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.
- Genomic discoveries in adult astrocytoma.
Wang J, Bettegowda C Genomic discoveries in adult astrocytoma. [REVIEW]Curr Opin Genet Dev 2015 Jan 20.:17-24.Astrocytomas are the most common glial tumor of the central nervous system. Within this category, glioblastoma is the most prevalent and malignant primary brain tumor. Glioblastoma can arise de novo, or through progression from lower-grade lesions, but is uniformly associated with poor outcomes despite surgical resection, chemotherapy, and radiation therapy. Recent genomic discoveries have provided new insight into gliomagenesis and have identified key genetic alterations that have diagnostic, prognostic and predictive capacity. Numerous molecular classification schemes have been proposed to sort tumors into clinically meaningful categories to guide treatment. However, creating therapy targeted towards these alterations has been made challenging by the redundancy of essential signal transduction pathways affected in these tumors, intratumoral heterogeneity, and the hypermutated profiles of recurrent tumors. Future treatment strategies will require a personalized approach with consideration of the unique genetic profile of a specific tumor and the use of multimodality therapies.
- Retinal gene delivery by adeno-associated virus (AAV) vectors: Strategies and applications.
Schön C, Biel M, Michalakis S Retinal gene delivery by adeno-associated virus (AAV) vectors: Strategies and applications. [JOURNAL ARTICLE]Eur J Pharm Biopharm 2015 Jan 20.Adeno-associated virus (AAV) vectors are the most widely used vehicle systems for neuronal gene transfer. This popularity is based on the non-pathogenic nature of AAVs and their versatility making them a multifunctional vector system for basic research and clinical applications. AAVs are successfully applied in clinical and pre-clinical gene therapy studies for inherited retinal disorders. Their excellent transduction profile and efficiency also boosted the use of AAV vectors in basic research. The AAV vector system can be easily modified and adjusted at multiple levels to allow for optimized and specific gene expression in target cells. Here, we will provide an overview on the AAV vector system and its applications focusing on gene transfer into retinal cells. Furthermore, we will outline and discuss strategies for the optimization of AAV gene transfer by modifications to the AAV vector expression cassette, the AAV capsid or the routes of vector administration.
- Experimental Study of Nasopharyngeal Carcinoma Radionuclide Imaging and Therapy Using Transferred Human Sodium/Iodide Symporter Gene.
Zhong X, Shi C, Gong J, et al. Experimental Study of Nasopharyngeal Carcinoma Radionuclide Imaging and Therapy Using Transferred Human Sodium/Iodide Symporter Gene. [JOURNAL ARTICLE]PLoS One 2015; 10(1):e0117053.The aim of this study was to design a method of radionuclide for imaging and therapy of nasopharyngeal carcinoma (NPC) using the transferred human sodium/iodide symporter (hNIS) gene.A stable NPC cell line expressing hNIS was established (CNE-2-hNIS). After 131I treatment, we detected proliferation and apoptosis of NPC cells, both in vitro and vivo. In vivo, the radioactivity of different organs of nude mice was counted and 99mTc imaging using SPECT was performed. The apparent diffusion coefficient (ADC) value changes of tumor xenografts were observed by diffusion-weighted magnetic resonance imaging (DW-MRI) within 6-24 days of 131I treatment. The correlation of ADC changes with apoptosis and proliferation was investigated. Post-treatment expression levels of P53, Bax, Bcl-2, Caspase-3, and Survivin proteins were detected by western blotting.131I uptake was higher in CNE-2-hNIS than in CNE-2 cells. The proliferation and apoptosis rate decreased and increased respectively both in vitro and vivo in the experimental group after 131I treatment. The experimental group tumors accumulated 99mTc in vivo, leading to a good visualization by SPECT. DW-MRI showed that ADC values increased in the experimental group 6 days after treatment, while ADC values were positively and negatively correlated with the apoptotic and Ki-67 proliferation indices, respectively. After treatment, CNE-2-hNIS cells up-regulated the expression of P53 and Survivin proteins and activated Caspase-3, and down-regulated the expression of Bcl-2 proteins.The radionuclide imaging and therapy technique for NPC hNIS-transfected cell lines can provide a new therapy strategy for monitoring and treatment of NPC.
- Lethality of PAK3 and SGK2 shRNAs to Human Papillomavirus Positive Cervical Cancer Cells Is Independent of PAK3 and SGK2 Knockdown.
