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Gene Therapy

Bijay Dhungel, Slawomir Andrzejewski, Aparna Jayachandran, Ritu Shrestha, Charmaine A Ramlogan-Steel, Christopher J Layton, Jason C Steel
Hepatocellular carcinoma (HCC) is a major health problem as evidenced by its increasing incidence and high morbidity and mortality rates. Most patients with HCC have underlying liver disease and dysfunction which limits the current therapeutic options. Treatments that spare the liver and destroy the HCC are needed. Targeting transcriptional differences between HCC and liver cells may provide this therapeutic window. In this study, we examine the potential of the Glypican 3 (GPC3) promoter as a targeting strategy...
March 21, 2018: Gene Therapy
Alan H Nagahara, Bayard R Wilson, Iryna Ivasyk, Imre Kovacs, Saytam Rawalji, John R Bringas, Phillip J Pivirotto, Waldy San Sebastian, Lluis Samaranch, Krystof S Bankiewicz, Mark H Tuszynski
Brain-derived neurotrophic factor (BDNF) gene delivery to the entorhinal cortex is a candidate for treatment of Alzheimer's disease (AD) to reduce neurodegeneration that is associated with memory loss. Accurate targeting of the entorhinal cortex in AD is complex due to the deep and atrophic state of this brain region. Using MRI-guided methods with convection-enhanced delivery, we were able to accurately and consistently target AAV2-BDNF delivery to the entorhinal cortex of non-human primates; 86 ± 3% of transduced cells in the targeted regions co-localized with the neuronal marker NeuN...
March 13, 2018: Gene Therapy
Hengchao Chen, Yazhi Xing, Li Xia, Zhengnong Chen, Shankai Yin, Jian Wang
The synapse between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) has been identified as a sensitive structure to noise-induced damage in the mammalian cochlea. Since this synapse provides the major information pathway from the cochlea to the auditory brain, it is important to maintain its integrity. Neurotrophin-3 (NT-3) has been known to play an important role in the development and the functional maintenance of this synapse. Application of exogenous NT-3, or overexpression of this gene in a transgenic animal model, have shown the value to protect this synapse from noise-induced damage...
March 13, 2018: Gene Therapy
Hale M Tasyurek, Yunus E Eksi, Ahter D Sanlioglu, Hasan A Altunbas, Mustafa K Balci, Thomas S Griffith, Salih Sanlioglu
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM...
March 9, 2018: Gene Therapy
Yan-Yi Wang, Shan Ma, Qingyong Chen, Demin Jiao, Yong Yang
Current in vivo selections for hematopoietic stem cell (HSC)-based gene therapy are drug dependent and not without risk of cytotoxicity or tumorigenesis. We developed a new in vivo selection system with the non-phosphorylatable Bcl2 mutant Bcl2T69A/S70A/S87A (Bcl2AAA ), which makes in vivo selection drug independent and without risk of cytotoxicity or tumorigenesis. We demonstrated in HSC-transplanted mice that Bcl2AAA facilitated efficient in vivo selection in the absence of any exogenously applied drugs under both myeloablative and non-myeloablative conditioning...
March 9, 2018: Gene Therapy
Melvin Y Rincon, Filip de Vin, Sandra I Duqué, Shelly Fripont, Stephanie A Castaldo, Jessica Bouhuijzen-Wenger, Matthew G Holt
Until recently, adeno-associated virus 9 (AAV9) was considered the AAV serotype most effective in crossing the blood-brain barrier (BBB) and transducing cells of the central nervous system (CNS), following systemic injection. However, a newly engineered capsid, AAV-PHP.B, is reported to cross the BBB at even higher efficiency. We investigated how much we could boost CNS transgene expression by using AAV-PHP.B carrying a self-complementary (sc) genome. To allow comparison, 6 weeks old C57BL/6 mice received intravenous injections of scAAV2/9-GFP or scAAV2/PHP...
March 9, 2018: Gene Therapy
Mehmet E Yalvac, Jakkrit Amornvit, Lei Chen, Kimberly M Shontz, Sarah Lewis, Zarife Sahenk
Neurotrophin 3 (NT-3) has well-recognized effects on peripheral nerve and Schwann cells, promoting axonal regeneration and associated myelination. In this study, we assessed the effects of AAV.NT-3 gene therapy on the oxidative state of the neurogenic muscle from the TremblerJ (TrJ ) mice at 16 weeks post-gene injection and found that the muscle fiber size increase was associated with a change in the oxidative state of muscle fibers towards normalization of the fiber type ratio seen in the wild type. NT-3-induced fiber size increase was most prominent for the fast twitch glycolytic fiber population...
