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Human Gene Therapy

Margarita Garcia, Rafael Moreno, Marta Gil, Manel Cascallo, Maria Ochoa de Olza, Carmen Cuadra, Josep Maria Piulat, Valentin Navarro, Marta Domenech, Ramon Alemany, Ramon Salazar
Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in USA and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically...
September 20, 2018: Human Gene Therapy
Amanda M Hamilton, Paula J Foster, John A Ronald
Reporter gene-based molecular imaging can provide invaluable information on the fate of cellular therapies postimplantation. Integrating lentiviral vectors (ILVs) are commonly used for stably engineering cells; however, their potential for insertional mutagenesis poses a significant safety concern and barrier to widespread clinical adoption. In cells that slowly divide or are postmitotic in vivo, such as mesenchymal stem cells (MSCs), nonintegrating lentiviral vectors (NILVs) may be a safer alternative option because NILVs remain episomal and can provide prolonged expression profiles...
September 14, 2018: Human Gene Therapy
Mark Basche, Daniel Kampik, Satoshi Kawasaki, Matthew J Branch, Martha Robinson, D Frank Larkin, Alexander J Smith, Robin R Ali
Corneal epithelial dystrophies are typically characterized by symptoms such as pain, light sensitivity, and corneal opacification leading to impaired vision. The development of gene therapy for such conditions has been hindered by an inability to achieve sustained and extensive gene transfer, as the epithelium is highly replicative and has evolved to exclude foreign material. We undertook a comprehensive study in mice aiming to overcome these impediments. Direct injection of lentiviral vector within the stem cell niche resulted in centripetal streaks of epithelial transgene expression sustained for >1 year, indicating limbal epithelial stem cell transduction in situ...
September 14, 2018: Human Gene Therapy
Shuaishuai Huang, Yu Ren, Xue Wang, Lissy Lazar, Suya Ma, Guobin Weng, Jinshun Zhao
Chronic renal disease or acute renal injury could result in end-stage renal disease or renal failure. Sonoporation, induced by ultrasound-targeted microbubble destruction (UTMD), evolved as a new technology for gene delivery. It increased the transfection efficiency of the genes into target kidney tissues. Moreover, UTMD-mediated gene delivery can directly repair the damaged tissues or improve the recruitment and homing of stem cells in the recovery of injured tissues, which has the potential to act as a non-viral and effective method to current gene therapy...
September 11, 2018: Human Gene Therapy
Bing Li, Zulong Sheng, Chang Liu, Linglin Qian, Yuehuan Wu, Yanping Wu, Genshan Ma, Yuyu Yao
Kallistatin has been recognized as a plasma protein with anti-inflammatory functions. Macrophages are the primary inflammatory cells in atherosclerotic plaques. However, it is unknown whether kallistatin plays a role in macrophage development and the pathogenesis of atherosclerosis. Herein, we investigated the role of kallistatin in macrophage development, a key pathological process in atherosclerosis. We established an atherosclerosis model in apoE-/- mice via partial left carotid artery (PLCA) ligation. An adenoviral vector (Ad...
September 11, 2018: Human Gene Therapy
Penghui Yang, Fang Sun, Ruilan Wang, Guanglin Lei, Hongjing Gu, Yueqiang Duan, Zhongpeng Zhao, Xiaolan Yang, Zhaohai Wang, Shaogeng Zhang, Xiliang Wang
Oncolytic virotherapy is a promising strategy for the treatment of cancer. Influenza A virus (IAV) has shown potential as an oncolytic agent. In this study, we generated a recombinant PR8 influenza viral vector, called delNS1-GM-CSF, with a partial deletion in NS and the granulocyte-macrophage colony-stimulating factor (GM-CSF) coding sequence inserted into the influenza nonstructural protein 1 gene. The morphological characteristics of delNS1-GM-CSF were examined. The delNS1-GM-CSF virus replicated well in various cell lines, including MDCK, A549, SMCC7721, and HepG2 cells...
