eXTReMe Tracker
Gene Therapy Net RSS feed Follow Gene Therapy Net on Twitter LinkedIn - Gene Therapy Net discussion group Facebook - Gene Therapy Net

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.


  • Systemic treatment and primary tumor location in patients with metastatic colorectal cancer.
    Systemic treatment and primary tumor location in patients with metastatic colorectal cancer. [Journal Article]J BUON 2017 Nov-Dec; 22(6):1447-1456.JBAntoniou E, Andreatos N, Margonis GA, et al. Consequently, primary tumor location should be a consideration, when the administration of systemic therapy is contemplated in mCRC.Tumor location (right-sided vs. left-sided) is known to exert a significant influence on the prognosis of primary colorectal cancer (CRC). Given the genetic continuity between primary and metastatic lesions, we aimed to summarize the existing literature on the prognostic implications of primary tumor site as well as to examine the response to chemotherapy by primary tumor location in patients with metastatic CRC (mCRC).A structured review of the literature was performed between 6/1/2016-7/1/2016 using the Pubmed database. Original research articles published between 1/1/2000- 07/01/2016 were considered eligible. The primary endpoints were overall survival (OS)/ progression free survival (PFS) and response to systemic treatment in patients with mCRC.Eleven studies were included. Tumor site was a strong independent predictor of worse OS/PFS in 9 studies, with right-sided tumors having worse prognosis in all cases. Furthermore, 6 studies demonstrated an inferior response to systemic treatment or worse prognosis following the administration of specific regimens among patients with right-sided cancers. As such, there is significant evidence that right-sided lesions are associated with poor outcomes and resistance to systemic treatment.Consequently, primary tumor location should be a consideration, when the administration of systemic therapy is contemplated in mCRC.

  • Downregulation of guanine nucleotide-binding protein beta 1 (GNB1) is associated with worsened prognosis of clearcell renal cell carcinoma and is related to VEGF signaling pathway.
    Downregulation of guanine nucleotide-binding protein beta 1 (GNB1) is associated with worsened prognosis of clearcell renal cell carcinoma and is related to VEGF signaling pathway. [Journal Article]J BUON 2017 Nov-Dec; 22(6):1441-1446.JBChen C, Chi H, Min L, et al. GNB1 was downregulated in ccRCC. Decreased GNB1 expression was associated with worsened disease characteristics and prognosis. GNB1 was related with VEGF signaling in ccRCC, implying a therapeutic pote...Clear-cell renal cell carcinoma (ccRCC) is characterized by genetic abnormalities, while the role of Guanine Nucleotide-Binding Protein Beta 1 (GNB1) in ccRCC has not been studied. We thus aimed to evaluate the expression and prognostic value of GNB1 in ccRCC.A two-stage study (exploration and validation) was conducted using in silico and immunohistochemical (IHC) scoring of ccRCC samples from our institute, to evaluate the association between GNB1 expression and clinicopathological parameters of ccRCC patients. Pathway analyses were performed for genes coexpressed with GNB1 using the KOBAS platform to profile the function of GNB1 and IHC validation.In the exploration stage, data from TCGA ccRCC dataset were reproduced, which contained 537 patients with ccRCC and found that downregulation of GNB1 was significantly associated with worse prognosis. IHC staining from the Human Protein Atlas showed significantly downregulation of GNB1 in ccRCC tissue compared with normal kidney. Pathway analysis showed significantly altered vascular endothelial growth factor (VEGF) signaling pathways among which expressions of 3 genes (WASF2, NRP1, and HIP1) were significantly associated with GNB1 expression, respectively. In the validation stage, included were 80 ccRCC samples and GNB1 expression was scored using IHC positivity. GNB1 expression was negatively associated with tumor stage, lymph node invasion, metastasis, older age, and increased tumor grade. Female gender and receiving neoadjuvant therapy were also associated with decreased GNB1 expression. The expressions of WASF2, NRP1 and HIP1 were also studied and found that they were significantly associated with GNB1.GNB1 was downregulated in ccRCC. Decreased GNB1 expression was associated with worsened disease characteristics and prognosis. GNB1 was related with VEGF signaling in ccRCC, implying a therapeutic potential of this factor.