March 9, 2018: Gene Therapy
C Burkart, A Mukhopadhyay, S A Shirley, R J Connolly, J H Wright, A Bahrami, J S Campbell, R H Pierce, D A Canton
The use of immunomodulatory cytokines has been shown effective in regressing a wide range of tumors. However, systemic delivery of recombinant cytokines results in serious, potentially life-threatening, adverse effects. By contrast, nucleic acid transfer via electroporation (EP) is a safe and effective method of delivering plasmid-encoded cytokines to tumors. Intratumoral delivery of IL-12 plasmid DNA by electroporation (IT-pIL12-EP) produced objective response rates in Phase 2 clinical trials in metastatic melanoma...
March 9, 2018: Gene Therapy
Chongwen Xu, Guodong Xiao, Boxiang Zhang, Meng Wang, Jichang Wang, Dapeng Liu, Jing Zhang, Hong Ren, Xin Sun
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities worldwide, yet this condition remains a poorly understood malignancy, and the subgroup of cancer stem cells (CSCs) leading to therapeutic resistance and adverse prognosis have not been well studied. CSCs frequently undergo symmetric division, which facilitates expansion of the stem cell pool, contributing to long-term relapse and therapy failure. CCAT1 could act as a miRNA sponge to influence downstream genes; however, its roles in NSCLC stem cell are unclear...
January 19, 2018: Gene Therapy
M Renteln
Recently, split intein-based detection sensors for RNA have been developed that can target custom sequences in a modular fashion. If multi-region, multi-sample sequencing were to be applied to a patient's cancer, truncal (that is, earliest-occurring) mutations could be identified and could serve as targets for these sense-and-respond modules. The next step would be to utilize an effective vector for treatment. A hyper-virulent herpes simplex virus could possibly serve as this vector, with concurrent immunosuppression to allow for unhindered infection of the tumor regions...
January 2018: Gene Therapy
D M Schwab, L Tilemann, R Bauer, M Heckmann, A Jungmann, M Wagner, J Burgis, C Vettel, H A Katus, A El-Armouche, O J Müller
The downregulation of β-adrenergic receptors (β-AR) and decreased cAMP-dependent protein kinase activity in failing hearts results in decreased phosphorylation and inactivation of phosphatase-inhibitor-1 (I-1), a distal amplifier element of β-adrenergic signaling, leading to increased protein phosphatase 1 activity and dephosphorylation of key phosphoproteins, including phospholamban. Downregulated and hypophosphorylated I-1 likely contributes to β-AR desensitization; therefore its modulation is a promising approach in heart failure treatment...
January 2018: Gene Therapy
S Takai, T Majima, B Reinhart, W F Goins, Y Funahashi, M Gotoh, P Tyagi, J C Glorioso, N Yoshimura
Enhanced afferent excitability is considered to be an important pathophysiological basis of interstitial cystitis/bladder pain syndrome (IC/BPS). In addition, transient receptor potential vanilloid-1 (TRPV1) receptors are known to be involved in afferent sensitization. Animals with hydrogen peroxide (HP)-induced cystitis have been used as a model exhibiting pathologic characteristics of chronic inflammatory condition of the bladder. This study investigated the effect of gene therapy with replication-defective herpes simplex virus (HSV) vectors encoding poreless TRPV1 (PL) or protein phosphatase 1 α (PP1α), a negative regulator of TRPV1, using a HP-induced rat model of cystitis...
January 2018: Gene Therapy
R Eggers, A Philippi, M O Altmeyer, F Breinig, M J Schmitt
Immune cells become increasingly attractive as delivery system for immunotoxins in cancer therapy to reduce the intrinsic toxicity and severe side effects of chimeric protein toxins. In this study, we investigated the potential of human primary T cells to deliver a secreted immunotoxin through transient messenger RNA (mRNA) transfection. The chimeric protein toxin was directed toward the neovasculature of cancer cells by fusing a truncated version of Pseudomonas exotoxin A (PE38) to human vascular endothelial growth factor (VEGF) and to the single chain variable fragment (scFv) of anti-Her2/neu...
