cytometry at different N/P ratios, and the silencing effect of the transfected siRNA was compared to that of the control sequence for different PECs by real time RT-PCR. The cytotoxicity of PEI decreased significantly by PEG grafting, even at a low degree of PEGylation. Moreover, the nonspecific cytotoxicity of PECs decreased by PEG grafting. PECs of PEG-g-PEI showed more biologic stability on incubation with heparin sulfate. Average particle size and zeta potential of PEC nanoparticles were diminished for those of PEG-g-PEI. The cellular association was more pronounced at an N/P ratio of 2.5 for PECs of PEI and PEG-g-PEI alike. The level of silencing of hTERT mRNA by PEC of PEG-g-PEI was sequence-dependent, and determined non-inferior when compared to the native PEI. Conclusively, the biocompatibility of PEI was improved by a low degree of PEGylation, with no adverse effect on the cellular uptake and the transfection activity. PEC nanoparticles of hTERT siRNA and PEG-g-PEI could act as a promising weapon against A549 cells, which has to be considered for an in vivo evaluation.

  • Shortened Telomere Length is Associated with Paroxysmal Atrial Fibrillation Among Cardiovascular Patients Enrolled in the Intermountain Heart Collaborative Study.
    Carlquist JF, Knight S, Cawthon RM, et al. Shortened Telomere Length is Associated with Paroxysmal Atrial Fibrillation Among Cardiovascular Patients Enrolled in the Intermountain Heart Collaborative Study. [JOURNAL ARTICLE]Heart Rhythm 2015 Jul 28.Atrial fibrillation (AF) diminishes quality of life and accounts for approximately one-third of all strokes. Studies have associated mitochondrial dysfunction with both AF and telomere length (TL).We hypothesized a relationship between AF and TL.Blood was collected from consenting participants in the Intermountain Heart Collaborative Study (n=3576) and DNA extracted. TL was determined by multiplex quantitative PCR and normalized to a single copy gene and reported as telomere/single gene ratio (t/s). Patient information was extracted from Intermountain Healthcare's electronic records database; prevalent AF was determined by discharge ICD-9 code; AF subtype [paroxysmal(Px), persistent (Ps), long-standing persistent/permanent (Pm)] determined by chart review.t/s decreased with age (p<0.00001). Subjects with a history of AF (n=379, 10.6%) had shorter telomeres (mean t/s ± SD =0.87 ± 0.29) compared to subjects without AF (mean t/s =0.95 ± 0.32, p<0.0001). The association remained after adjustment for age (p=0.017) and cardiovascular risk factors (p=0.016). AF subtype was determined for 277 subjects; 110 (39.7%) had Px AF, 65 (23.5%) Ps, and 102 (36.8%) Pm AF. Mean t/s did not differ between Ps, Pm and subjects without AF (0.94 ± 0.40, 0.94 ± 0.27, and 0.95 ± 0.32, respectively). However, for Px, the mean t/s Px (0.81 ± 0.22) was significantly shorter than for Ps (p=0.026), Pm (p=0.004) or subjects without AF (p<0.0001).The present study supports an association between Px AF and TL. Short TL may be a previously unrecognized risk factor for AF with potential applications in diagnosis and therapy.

  • Effects of Tanshinone IIA on osteogenic differentiation of mouse bone marrow mesenchymal stem cells.
    Qian K, Xu H, Dai T, et al. Effects of Tanshinone IIA on osteogenic differentiation of mouse bone marrow mesenchymal stem cells. [JOURNAL ARTICLE]Naunyn Schmiedebergs Arch Pharmacol 2015 Aug 1.Tanshinone IIA (TSA) is a lipophilic diterpene purified from the Chinese herb Danshen, which exhibits potent antioxidant and anti-inflammatory properties. Effect of TSA remains largely uninvestigated on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs), which are widely used in cell-based therapy of bone diseases. In the present study, both ALP activity at day 7 and calcium content at day 24 were upregulated during the osteogenesis of mouse BM-MSCs treated with TSA (1 and 5 μM), demonstrating that it promoted the osteogenesis at both early and late stages. We found that TSA promoted osteogenesis and inhibited osteoclastogenesis, evident by RT-PCR analysis of osteogenic marker gene expressions. However, osteogenesis was inhibited by TSA at 20 μM. We further revealed that TSA (1 and 5 μM) upregulated BMP and Wnt signaling. Co-treatment with Wnt inhibitor DKK-1 or BMP inhibitor noggin significantly decreased the TSA-promoted osteogenesis, indicating that upregulation of BMP and Wnt signaling plays a significant role and contributes to the TSA-promoted osteogenesis. Of clinical interest, our study suggests TSA as a promising therapeutic strategy during implantation of BM-MSCs for a more effective treatment of bone diseases.

  • Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.
    Sahashi K, Katsuno M, Hung G, et al. Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy. [JOURNAL ARTICLE]Hum Mol Genet 2015 Jul 30.AbstractPublisher Full TextSpinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAGs expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target.

  • A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function.
    Liu Y, Huang X, He X, et al. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. [JOURNAL ARTICLE]FASEB J 2015 Jul 31.AbstractPublisher Full TextThe immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin-4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48-linked polyubiquitin chains and that thalidomide blocks the formation of CRBN-ubiquitin conjugates. Furthermore, we show that ubiquitinated CRBN is targeted for proteasomal degradation. Treatment of human myeloma cell lines such as MM1.S, OPM2, and U266 with thalidomide (100 μM) and its structural analog lenalidomide (10 μM) results in stabilization of CRBN and elevation of CRBN protein levels. This in turn leads to the reduced level of CRBN target proteins and enhances the sensitivity of human multiple myeloma cells to IMiDs. Our results reveal a novel mechanism by which thalidomide and its analogs modulate the CRBN function in cells. Through inhibition of CRBN ubiquitination, thalidomide and its analogs allow CRBN to accumulate, leading to the increased cullin-4 RING E3 ligase-mediated degradation of target proteins.-Liu, Y., Huang, X., He, X., Zhou, Y., Jiang, X., Chen-Kiang, S., Jaffrey, S. R., Xu, G. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function.

  • Effect of Longan polysaccharides on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro.
    Zhu S, Zhou B, Liu Q, et al. Effect of Longan polysaccharides on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro. [JOURNAL ARTICLE]Med Biol Eng Comput 2015 Aug 1.For autologous chondrocyte implantation (ACI) to restore cartilage defect, limited cell numbers and dedifferentiation of chondrocytes are the major difficulties. An alternative is the use of growth factors, but the high cost and potential tumorigenesis are the major obstacles. To ensure successful ACI therapy, it is of significance to find effective substituted pro-chondrogenic agent. Polysaccharides from plant extract have low toxicity and few undesirable side effects, which were reported to facilitate cartilage regeneration. In this study, we investigated the effect of Longan polysaccharides (LP) on rabbit articular chondrocytes through examination of the cell proliferation, morphology, viability, glycosaminoglycan synthesis and cartilage-specific gene expression. Results showed that close to the positive group which used the growth factor of TGF-β, LP could effectively promote chondrocytes growth and enhance secretion and synthesis of cartilage extracellular matrix by up-regulating expression levels of aggrecan, collagen II and sox9 compared to the negative control. Expression of collagen I gene was effectively down-regulated, demonstrating the inhibition of chondrocytes dedifferentiation by LP. Hypertrophy that might lead to chondrocyte ossification was also undetectable in LP groups. Range of 4.69-18.76 µg/ml was recommended dose of LP, among which the most profound response was observed with 9.38 μg/ml. All the evidences revealed that LP may replace the growth factors to be applied in ACI therapy. This study might provide a basis for development of a novel agent in the treatment of articular cartilage defect.

  • CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186.
    Zheng J, Li XD, Wang P, et al. CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186. [JOURNAL ARTICLE]Oncotarget 2015 Jul 13.AbstractPublisher Full TextThe long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) is a novel gene that activated early in colorectal neoplasia, but it is also up-regulated in many other solid tumors. Herein, the function and underlying mechanism of CRNDE in regulating glioma stem cells (GSCs) were investigated. We found that CRNDE expression was up-regulated while miR-186 expression was down-regulated in GSCs. Overexpression of CRNDE could promote the cellular proliferation, migration, invasion and inhibit the apoptosis in GSCs. Overexpression of miR-186 exerted functions of inhibiting the proliferation, migration and invasion of GSCs and promoting apoptosis. And CRNDE decreased the expression levels of XIAP and PAK7 by binding to miR-186 and negatively regulating it. In addition, miR-186 binded to XIAP and PAK7 3'UTR region, and decrease the expression of them, thus regulating the expression levels of downstream target proteins such as caspase 3, BAD, cyclin D1 and MARK2. The in vivo effect of CRNDE and miR-186 showed that the tumor formation rate was minimum in tumor-bearing nude mice with the knockdown of CRNDE and the overexpression of miR-186. In conclusion, CRNDE played an oncogenic role of GSCs through the negative regulation of miR-186. Both CRNDE and miR-186 could be regarded as potential targets in the glioma therapy.