  • Carcinogenic potential of antitumor therapies - is the risk predictable?
    Carcinogenic potential of antitumor therapies - is the risk predictable? [Journal Article]J BUON 2017 Nov-Dec; 22(6):1378-1384.JBNenova I, Grudeva-Popova J The growing number of successfully cured cancer patients has created a new field in oncogenesis. The life expectancy of such patients has increased, however this favorable event may create enough time ...The growing number of successfully cured cancer patients has created a new field in oncogenesis. The life expectancy of such patients has increased, however this favorable event may create enough time for epigenetic events to occur which can cause a new carcinognic event, i.e. a secondary malignancy. The terms in use are second primary malignancies as well as therapy-related neoplasms in case the treatment of the first neoplasm is a direct cause. Second primary malignancies can be hematological neoplasms or solid tumors, with solid tumors having higher frequency. Hematological malignancies, especially t MDS (therapy-related myelodysplastic syndrome) and t AML (therapy-related acute myeloid leukemia), are causally associated with cytotoxic chemotherapy, while secondary solid tumors are related to radiotherapy. The pathogenic mechanisms of clonal selection in second malignancies are in connection with induction of fusion oncogenes, induction of genetic instability, selection of resistant cell clones and hereditary predisposition. The most common oncogenic agents are external (antineoplastic systemic treatments including radiation therapy), patient-specific factors (genetic, demographic, hormonal) and tumorspecific factors (tissue radiosensitivity, immunodeficiency). There are special features in the clinical picture, biological characteristics and evolution of the second neoplasm - different latency period, aggressive course and treatment resistance. Risks, types and characteristics of secondary malignancies are analyzed in specific groups of patients. For example, the peak of t-AML is several years after a primary malignancy and for solid tumors, the risk increases progressively during the observation period. In this review, the authors outline that the risk of second malignancies is predictable and can be controllable by adequate monitoring of patients as well as by personalized treatment of the first neoplasm.

  • Gene Therapy for Parkinson's Disease.
    Gene Therapy for Parkinson's Disease. [Journal Article]Prog Neurol Surg 2018.:253-264.PNSudhakar V, Richardson RM Gene therapy is a clinical tool that may eventually provide therapeutic benefit to patients suffering from movement disorders through a few potential mechanisms: direct correction of the pathogenic mec...Publisher Full TextGene therapy is a clinical tool that may eventually provide therapeutic benefit to patients suffering from movement disorders through a few potential mechanisms: direct correction of the pathogenic mechanism, neuroprotection, neurorestoration or symptom control. The therapeutic mechanism is therefore dependent on knowledge of disease pathogenesis and the required temporal and spatial specificities of gene expression. An additional critical challenge is achieving the most complete transduction of the target structure while avoiding leakage into neighboring regions or perivascular spaces. Although critical clinical work is ongoing to optimize the direct intracerebral delivery of transgenes to the brain, the field has recently entered a new technological era, where interventional-MRI-guided convection-enhanced delivery is the gold standard for verifying accurate vector delivery in real-time.

  • Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell (ILC2) cytokine production in vivo.
    Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell (ILC2) cytokine production in vivo. [Journal Article]J Allergy Clin Immunol 2018 Jan 10.JAToki S, Goleniewska K, Reiss S, et al. These results reveal that GLP-1R signaling may be a potential therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.Publisher Full TextIL-33 is one of the most consistently associated gene candidates for asthma identified by GWAS. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type-2 cytokine production from both group 2 innate lymphoid cells (ILC2) and Th2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells.To determine the effect of glucagon like peptide receptor-1 GLP-1R signaling on aeroallergen-induced airway IL-33 production and release and on innate type-2 airway inflammation.BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or the vehicle was administered starting either 2 days before the first Alternaria extract-challenge or 1 day after the first Alternaria extract-challenge.GLP-1R agonist treatment starting 2 days before the first Alternaria extract-challenge decreased IL-33 release in the BAL fluid and DUOX1 mRNA expression 1 h after the first Alternaria extract-challenge, and IL-33 expression in lung epithelial cells 24 h after the last Alternaria extract-challenge. Further, GLP-1R agonist significantly decreased the number of ILC2 expressing IL-5 and IL-13, the lung protein expression of type-2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting one day after the first Alternaria extract-challenge also significantly decreased eosinophilia and type-2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract-challenge.These results reveal that GLP-1R signaling may be a potential therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.

