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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.


  • Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes.
    Prattichizzo F, Giuliani A, Ceka A, et al. Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes. [Journal Article]Clin Epigenetics 2015; 7(1):56.The development of type-2 diabetes mellitus (T2DM) and its complications is largely due to the complex interaction between genetic factors and environmental influences, mainly dietary habits and lifestyle, which can either accelerate or slow down disease progression. Recent findings suggest the potential involvement of epigenetic mechanisms as a crucial interface between the effects of genetic predisposition and environmental factors. The common denominator of environmental factors promoting T2DM development and progression is that they trigger an inflammatory response, promoting inflammation-mediated insulin resistance and endothelial dysfunction. Proinflammatory stimuli, including hyperglycemia, oxidative stress, and other inflammatory mediators, can affect epigenetic mechanisms, altering the expression of specific genes in target cells without changes in underlying DNA sequences. DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms. Over the past few years, non-coding RNA, including microRNAs (miRNAs), have also emerged as key players in gene expression modulation. MiRNAs can be actively released or shed by cells in the bloodstream and taken up in active form by receiving cells, acting as efficient systemic communication tools. The miRNAs involved in modulation of inflammatory pathways (inflammamiRs), such as miR-146a, and those highly expressed in endothelial lineages and hematopoietic progenitor cells (angiomiRs), such as miR-126, are the most extensively studied circulating miRNAs in T2DM. However, data on circulating miRNA signatures associated with specific diabetic complications are still lacking. Since immune cells and endothelial cells are primarily involved in the vascular complications of T2DM, their relative contribution to circulating miRNA signatures needs to be elucidated. An integrated approach encompassing different epigenetic mechanisms would have the potential to provide new mechanistic insights into the genesis of diabetes and its severe vascular complications and identify a panel of epigenetic markers with diagnostic/prognostic and therapeutic relevance.

  • Molecular insight into thiopurine resistance: transcriptomic signature in lymphoblastoid cell lines.
    Chouchana L, Fernández-Ramos AA, Dumont F, et al. Molecular insight into thiopurine resistance: transcriptomic signature in lymphoblastoid cell lines. [Journal Article]Genome Med 2015; 7(1):37.There has been considerable progress in the management of acute lymphoblastic leukemia (ALL) but further improvement is needed to increase long-term survival. The thiopurine agent 6-mercaptopurine (6-MP) used for ALL maintenance therapy has a key influence on clinical outcomes and relapse prevention. Genetic inheritance in thiopurine metabolism plays a major role in interindividual clinical response variability to thiopurines; however, most cases of thiopurine resistance remain unexplained.We used lymphoblastoid cell lines (LCLs) from healthy donors, selected for their extreme thiopurine susceptibility. Thiopurine metabolism was characterized by the determination of TPMT and HPRT activity. We performed genome-wide expression profiling in resistant and sensitive cell lines with the goal of elucidating the mechanisms of thiopurine resistance.We determined a higher TPMT activity (+44%; P = 0.024) in resistant compared to sensitive cell lines, although there was no difference in HPRT activity. We identified a 32-gene transcriptomic signature that predicts thiopurine resistance. This signature includes the GTPBP4 gene coding for a GTP-binding protein that interacts with p53. A comprehensive pathway analysis of the genes differentially expressed between resistant and sensitive cell lines indicated a role for cell cycle and DNA mismatch repair system in thiopurine resistance. It also revealed overexpression of the ATM/p53/p21 pathway, which is activated in response to DNA damage and induces cell cycle arrest in thiopurine resistant LCLs. Furthermore, overexpression of the p53 target gene TNFRSF10D or the negative cell cycle regulator CCNG2 induces cell cycle arrest and may also contribute to thiopurine resistance. ARHGDIA under-expression in resistant cell lines may constitute a novel molecular mechanism contributing to thiopurine resistance based on Rac1 inhibition induced apoptosis and in relation with thiopurine pharmacodynamics.Our study provides new insights into the molecular mechanisms underlying thiopurine resistance and suggests a potential research focus for developing tailored medicine.

  • Estrogen Receptor α Regulates Beta Cell Formation During Pancreas Development and Following Injury.
    Yuchi Y, Cai Y, Legein B, et al. Estrogen Receptor α Regulates Beta Cell Formation During Pancreas Development and Following Injury. [JOURNAL ARTICLE]Diabetes 2015 May 26.Identifying pathways for beta cell generation is essential for cell therapy in diabetes. Here we investigate the potential of 17β-estradiol (E2) and estrogen receptor (ER) signaling for stimulating beta cell generation during embryonic development and in severely injured adult pancreas. Estradiol concentration, ER activity and number of ERα transcripts were enhanced in pancreas injured by partial duct ligation (PDL), along with nuclear localization of ERα in beta cells. PDL-induced proliferation of beta cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and beta cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα(-/-)), while in situ delivery of E2 promoted beta cell formation. In embryonic pancreas, beta cell replication, number of Ngn3(+) progenitor cells and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The present study reveals that E2 and ERα signaling can drive beta cell replication and formation in mouse pancreas.

  • Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer.
    Stewart GD, O'Mahony F, Laird A, et al. Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer. [JOURNAL ARTICLE]Clin Cancer Res 2015 May 26.The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC).Multiple tumor samples (n=187 samples) were taken from the primary renal tumors of mccRCC patients who were sunitinib treated (n=23, SuMR clinical trial) or untreated (n=23, SCOTRRCC study). ITH of pathological grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia and stromal related genes). ITH was analysed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene expression clustering.Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples.These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy.

