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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.


  • Ultradeep sequencing of B and non-B HIV-1 subtypes: Viral diversity and drug resistance mutations before and after one month of antiretroviral therapy in naive patients.
    Ultradeep sequencing of B and non-B HIV-1 subtypes: Viral diversity and drug resistance mutations before and after one month of antiretroviral therapy in naive patients. [Journal Article]J Clin Virol 2017 Jul 25.:13-19.JCEpaulard O, Signori-Schmuck A, Larrat S, et al. A high pre-HAART viral diversity might have a positive effect on the outcome of HAART. Pre-therapeutic minority drug resistance mutations are uncommon in naive patients.Ultradeep pyrosequencing technologies permit an assessment of the genetic diversity and the presence and frequency of minority variants in a viral population. The effect of these parameters on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected patients is poorly understood.The present study used the pyrosequencing Roche 454 prototype assay to determine whether antiretroviral efficacy is correlated with viral diversity and minority drug resistance mutations in HIV-infected treatment-naive patients and to compare assay performance in B and non-B subtypes.The study included 30 HIV-1 infected naive patients (20 with subtype non-B and 10 with subtype B). Ultradeep pyrosequencing of protease and reverse transcriptase genes was performed at baseline and 1 month after HAART initiation. Plasma HIV VL was measured at 0 and after 1, 3, and 6 months of HAART.Pre-HAART minority drug resistance mutations were observed to NRTI in 4 patients, to NNRTI in 6 patients, and to PI in 1 patient; there was no difference in HAART-induced VL decay between patients. Pre-HAART diversity was significantly correlated with the time elapsed since HIV-1 infection diagnosis, but not with the subtype, VL, or CD4 count. Patients with an undetectable VL after 3 months of HAART had a higher pre-HAART diversity. Pre- and post-HAART diversities were not statistically different. There was no difference in assay performance between subtype B and non-B.A high pre-HAART viral diversity might have a positive effect on the outcome of HAART. Pre-therapeutic minority drug resistance mutations are uncommon in naive patients.

  • Subretinal Injection for Gene Therapy Does Not Cause Clinically Significant Outer Nuclear Layer Thinning in Normal Primate Foveae.
    Subretinal Injection for Gene Therapy Does Not Cause Clinically Significant Outer Nuclear Layer Thinning in Normal Primate Foveae. [Journal Article]Invest Ophthalmol Vis Sci 2017 Aug 01; 58(10):4155-4160.IOOchakovski GA, Peters T, Michalakis S, et al. Despite limited ONL thinning following SRi, the observed effect was under the predefined clinical significance threshold. The SRi has proven not to be inferior to the IVTi in terms of ONL thickness los...Despite ever-growing adoption of subretinal (SRi) and intravitreal injections (IVTi) in ocular gene therapy trials, concerns regarding possible deleterious effects of the SRi on the outer retina are yet to be addressed. SRi offers several advantages over IVTi, such as a better photoreceptor transduction efficiency and a limited off-target exposure. We assessed structural changes in the outer retina in nonhuman primates following either SRi or IVTi of a gene therapeutic or control solution and compared both techniques in a noninferiority analysis.In a toxicology study, 22 cynomolgus monkeys underwent single intraocular injections with rAAV2/8 or vehicle; 18 animals received SRi, 4 animals received IVTi. Outer nuclear layer (ONL) thickness change on optical coherence tomography was used for a noninferiority analysis. Preservation of the physiological foveal bulge was used as a secondary outcome measure.The average ONL change from baseline after 2 weeks was -6.54 ± 5.16 (mean ± SD μm) and +1.50 ± 4.36 for SRi and IVTi groups accordingly. At 13 weeks, the SRi group maintained a difference of -6.54 ± 9.66 while IVTi group gained +1.00 ± 4.24. The ellipsoid zone line was transiently lost after SRi and completely recovered by 13 weeks in 77% of eyes. One SRi case resulted in subfoveal pigment accumulation and 39% ONL thinning.Despite limited ONL thinning following SRi, the observed effect was under the predefined clinical significance threshold. The SRi has proven not to be inferior to the IVTi in terms of ONL thickness loss and estimated loss of visual acuity.

  • Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine.
    Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine. [Journal Article]PLoS Negl Trop Dis 2017 Aug; 11(8):e0005805.PNVilla-Pulgarín JA, Gajate C, Botet J, et al. The present study shows that the antileishmanial and anticancer actions of edelfosine share some common signaling processes, with mitochondria and raft-located FOF1-ATP synthase being critical in the k...Leishmaniasis is the world's second deadliest parasitic disease after malaria, and current treatment of the different forms of this disease is far from satisfactory. Alkylphospholipid analogs (APLs) are a family of anticancer drugs that show antileishmanial activity, including the first oral drug (miltefosine) for leishmaniasis and drugs in preclinical/clinical oncology trials, but their precise mechanism of action remains to be elucidated.Here we show that the tumor cell apoptosis-inducer edelfosine was the most effective APL, as compared to miltefosine, perifosine and erucylphosphocholine, in killing Leishmania spp. promastigotes and amastigotes as well as tumor cells, as assessed by DNA breakdown determined by flow cytometry. In studies using animal models, we found that orally-administered edelfosine showed a potent in vivo antileishmanial activity and diminished macrophage pro-inflammatory responses. Edelfosine was also able to kill Leishmania axenic amastigotes. Edelfosine was taken up by host macrophages and killed intracellular Leishmania amastigotes in infected macrophages. Edelfosine accumulated in tumor cell mitochondria and Leishmania kinetoplast-mitochondrion, and led to mitochondrial transmembrane potential disruption, and to the successive breakdown of parasite mitochondrial and nuclear DNA. Ectopic expression of Bcl-XL inhibited edelfosine-induced cell death in both Leishmania parasites and tumor cells. We found that the cytotoxic activity of edelfosine against Leishmania parasites and tumor cells was associated with a dramatic recruitment of FOF1-ATP synthase into lipid rafts following edelfosine treatment in both parasites and cancer cells. Raft disruption and specific FOF1-ATP synthase inhibition hindered edelfosine-induced cell death in both Leishmania parasites and tumor cells. Genetic deletion of FOF1-ATP synthase led to edelfosine drug resistance in Saccharomyces cerevisiae yeast.The present study shows that the antileishmanial and anticancer actions of edelfosine share some common signaling processes, with mitochondria and raft-located FOF1-ATP synthase being critical in the killing process, thus identifying novel druggable targets for the treatment of leishmaniasis.

  • RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses.
    RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses. [Journal Article]Br J Cancer 2017 Aug 22.BJDolly SO, Gurden MD, Drosopoulos K, et al. These data suggest a putative therapeutic strategy for a large number of different types of human cancers with FBXW7 loss, many of which have a paucity of molecular abnormalities and treatment options....F-box and WD40 repeat domain-containing 7 (FBXW7) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of multiple oncogenic substrates. The tumour suppressor function is frequently lost in multiple cancers through genetic deletion and mutations in a broad range of tumours. Loss of FBXW7 functionality results in the stabilisation of multiple major oncoproteins, culminating in increased cellular proliferation and pro-survival pathways, cell cycle deregulation, chromosomal instability and altered metabolism. Currently, there is no therapy to specifically target FBXW7-deficient tumours.We performed a siRNA kinome screen to identify synthetically lethal hits to FBXW7 deficiency.We identified and validated cyclin G-associated kinase (GAK) as a potential new therapeutic target. Combined loss of FBXW7 and GAK caused cell cycle defects, formation of multipolar mitoses and the induction of apoptosis. The synthetic lethal mechanism appears to be independent of clathrin-mediated receptor endocytosis function of GAK.These data suggest a putative therapeutic strategy for a large number of different types of human cancers with FBXW7 loss, many of which have a paucity of molecular abnormalities and treatment options.British Journal of Cancer advance online publication: 22 August 2017; doi:10.1038/bjc.2017.277 www.bjcancer.com.

  • Gene therapy for inherited retinal degenerations: initial successes and future challenges.
    Gene therapy for inherited retinal degenerations: initial successes and future challenges. [Journal Article]J Neural Eng 2017 Aug 22; 14(5):051002.JNGupta PR, Huckfeldt RM Inherited retinal degenerations are a clinically and genetically heterogeneous group of conditions that have historically shared an untreatable course. In recent years, however, a wide range of therape...Inherited retinal degenerations are a clinically and genetically heterogeneous group of conditions that have historically shared an untreatable course. In recent years, however, a wide range of therapeutic strategies have demonstrated efficacy in preclinical studies and entered clinical trials with a common goal of improving visual function for patients affected with these conditions. Gene therapy offers a particularly elegant and precise opportunity to target the causative genetic mutations underlying these monogenic diseases. The present review will provide an overview of gene therapy with particular emphasis on key clinical results to date and challenges for the future.