September 11, 2018: Human Gene Therapy
Marina Cavazzana, Fulvio Mavilio
Gene therapy for β-thalassemia and sickle cell disease is based on transplantation of genetically corrected, autologous hematopoietic stem cells. Pre-clinical and clinical studies have shown the safety and efficacy of this therapeutic approach, currently based on lentiviral vectors to transfer a β-globin gene under the transcriptional control of regulatory elements of the β-globin locus. Nevertheless, a number of factors are still limiting its efficacy, such as limited stem cell dose and quality, suboptimal gene transfer efficiency and gene expression levels and toxicity of myeloablative regimens...
September 10, 2018: Human Gene Therapy
Joana Serra, Cláudia P A Alves, Liliana Brito, Gabriel A Monteiro, Joaquim M S Cabral, Duarte Miguel F Prazeres, Cláudia Lobato da Silva
Peripheral artery disease (PAD) is a debilitating and prevalent condition characterized by the blockage of arteries, leading to limb amputation in more severe cases. Mesenchymal stem/stromal cells (MSC) are known to have intrinsic regenerative properties that can be potentiated by the introduction of pro-angiogenic genes such as the vascular endothelial growth factor (VEGF). Herein we propose the use of human bone marrow (BM) MSC transiently transfected with minicircles encoding for VEGF as an <i>ex vivo</i> gene therapy strategy to enhance angiogenesis in PAD patients...
September 10, 2018: Human Gene Therapy
Fabrizia Urbinati, Beatriz Campo Fernandez, Katelyn E Masiuk, Valentina Poletti, Roger P Hollis, Colin Koziol, Michael Kaufman, Devin Brown, Fulvio Mavilio, Donald B Kohn
Sickle cell disease is an inherited blood disorder caused by a single amino acid substitution in the β-globin chain of hemoglobin. Gene therapy is a promising therapeutic alternative, particularly in patients lacking an allogeneic bone marrow donor. One of the major challenges for an effective gene therapy approach is the design of an efficient vector that combines high-level and long term β-globin expression with high infectivity in primary CD34+ cells. We directly compared two lentiviral vectors carrying an anti-sickling β-globin transgene (AS3): the Lenti/βAS3-FB and Globe-AS3 with and without the FB insulator...
September 10, 2018: Human Gene Therapy
Wei Wei, Jianhui Luo
Cell therapy has emerged as a promising new treatment in medicine, which is expected to be able to cure diseases by repairing, replacing, and regenerating tissues, as well as immune-modulation. However, challenges remain in ensuring consistent quality, clinical efficacy and safety profiles because of the diversity of cell types and clinical indications for cell therapy products (CTPs), as well as different and complex manufacturing process. Therefore, scientific consensus and regulatory measurements are urgently warranted to promote the translation of the latest scientific advances and innovative manufacturing technologies into clinical application...
September 10, 2018: Human Gene Therapy
Omar Akil, Bas Blits, Lawrence R Lustig, Patricia A Leake
Contemporary cochlear implants (CI) are generally very effective for remediation of severe to profound sensorineural hearing loss, but outcomes are still highly variable. Auditory nerve survival is likely one of the major factors underlying this variability. Neurotrophin therapy therefore has been proposed for CI recipients, with the goal of improving outcomes by promoting improved survival of cochlear spiral ganglion neurons (SGN) and/or residual hair cells. Previous studies have shown that glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor, and neurotrophin-3 can rescue SGNs following insult...
September 5, 2018: Human Gene Therapy
Danyang Wang, Wei Dai, Jinke Wang
In recent years, the immunotherapy greatly contributes to the cancer treatment. However, the current cancer immunotherapies are still seriously prevented by the limited cancer cell-specific antigens. Therefore, scientists have to look for neoantigens by tumor sequencing and bioinformatics prediction for developing personalized cancer vaccines. Anyway, this is still an expensive, challenging and long-term exploration. Here we testified a new immunotherapy for cancers by developing a cancer cell-specific gene expression technique that employed a NF-κB-activating gene expression vector to express a protein or peptide on cancer cell surface...
September 5, 2018: Human Gene Therapy
Sophia Stock, