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Gene Therapy

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https://www.readbyqxmd.com/read/29785047/rationally-designed-aav2-and-aavrh8r-capsids-provide-improved-transduction-in-the-retina-and-brain
#1
Jennifer A Sullivan, Lisa M Stanek, Michael J Lukason, Jie Bu, Shayla R Osmond, Elizabeth A Barry, Catherine R O'Riordan, Lamya S Shihabuddin, Seng H Cheng, Abraham Scaria
The successful application of adeno-associated virus (AAV) gene delivery vectors as a therapeutic paradigm will require efficient gene delivery to the appropriate cells in affected organs. In this study, we utilized a rational design approach to introduce modifications to the AAV2 and AAVrh8R capsids and the resulting variants were evaluated for transduction activity in the retina and brain. The modifications disrupted either capsid/receptor binding or altered capsid surface charge. Specifically, we mutated AAV2 amino acids R585A and R588A, which are required for binding to its receptor, heparan sulfate proteoglycans, to generate a variant referred to as AAV2-HBKO...
May 22, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29789639/fludarabine-and-neurotoxicity-in-engineered-t-cell-therapy
#2
Kate L Lowe, Crystal L Mackall, Elliot Norry, Rafael Amado, Bent K Jakobsen, Gwendolyn Binder
Adoptive T-cell therapy, incorporating engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs), target tumor antigens with high affinity and specificity. To increase the potency of adoptively transferred T cells, patients are conditioned with lymphodepleting chemotherapy regimens prior to adoptive T-cell transfer (ACT), and data suggest that fludarabine is an important component of an effective regimen. In a recent clinical trial using CAR-T cells engineered to target the CD19 B-cell antigen to treat acute lymphoblastic leukemia, JCAR-015 (NCT02535364), two patient deaths due to cerebral edema led to trial suspension...
May 7, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29789638/human-carbonic-anhydrase-8-aav8-gene-therapy-inhibits-nerve-growth-factor-signaling-producing-prolonged-analgesia-and-anti-hyperalgesia-in-mice
#3
Gerald Z Zhuang, Udita Upadhyay, Xiaoying Tong, Yuan Kang, Diana M Erasso, Eugene S Fu, Konstantinos D Sarantopoulos, Eden R Martin, Tim Wiltshire, Luda Diatchenko, Shad B Smith, William Maixner, Roy C Levitt
Carbonic anhydrase-8 (Car8; murine gene symbol) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates neuronal intracellular calcium release. We previously reported that wild-type Car8 overexpression corrects the baseline allodynia and hyperalgesia associated with calcium dysregulation in the waddle (wdl) mouse due to a 19 bp deletion in exon 8 of the Car8 gene. In this report, we provide preliminary evidence that overexpression of the human wild-type ortholog of Car8 (CA8 WT ), but not the reported CA8 S100P loss-of-function mutation (CA8 MT ), inhibits nerve growth factor (NGF)-induced phosphorylation of ITPR1, TrkA (NGF high-affinity receptor), and ITPR1-mediated cytoplasmic free calcium release in vitro...
April 24, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29686331/car-t-trailblazing-the-path-from-clinical-development-to-the-clinic
#4
EDITORIAL
Samuele Butera
No abstract text is available yet for this article.
April 23, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29670247/effects-of-microrna-292-5p-on-myocardial-ischemia-reperfusion-injury-through-the-peroxisome-proliferator-activated-receptor-%C3%AE-%C3%AE-signaling-pathway
#5
Zhen-Dong Zhu, Ji-Yun Ye, Hua Niu, Yu-Mei Ma, Xue-Mei Fu, Zhong-Hua Xia, Xuan Zhang
Ischemia-reperfusion injury (IRI) is a major cause of cardiac damage following various pathological processes, such as free radical damage and cell apoptosis. This study aims to investigate whether microRNA-292-5p (miR-292-5p) protects against myocardial ischemia-reperfusion injury (IRI) via the peroxisome proliferator-activated receptor (PPAR)-α/-γ signaling pathway in myocardial IRI mice models. Mouse models of myocardial IRI were established. Adult male C57BL/6 mice were divided into different groups. The hemodynamic indexes, levels of related inflammatory factors and serum myocardial enzymes, and malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were detected...
April 18, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29654247/the-revving-up-of-cars
#6
Muhammad Bilal Abid
No abstract text is available yet for this article.