January 2018: Gene Therapy
D Kampik, M Basche, U F O Luhmann, K M Nishiguchi, J A E Williams, J Greenwood, S E Moss, H Han, S Azam, Y Duran, S J Robbie, J W B Bainbridge, D F Larkin, A J Smith, R R Ali
The retinal pigment epithelium (RPE) interacts closely with photoreceptors to maintain visual function. In degenerative diseases such as Stargardt disease and age-related macular degeneration, the leading cause of blindness in the developed world, RPE cell loss is followed by photoreceptor cell death. RPE cells can proliferate under certain conditions, suggesting an intrinsic regenerative potential, but so far this has not been utilised therapeutically. Here, we used E2F2 to induce RPE cell replication and thereby regeneration...
December 2017: Gene Therapy
B D Greenbaum, N Vabret
No abstract text is available yet for this article.
December 2017: Gene Therapy
L Falese, K Sandza, B Yates, S Triffault, S Gangar, B Long, L Tsuruda, B Carter, C Vettermann, S J Zoog, S Fong
Gene therapy may offer a new treatment option, particularly for patients with severe hemophilia, based on recent research. However, individuals with pre-existing immunity to adeno-associated viruses (AAVs) may be less likely to benefit from AAV vector-based therapies. To study pre-existing AAV5 immunity in humans, we validated two complementary, sensitive, and scalable in vitro assays to detect AAV5 total antibodies and transduction inhibition (TI). Using these two assays, we found that 53% of samples from 100 healthy male individuals were negative in both assays, 18% were positive in both assays, 5% were positive for total antibodies but negative for TI and, of interest, 24% were negative for total antibodies but positive for TI activity, suggesting the presence of non-antibody-based neutralizing factors in human plasma...
December 2017: Gene Therapy
P D Fisher, C J Brambila, J R McCoy, W B Kiosses, J M Mendoza, J Oh, B S Yung, K Schultheis, T R F Smith, K E Broderick
DNA vaccines delivered using electroporation (EP) have had clinical success, but these EP methods generally utilize invasive needle electrodes. Here, we demonstrate the delivery and immunogenicity of a DNA vaccine into subcutaneous adipose tissue cells using noninvasive EP. Using finite element analysis, we predicted that plate electrodes, when oriented properly, could effectively concentrate the electric field within adipose tissue. In practice, these electrodes generated widespread gene expression persisting for at least 60 days in vivo within interscapular subcutaneous fat pads of guinea pigs...
December 2017: Gene Therapy
Md T A Azad, S Bhakta, T Tsukahara
Site-directed RNA editing is an important technique for correcting gene sequences and ultimately tuning protein function. In this study, we engineered the deaminase domain of adenosine deaminase acting on RNA (ADAR1) and the MS2 system to target-specific adenosines, with the goal of correcting G-to-A mutations at the RNA level. For this purpose, the ADAR1 deaminase domain was fused downstream of the RNA-binding protein MS2, which has affinity for the MS2 RNA. To direct editing to specific targets, we designed guide RNAs complementary to target RNAs...
December 2017: Gene Therapy
L Chansel-Debordeaux, M Bourdenx, S Dovero, V Grouthier, N Dutheil, A Espana, L Groc, C Jimenez, E Bezard, B Dehay
Animal models are essential tools for basic pathophysiological research as well as validation of therapeutic strategies for curing human diseases. However, technical difficulties associated with classical transgenesis approaches in rodent species higher than Mus musculus have prevented this long-awaited development. The availability of viral-mediated gene delivery systems in the past few years has stimulated the production of viruses with unique characteristics. For example, the recombinant adeno-associated virus serotype 9 (rAAV2/9) crosses the blood-brain barrier, is capable of transducing developing cells and neurons after intravenous injection and mediates long-term transduction...
December 2017: Gene Therapy
Y Yun, J Oh, Y Kim, G Kim, M Lee, Y Ha
Spinal cord injury (SCI) is an incurable disease causing an ischemic environment and functional defect, thus a new therapeutic approach is needed for SCI treatment. Vascular endothelial growth factor (VEGF) is a potent therapeutic gene to treat SCI via angiogenesis and neuroprotection, and both tissue-specific gene expression and high gene delivery efficiency are important for successful gene therapy. Here we design the hypoxia/neuron dual-specific gene expression system (pEpo-NSE) and efficient gene delivery platform can be achieved by the combination ex vivo gene therapy with erythropoietin (Epo) enhancer, neuron-specific enolase (NSE) promoter and neural stem cells (NSCs)...
November 20, 2017: Gene Therapy
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