  • Long-Term Reduction of High Blood Pressure by Angiotensin II DNA Vaccine in Spontaneously Hypertensive Rats.
    Koriyama H, Nakagami H, Nakagami F, et al. Long-Term Reduction of High Blood Pressure by Angiotensin II DNA Vaccine in Spontaneously Hypertensive Rats. [JOURNAL ARTICLE]Hypertension 2015 May 26.Recent research on vaccination has extended its scope from infectious diseases to chronic diseases, including Alzheimer disease, dyslipidemia, and hypertension. The aim of this study was to design DNA vaccines for high blood pressure and eventually develop human vaccine therapy to treat hypertension. Plasmid vector encoding hepatitis B core-angiotensin II (Ang II) fusion protein was injected into spontaneously hypertensive rats using needleless injection system. Anti-Ang II antibody was successfully produced in hepatitis B core-Ang II group, and antibody response against Ang II was sustained for at least 6 months. Systolic blood pressure was consistently lower in hepatitis B core-Ang II group after immunization, whereas blood pressure reduction was continued for at least 6 months. Perivascular fibrosis in heart tissue was also significantly decreased in hepatitis B core-Ang II group. Survival rate was significantly improved in hepatitis B core-Ang II group. This study demonstrated that Ang II DNA vaccine to spontaneously hypertensive rats significantly lowered high blood pressure for at least 6 months. In addition, Ang II DNA vaccines induced an adequate humoral immune response while avoiding the activation of self-reactive T cells, assessed by ELISPOT assay. Future development of DNA vaccine to treat hypertension may provide a new therapeutic option to treat hypertension.

  • Use of whole exome sequencing for the identification of ito-based arrhythmia mechanism and therapy.
    Sturm AC, Kline CF, Glynn P, et al. Use of whole exome sequencing for the identification of ito-based arrhythmia mechanism and therapy. [Journal Article]J Am Heart Assoc 2015; 4(5)Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment.We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito.We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams.

  • From whole exome sequencing to patient-specific therapy: another example of how basic research pays off in patient care.
    Wilde AA, Viskin S From whole exome sequencing to patient-specific therapy: another example of how basic research pays off in patient care. [Editorial]J Am Heart Assoc 2015; 4(5)

  • Ex vivo drug susceptibility and molecular profiling of clinical Plasmodium falciparum isolates from Cambodia in 2008-2013 suggest emerging piperaquine resistance.
    Chaorattanakawee S, Saunders DL, Sea D, et al. Ex vivo drug susceptibility and molecular profiling of clinical Plasmodium falciparum isolates from Cambodia in 2008-2013 suggest emerging piperaquine resistance. [JOURNAL ARTICLE]Antimicrob Agents Chemother 2015 May 26.Cambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008-2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia, by surveying for ex vivo drug susceptibility and molecular drug resistance markers, to guide selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean IC50 increased from 12.8 to 29.6 nM) while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (pfmdr1) multiple copy isolates and coincided with timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum Kelch13 mutations indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of pfmdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure.

  • Discovery and Validation of Vascular Endothelial Growth Factor (VEGF) Pathway Polymorphisms in Esophageal Adenocarcinoma Outcome.
    Eng L, Azad AK, Qiu X, et al. Discovery and Validation of Vascular Endothelial Growth Factor (VEGF) Pathway Polymorphisms in Esophageal Adenocarcinoma Outcome. [JOURNAL ARTICLE]Carcinogenesis 2015 May 25.Polymorphisms in the VEGF/angiogenesis pathway have been previously implicated in cancer risk, prognosis, and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP approach to identify new VEGF-pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA, 33 FLT1), selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio,aHR=0.69, 95%CI:0.53-0.90;P=5.2E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR=1.44, 95%CI:1.04-1.99;P=0.03 and aHR=1.50, 95%CI:1.01- 2.24;P=0.04, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR=1.59, 95%CI:1.04-2.44;P=0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma; whereby each variant allele confers a 45-60% increased risk in mortality. Validation and evaluation of this association in other cancer sites is warranted.

  • Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials.
    Meric-Bernstam F, Brusco L, Shaw K, et al. Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials. [JOURNAL ARTICLE]J Clin Oncol 2015 May 26.We report the experience with 2,000 consecutive patients with advanced cancer who underwent testing on a genomic testing protocol, including the frequency of actionable alterations across tumor types, subsequent enrollment onto clinical trials, and the challenges for trial enrollment.Standardized hotspot mutation analysis was performed in 2,000 patients, using either an 11-gene (251 patients) or a 46- or 50-gene (1,749 patients) multiplex platform. Thirty-five genes were considered potentially actionable based on their potential to be targeted with approved or investigational therapies.Seven hundred eighty-nine patients (39%) had at least one mutation in potentially actionable genes. Eighty-three patients (11%) with potentially actionable mutations went on genotype-matched trials targeting these alterations. Of 230 patients with PIK3CA/AKT1/PTEN/BRAF mutations that returned for therapy, 116 (50%) received a genotype-matched drug. Forty patients (17%) were treated on a genotype-selected trial requiring a mutation for eligibility, 16 (7%) were treated on a genotype-relevant trial targeting a genomic alteration without biomarker selection, and 40 (17%) received a genotype-relevant drug off trial. Challenges to trial accrual included patient preference of noninvestigational treatment or local treatment, poor performance status or other reasons for trial ineligibility, lack of trials/slots, and insurance denial.Broad implementation of multiplex hotspot testing is feasible; however, only a small portion of patients with actionable alterations were actually enrolled onto genotype-matched trials. Increased awareness of therapeutic implications and access to novel therapeutics are needed to optimally leverage results from broad-based genomic testing.