April 13, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29599530/excessive-activated-t-cell-proliferation-after-anti-cd19-car-t-cell-therapy
#7
Wen-Ying Zhang, Yang Liu, Yao Wang, Jing Nie, Ye-Lei Guo, Chun-Meng Wang, Han-Ren Dai, Qing-Ming Yang, Zhi-Qiang Wu, Wei-Dong Han
Excessive activated T-cell proliferation was observed in vivo in one patient after an anti-CD19-chimeric antigen receptor (CAR) T-cell infusion. The patient, who had chemotherapy refractory and CD19+ diffuse large B-cell lymphoma (DLBCL), received an anti-CD19 CAR T-cell infusion following conditioning chemotherapy (fludarabine/cyclophosphamide). The lymphocyte count in the peripheral blood (PB) increased to 77 × 109 /L on day 13 post infusion, and the proportion of CD8+ actived T cells was 93.06% of the lymphocytes...
March 29, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29588497/targeted-in-vivo-knock-in-of-human-alpha-1-antitrypsin-cdna-using-adenoviral-delivery-of-crispr-cas9
#8
Calvin J Stephens, Elena Kashentseva, William Everett, Lyudmila Kaliberova, David T Curiel
Serum deficiency diseases such as alpha-1-antitrypsin deficiency are characterized by reduced function of serum proteins, caused by deleterious genetic mutations. These diseases are promising targets for genetic interventions. Gene therapies using viral vectors have been used to introduce correct copies of the disease-causing gene in preclinical and clinical studies. However, these studies highlighted that disease-alleviating gene expression is lost over time. Integration into a specific chromosomal site could provide lasting therapeutic expression to overcome this major limitation...
March 27, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29567950/understanding-the-molecular-biology-of-intervertebral-disc-degeneration-and-potential-gene-therapy-strategies-for-regeneration-a-review
#9
LETTER
Prasanthi Sampara, Rajkiran Reddy Banala, Satish Kumar Vemuri, Gurava Reddy Av, Subbaiah Gpv
Intervertebral disc degeneration (IVDD) is a multi-factorial process characterized by phenotypic and genotypic changes, which leads to low back pain and disability. Prolonged imbalance between anabolism and catabolism in discs alters their composition resulting in progressive loss of proteoglycans and hydration leading to IVDD. The current managements for IVDD are only able to relieve the symptoms but do not address the underlying pathology of degeneration. Researchers have tried to find out differences between the aging and degeneration of the disc...
March 22, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29563582/evaluation-of-the-glypican-3-promoter-for-transcriptional-targeting-of-hepatocellular-carcinoma
#10
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
https://www.readbyqxmd.com/read/29535374/aav-mediated-nt-3-overexpression-protects-cochleae-against-noise-induced-synaptopathy
#11
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
https://www.readbyqxmd.com/read/29523882/hiv-based-lentivirus-mediated-vasoactive-intestinal-peptide-gene-delivery-protects-against-dio-animal-model-of-type-2-diabetes
#12
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
https://www.readbyqxmd.com/read/29523881/in-vivo-selection-with-lentiviral-expression-of-bcl2-t69a-s70a-s87a-mutant-in-hematopoietic-stem-cell-transplanted-mice
#13
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 Bcl2 T69A/S70A/S87A (Bcl2 AAA ), 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
https://www.readbyqxmd.com/read/29535375/mr-guided-delivery-of-aav2-bdnf-into-the-entorhinal-cortex-of-non-human-primates
#14
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...
April 2018: Gene Therapy
https://www.readbyqxmd.com/read/29523880/widespread-transduction-of-astrocytes-and-neurons-in-the-mouse-central-nervous-system-after-systemic-delivery-of-a-self-complementary-aav-php-b-vector
#15
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...
April 2018: Gene Therapy
https://www.readbyqxmd.com/read/29523879/aav1-nt-3-gene-therapy-increases-muscle-fiber-diameter-through-activation-of-mtor-pathway-and-metabolic-remodeling-in-a-cmt-mouse-model
#16
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 (Tr J ) 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...
April 2018: Gene Therapy
https://www.readbyqxmd.com/read/29523878/improving-therapeutic-efficacy-of-il-12-intratumoral-gene-electrotransfer-through-novel-plasmid-design-and-modified-parameters
#17
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...
April 2018: Gene Therapy
https://www.readbyqxmd.com/read/29350683/ccat1-stimulation-of-the-symmetric-division-of-nsclc-stem-cells-through-activation-of-the-wnt-signalling-cascade
#18
C Xu, G Xiao, B Zhang, M Wang, J Wang, D Liu, J Zhang, H Ren, X 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 2018: Gene Therapy
https://www.readbyqxmd.com/read/29350682/conditional-replication-of-oncolytic-viruses-based-on-detection-of-oncogenic-mrna
#19
REVIEW
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
https://www.readbyqxmd.com/read/29350681/aav-9-mediated-phosphatase-1-inhibitor-1-overexpression-improves-cardiac-contractility-in-unchallenged-mice-but-is-deleterious-in-pressure-overload
#20
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
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