  • Regulation of miRNAs on c-met protein expression in ovarian cancer and its implication.
    Regulation of miRNAs on c-met protein expression in ovarian cancer and its implication. [Journal Article]Eur Rev Med Pharmacol Sci 2017 Aug; 21(15):3353-3359.ERLiu H, Li SR, Si Q The up-regulation of miR-204 suppressed the expression of c-met in ovarian cancer cells and inhibited cell infiltration. The suppression of miR-204 expression, however, presented no significant impact ...HGF/c-met signal pathway exerts important roles in tumor pathogenesis. The study of c-met related regulatory mechanism provides the basis for finding anti-tumor molecular drugs. MiRNAs can effectively regulate gene expression and work as gene therapy. The identification of miRNAs for c-met regulation and study of related mechanism are of critical importance.Bioinformatics approach was used to search for possible miRNAs with regulatory functions on c-met gene. Using pcDNA3.1-EGFP as the scaffold, miRNAs over-expression and inhibitor plasmids were constructed for electroporation-transfection in ovarian cell line ES-2, and pcDNA3.1-EGFP empty plasmid was used as the control group. qRT-PCR and Western blot were applied to measure c-met mRNA and protein expression, followed by transwell chamber in vitro assay for the evaluation of invasion potency.Bioinformatics prediction showed favorable regulatory function on c-met gene by miR-204. The differential expressions of EGFP were observed between pcDNA3.1-EGFP-204-up and inhibitor plasmid pcDNA3.1-EGFP-204-down. After transfection for 24 h and 48 h, c-met expression in miR-204 over-expression group gradually decreased (p<0.05 compared to control group), accompanied with reducing cell migration or invasion potency in a time dependent manner (p<0.05). In contrast, no significant difference in the level of c-met was found in the inhibitor group and control group (p>0.05).The up-regulation of miR-204 suppressed the expression of c-met in ovarian cancer cells and inhibited cell infiltration. The suppression of miR-204 expression, however, presented no significant impact on cell infiltration potency.

  • Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins.
    Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins. [Journal Article]J Vis Exp 2017 Aug 15; (126)JVJang SS, Jeong HG, Chung HJ Electroconvulsive seizure (ECS) is an experimental animal model of electroconvulsive therapy, the most effective treatment for severe depression. ECS induces generalized tonic-clonic seizures with low ...Electroconvulsive seizure (ECS) is an experimental animal model of electroconvulsive therapy, the most effective treatment for severe depression. ECS induces generalized tonic-clonic seizures with low mortality and neuronal death and is a widely-used model to screen anti-epileptic drugs. Here, we describe an ECS induction method in which a brief 55-mA current is delivered for 0.5 s to male rats 200 - 250 g in weight via ear-clip electrodes. Such bilateral stimulation produced stage 4 - 5 clonic seizures that lasted about 10 s. After the cessation of acute or chronic ECS, most rats recovered to be behaviorally indistinguishable from sham "no seizure" rats. Because ECS globally elevates brain activity, it has also been used to examine activity-dependent alterations of synaptic proteins and their effects on synaptic strength using multiple methods. In particular, subcellular fractionation of the postsynaptic density (PSD) in combination with Western blotting allows for the quantitative determination of the abundance of synaptic proteins at this specialized synaptic structure. In contrast to a previous fractionation method that requires large amount of rodent brains, we describe here a small-scale fractionation method to isolate the PSD from the hippocampi of a single rat, without sucrose gradient centrifugation. Using this method, we show that the isolated PSD fraction contains postsynaptic membrane proteins, including PSD95, GluN2B, and GluA2. Presynaptic marker synaptophysin and soluble cytoplasmic protein α-tubulin were excluded from the PSD fraction, demonstrating successful PSD isolation. Furthermore, chronic ECS decreased GluN2B expression in the PSD, indicating that our small-scale PSD fractionation method can be applied to detect the changes in hippocampal PSD proteins from a single rat after genetic, pharmacological, or mechanical treatments.