  • Blood phenylalanine reduction corrects CNS dopamine and serotonin deficiencies and partially improves behavioral performance in adult phenylketonuric mice.
    Blood phenylalanine reduction corrects CNS dopamine and serotonin deficiencies and partially improves behavioral performance in adult phenylketonuric mice. [Journal Article]Mol Genet Metab 2018 Jan; 123(1):6-20.MGWinn SR, Scherer T, Thöny B, et al. Central nervous system (CNS) deficiencies of the monoamine neurotransmitters dopamine and serotonin have been implicated in the pathophysiology of neuropsychiatric dysfunction in human phenylketonuria ...Central nervous system (CNS) deficiencies of the monoamine neurotransmitters dopamine and serotonin have been implicated in the pathophysiology of neuropsychiatric dysfunction in human phenylketonuria (PKU). In this study, we confirmed the occurrence of brain dopamine and serotonin deficiencies in association with severe behavioral alterations and cognitive impairments in hyperphenylalaninemic C57BL/6-Pahenu2/enu2 mice, a model of human PKU. Phenylalanine-reducing treatments, including either dietary phenylalanine restriction or liver-directed gene therapy, initiated during adulthood were associated with increased brain monoamine content along with improvements in nesting behavior but without a change in the severe cognitive deficits exhibited by these mice. At euthanasia, there was in Pahenu2/enu2 brain a significant reduction in the protein abundance and maximally stimulated activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2), the rate limiting enzymes catalyzing neuronal dopamine and serotonin synthesis respectively, in comparison to levels seen in wild type brain. Phenylalanine-reducing treatments initiated during adulthood did not affect brain TH or TPH2 content or maximal activity. Despite this apparent fixed deficit in striatal TH and TPH2 activities, initiation of phenylalanine-reducing treatments yielded substantial correction of brain monoamine neurotransmitter content, suggesting that phenylalanine-mediated competitive inhibition of already constitutively reduced TH and TPH2 activities is the primary cause of brain monoamine deficiency in Pahenu2 mouse brain. We propose that CNS monoamine deficiency may be the cause of the partially reversible adverse behavioral effects associated with chronic HPA in Pahenu2 mice, but that phenylalanine-reducing treatments initiated during adulthood are unable to correct the neuropathology and attendant cognitive deficits that develop during juvenile life in late-treated Pahenu2/enu2 mice.

  • The genotypic and phenotypic spectrum of MTO1 deficiency.
    The genotypic and phenotypic spectrum of MTO1 deficiency. [Journal Article]Mol Genet Metab 2018 Jan; 123(1):28-42.MGO'Byrne JJ, Tarailo-Graovac M, Ghani A, et al. MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features aff...Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10).Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail.For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients.MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists.