Zhou N, Ding B, Agler M, et al. Lethality of PAK3 and SGK2 shRNAs to Human Papillomavirus Positive Cervical Cancer Cells Is Independent of PAK3 and SGK2 Knockdown. [JOURNAL ARTICLE]PLoS One 2015; 10(1):e0117357.The p21-activated kinase 3 (PAK3) and the serum and glucocorticoid-induced kinase 2 (SGK2) have been previously proposed as essential kinases for human papillomavirus positive (HPV+) cervical cancer cell survival. This was established using a shRNA knockdown approach. To validate PAK3 and SGK2 as potential targets for HPV+ cervical cancer therapy, the relationship between shRNA-induced phenotypes in HPV+ cervical cancer cells and PAK3 or SGK2 knockdown was carefully examined. We observed that the phenotypes of HPV+ cervical cancer cells induced by various PAK3 and SGK2 shRNAs could not be rescued by complement expression of respective cDNA constructs. A knockdown-deficient PAK3 shRNA with a single mismatch was sufficient to inhibit HeLa cell growth to a similar extent as wild-type PAK3 shRNA. The HPV+ cervical cancer cells were also susceptible to several non-human target shRNAs. The discrepancy between PAK3 and SGK2 shRNA-induced apoptosis and gene expression knockdown, as well as cell death stimulation, suggested that these shRNAs killed HeLa cells through different pathways that may not be target-specific. These data demonstrated that HPV+ cervical cancer cell death was not associated with RNAi-induced PAK3 and SGK2 knockdown but likely through off-target effects.
- Genetic Heterogeneity of Pseudoxanthoma Elasticum: The Chinese Signature Profile of ABCC6 and ENPP1 Mutations.
Jin L, Jiang Q, Wu Z, et al. Genetic Heterogeneity of Pseudoxanthoma Elasticum: The Chinese Signature Profile of ABCC6 and ENPP1 Mutations. [JOURNAL ARTICLE]J Invest Dermatol 2015 Jan 23.Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder characterized by ectopic mineralization, is caused by mutations in the ABCC6 gene. We examined clinically 29 Chinese PXE patients from unrelated families, so far the largest cohort of Asian PXE patients. In a subset of 22 patients, we sequenced ABCC6 and another candidate gene, ENPP1, followed by pathogenicity analyses for each variant. We identified a total of 17 distinct mutations in ABCC6, 15 of them being previously unreported, including 5 frame-shift and 10 missense variants. In addition, a missense mutation in combination with a recurrent nonsense mutation in ENPP1 was discovered in a pediatric PXE case. No cases with p.R1141X or del23-29 mutations, common in Caucasian patient populations, were identified. The 10 missense mutations in ABCC6 were expressed in mouse liver via hydrodynamic tail-vein injections. One mutant protein showed cytoplasmic accumulation indicating abnormal subcellular trafficking, while the other nine mutants showed correct plasma membrane location. These nine mutations were further investigated for their pathogenicity using a recently developed zebrafish mRNA rescue assay. Minimal rescue of the morpholino-induced phenotype was achieved with 8 of the 9 mutant human ABCC6 mRNAs tested, implying pathogenicity. This study demonstrates that the Chinese PXE population harbors unique ABCC6 mutations. These genetic data have implications for allele-specific therapy currently being developed for PXE.Journal of Investigative Dermatology accepted article preview online, 23 January 2015. doi:10.1038/jid.2015.10.
- Zinc oxide nanoparticles inhibit murine photoreceptor-derived cell proliferation and migration via reducing TGF-β and MMP-9 expression in vitro.
Guo DD, Li QN, Li CM, et al. Zinc oxide nanoparticles inhibit murine photoreceptor-derived cell proliferation and migration via reducing TGF-β and MMP-9 expression in vitro. [JOURNAL ARTICLE]Cell Prolif 2015 Jan 23.To investigate behaviour and expression of transforming growth factor-β (TGF-β) and matrix metalloproteinases (MMP-9) in murine photoreceptor-derived cells (661W) after incubation with zinc oxide (ZnO) nanoparticles.We explored effects of ZnO nanoparticles on 661W cells using a real-time cell electronic sensing system, flow cytometry, multiple function microplate reading, real-time quantitative PCR detection system and enzyme-linked immunosorbent assay respectively.Our results indicate that ZnO nanoparticles induced overload of calcium and reactive oxygen species within cells, causing formation of apoptotic bodies, disruption of cell cycle distribution, and reduction in expression of TGF-β and MMP-9, to suppress cell proliferation and migration. Our findings show that disruption of intracellular calcium homoeostasis and overproduction of reactive oxygen species were closely associated with reduction of TGF-β and MMP-9 in 661W cells under ZnO nanoparticle treatment.Results of our study indicate that ZnO nanoparticles suppressed cell proliferation and migration, and reduced production of TGF-β and MMP-9 at both gene and protein levels. Our findings contribute to the understanding of the molecular mechanisms that reduced TGF-β and MMP-9 levels inhibit cell proliferation and migration under ZnO nanoparticle influence.
- Synovial Sarcoma: Recent Discoveries as a Roadmap to New Avenues for Therapy.
Nielsen TO, Poulin NM, Ladanyi M Synovial Sarcoma: Recent Discoveries as a Roadmap to New Avenues for Therapy. [REVIEW]Cancer Discov 2015 Jan 22.Oncogenesis in synovial sarcoma is driven by the chromosomal translocation t(X,18; p11,q11), which generates an in-frame fusion of the SWI/SNF subunit SS18 to the C-terminal repression domains of SSX1 or SSX2. Proteomic studies have identified an integral role of SS18-SSX in the SWI/SNF complex, and provide new evidence for mistargeting of polycomb repression in synovial sarcoma. Two recent in vivo studies are highlighted, providing additional support for the importance of Wnt signaling in synovial sarcoma: One used a conditional mouse model in which knockout of β-catenin prevents tumor formation, and the other used a small-molecule inhibitor of β-catenin in xenograft models.Synovial sarcoma appears to arise from still poorly characterized immature mesenchymal progenitor cells through the action of its primary oncogenic driver, the SS18-SSX fusion gene, which encodes a multifaceted disruptor of epigenetic control. The effects of SS18-SSX on polycomb-mediated gene repression and SWI/SNF chromatin remodeling have recently come into focus and may offer new insights into the basic function of these processes. A central role for deregulation of WNT-β-catenin signaling in synovial sarcoma has also been strengthened by recent in vivo studies. These new insights into the the biology of synovial sarcoma are guiding novel preclinical and clinical studies in this aggressive cancer. Cancer Discov; 5(2); 1-11. ©2015 AACR.
- Gene expression pattern of some classes of cytochrome P-450 and glutathione S-transferase enzymes in differentiated hepatocytes-like cells from menstrual blood stem cells.
Esmaeili-Rad A, Khanjani S, Vaziri H, et al. Gene expression pattern of some classes of cytochrome P-450 and glutathione S-transferase enzymes in differentiated hepatocytes-like cells from menstrual blood stem cells. [JOURNAL ARTICLE]In Vitro Cell Dev Biol Anim 2015 Jan 23.Recently, valuable characteristics of menstrual blood stem cells (MenSCs) have impelled scientists to take its advantages for cell therapy of different diseases including liver disorders. In this study, we examined messenger RNA (mRNA) expression levels of phases I and II drug metabolizing enzymes including glutathione S-transferase (GST) and cytochrome P-450 (CYP) in differentiated hepatocyte-like cells from MenSCs. The isolated MenSCs were characterized and differentiated into hepatocyte-like cells using hepatocyte growth factor (HGF) and oncostatin M (OSM) in combination with other components in serum-free culture media. After primary characterization of hepatocyte markers, mRNA expression of GSTA1, GSTA2, GSTP1, CYP3A4, and CYP7A1 was assessed in differentiated cells in reference to undifferentiated cells using real-time PCR. Based on immunofluorescent staining and real-time PCR data, the differentiated MenSCs could express functional hepatocyte markers at mRNA and/or protein levels suggesting development of hepatocyte-like cells from MenSCs. Moreover, the expression levels of GSTA1, GSTA2, and CYP3A4 mRNA were upregulated in differentiated cells compared to undifferentiated cells. The expression of CYP7A1 gene was also remarkable on the last day of differentiation process. However, the expression level of GSTP1 did not exhibit statistically significant change during differentiation (P = 0.6). Based on accumulative data, MenSCs could be viewed as an accessible population of stem cells with differentiation ability into drug-metabolizing hepatocyte-like cells.
- Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With Hypercholesterolemia: Results of 4 Phase III Trials.
Santos RD, Raal FJ, Catapano AL, et al. Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With Hypercholesterolemia: Results of 4 Phase III Trials. [JOURNAL ARTICLE]Arterioscler Thromb Vasc Biol 2015 Jan 22.Lp(a) is an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis. Current pharmacological lipid-lowering therapies do not optimally lower Lp(a), particularly in patients with familial hypercholesterolemia (FH).In 4 phase III trials, 382 patients on maximally tolerated lipid-lowering therapy were randomized 2:1 to weekly subcutaneous mipomersen 200 mg (n=256) or placebo (n=126) for 26 weeks. Populations included homozygous FH, heterozygous FH with concomitant coronary artery disease (CAD), severe hypercholesterolemia, and hypercholesterolemia at high risk for CAD. Lp(a) was measured 8× between baseline and week 28 inclusive. Of the 382 patients, 57% and 44% had baseline Lp(a) levels >30 and >50 mg/dL, respectively. In the pooled analysis, the mean percent decrease (median, interquartile range in Lp(a) at 28 weeks was significantly greater in the mipomersen group compared with placebo (-26.4 [-42.8, -5.4] versus -0.0 [-10.7, 15.3]; P<0.001). In the mipomersen group in patients with Lp(a) levels >30 or >50 mg/dL, attainment of Lp(a) values ≤30 or ≤50 mg/dL was most frequent in homozygous FH and severe hypercholesterolemia patients. In the combined groups, modest correlations were present between percent change in apolipoprotein B-100 and Lp(a) (r=0.43; P<0.001) and low-density lipoprotein cholesterol and Lp(a) (r=0.36; P<0.001) plasma levels.Mipomersen consistently and effectively reduced Lp(a) levels in patients with a variety of lipid abnormalities and cardiovascular risk. Modest correlations were present between apolipoprotein B-100 and Lp(a) lowering but the mechanistic relevance mediating Lp(a) reduction is currently unknown.
- Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.
Mayanagi S, Kitago M, Sakurai T, et al. Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer. [JOURNAL ARTICLE]Cancer Sci 2015 Jan 23.This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1,000 mg/m(2) ) on days 1, 8, and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot, and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all 3 patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (p = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and IL-8 showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This article is protected by copyright. All rights reserved.