  • Molecular biomarkers of anaplastic thyroid carcinoma.
    Molecular biomarkers of anaplastic thyroid carcinoma. [Journal Article]Curr Mol Med 2017 Aug 21.CMBozorg-Ghalati F, Hedayati M Anaplastic thyroid carcinoma is the rarest but extremely aggressive thyroid cancer subtype. This neoplasia is composed of undifferentiated tumor cells with poor prognosis and resistant to common thyroi...Anaplastic thyroid carcinoma is the rarest but extremely aggressive thyroid cancer subtype. This neoplasia is composed of undifferentiated tumor cells with poor prognosis and resistant to common thyroid cancer therapy. Early stage identification of this cancer for prompt treatment is very vital. Presently, cytological evaluation of fine needle aspiration biopsy (FNAB) which is known as invasive recognition assay, is the standard diagnostic method for the diagnosis of malignant thyroid tumors. Frequent studies have suggested that using the molecular biomarkers of thyroid cancer tissue alongside cytological examination, increase the accuracy of diagnostic tests. Also, these agents could be beneficial for effective target therapy and personalize medicine. In this review, the molecular biomarkers that are involved in anaplastic thyroid carcinoma in four category (gene mutation profile, epigenetic profile, microRNA profile and cancer stem cell markers) were summarized.

  • Kawasaki disease and coronary artery aneurysms: from childhood to adulthood.
    Kawasaki disease and coronary artery aneurysms: from childhood to adulthood. [Journal Article]Future Cardiol 2017 Aug 22.FCJoshi M, Tulloh R Kawasaki disease is an acute, systemic vasculitis of childhood and confers a 25% risk of developing coronary artery aneurysms. Its etiology is unknown, but the incidence is increasing rapidly with link...Kawasaki disease is an acute, systemic vasculitis of childhood and confers a 25% risk of developing coronary artery aneurysms. Its etiology is unknown, but the incidence is increasing rapidly with linked gene polymorphisms having been identified. A constellation of symptoms, epidemics and seasonality all implicate an unidentified infective or environmental cause. Intravenous immunoglobulin therapy, aspirin and steroids all form the mainstay of acute treatment and reduces the incidence of coronary artery aneurysms if given before 7 days. However, in some, these lesions persist and require ongoing management during follow-up during childhood and into adult life. Evidence for further investigations in order to minimize complications is presented in order to minimize the myofibroblast proliferation and stenosis in the long term.

  • Rerouting Native HDL to Predetermined Receptors for Improved Tumor-Targeted Gene Silencing Therapy.
    Rerouting Native HDL to Predetermined Receptors for Improved Tumor-Targeted Gene Silencing Therapy. [Journal Article]ACS Appl Mater Interfaces 2017 Aug 22.AADing Y, Han Y, Wang R, et al. High density lipoprotein (HDL) is an outstanding biocompatible nanovector for tumor-targeted delivery of multi-model drugs in cancer therapy. However, this seemingly promising delivery platform demonst...High density lipoprotein (HDL) is an outstanding biocompatible nanovector for tumor-targeted delivery of multi-model drugs in cancer therapy. However, this seemingly promising delivery platform demonstrates an adverse accumulation in liver and adrenal due to the primary expression of natural target scavenger receptor class B type I (SR-BI), which overexpressed in malignant cells as well. Therefore, we endowed native HDLs with rerouting capacity, i.e. enabling HDLs to get away from natural receptors (SR-BI) to selectively alternate tumor-rich receptors. The αvβ3-integrin specific cyclic-RGDyk peptide was conjugated with HDL-protein component apolipoprotein A-I (apoA-I), demonstrating high substitution degree of 26.2%. Afterward, RGD modified apoA-I was introduced to fabricate cholesterol siRNA-loaded HDL nanoparticles (RGD-HDL/Ch-siRNA) for specific affinity with tumor angiogenesis and αvβ3 integrin on tumor surface. After preparation, RGD-HDL/Ch-siRNA shared desirable particle size, efficient siRNA protection during blood circulation and favorable proton sponge effect. αvβ3 integrin associated superior rerouting capacity, endocytosis pathway, and rapid endo-lysosome escape were confirmed both in vitro and in vivo. For targeted gene silencing therapy, Pokemon specific siRNA (siPokemon) was introduced as RNA interference candidate; the enhanced antitumor efficacy and decreased Pokemon expression level were commendably confirmed by tumor growth inhibition, survival period extension, and western blot analysis. Collectively, cyclic-RGDyk modification endows native HDLs with rerouting capacity to specific αvβ3 integrin receptor, which provides a promising strategy to extend malignancy targeting potential of native HDL to a broader purview.

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