  • Jun, Gal, Cd74, and C1qb as potential indicator for neuropathic pain.
    Jun, Gal, Cd74, and C1qb as potential indicator for neuropathic pain. [Journal Article]J Cell Biochem 2018 Jan 13.JCYang JA, He JM, Lu JM, et al. Neuropathic pain is a kind of pain caused by primary or secondary impairment or dysfunction of peripheral or central nervous system. Patients with neuropathic pain were often with poor clinical outcome...Publisher Full TextNeuropathic pain is a kind of pain caused by primary or secondary impairment or dysfunction of peripheral or central nervous system. Patients with neuropathic pain were often with poor clinical outcome. We screened the differentially expressed genes between sciatic nerve injury and dorsal root ganglion gene in the sham operation model. Microarray and the spared nerve injury module were used to explore the molecular mechanism of neuropathic pain by injuries and the differentially expressed genes (DEGs) were identified out. Besides, the bioinformatics methods were used to figure out the signaling pathways and expression regulation pattern these DEGs were enriched in, which may provide a basis for the molecular research and medicine target of therapy. Besides, protein-protein interaction network analysis was performed on these selected intersection genes. A total of 40 DEGs were screened out and only pctp gene was down-regulated, the left 39 genes were all up-regulated. Then, GO and KEGG enrichment analysis were performed on these intersection genes by DAVID software. Furthermore, protein-protein interaction network analysis was used to analyze the critical genes of neuropathic pain. Finally, four genes, that is, Jun, Gal, Cd74, and C1qb were identified to have strong interactions with other genes, which may function as the prognostic and predictive genes of neuropathic pain caused by peripheral injuries. Our results suggested that four differentially expressed genes, Jun, Gal, Cd74, and C1qb, had the potential to serve as prognostic or predictive markers for neuropathic pain, suggesting a potential application in the improvement of prognostic tools and treatments. This article is protected by copyright. All rights reserved.

  • Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study.
    Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study. [Journal Article]Int J Hematol 2018 Jan 12.IJShimada A, Iijima-Yamashita Y, Tawa A, et al. Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AM...Publisher Full TextAcute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AMLFLT3-ITD patients were assigned to receive hematopoietic stem cell transplantation (HSCT) in the first remission (1CR). We also investigated the effects of additional genetic alterations on FLT3-ITD. The 5-year overall survival (OS) and event-free survival (EFS) rates among the 47 AMLFLT3-ITD patients were 42.2 and 36.8%, respectively. The 5-year disease-free survival rate among 29 patients without induction failure was 58.4%. We defined the allelic ratio (AR) of FLT3-ITD to WT > 0.7 as high. Significant differences were found in OS (AR-high, 20% vs. AR-low, 66%, p < 0.001) and EFS (13 vs. 50%, p = 0.004). All five patients with concurrent NPM1 mutations survived, while seven of eight patients who expressed the NUP98-NSD1 chimera failed to achieve 1CR and died. Multivariate analysis revealed that AR > 0.7 and expression of the NUP98-NSD1 chimera strongly impacted OS and EFS. Although all the AMLFLT3-ITD patients received HSCT at 1CR, the treatment outcome of AMLFLT3-ITD patients did not improve compared with those in a previous study. Heterogeneity was observed among AMLFLT3-ITD patients.

  • Functional transcriptomic annotation and protein-protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer.
    Functional transcriptomic annotation and protein-protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer. [Journal Article]Breast Cancer Res Treat 2018 Jan 12.BCNuncia-Cantarero M, Martinez-Canales S, Andrés-Pretel F, et al. In summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.Publisher Full TextAlthough obesity is a risk factor for breast cancer, little effort has been made in the identification of druggable molecular alterations in obese-breast cancer patients. Tumors are controlled by their surrounding microenvironment, in which the adipose tissue is a main component. In this work, we intended to describe molecular alterations at a transcriptomic and protein-protein interaction (PPI) level between obese and non-obese patients.Gene expression data of 269 primary breast tumors were compared between normal-weight (BMI < 25, n = 130) and obese (IMC > 30, n = 139) patients. No significant differences were found for the global breast cancer population. However, within the luminal A subtype, upregulation of 81 genes was observed in the obese group (FC ≥ 1.4). Next, we explored the association of these genes with patient outcome, observing that 39 were linked with detrimental outcome. Their PPI map formed highly compact cluster and functional annotation analyses showed that cell cycle, cell proliferation, cell differentiation, and cellular response to extracellular stimuli were the more altered functions. Combined analyses of genes within the described functions are correlated with poor outcome. PPI network analyses for each function were to search for druggable opportunities. We identified 16 potentially druggable candidates. Among them, NEK2, BIRC5, and TOP2A were also found to be amplified in breast cancer, suggesting that they could act as strategic players in the obese-deregulated transcriptome.In summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.

Suggestions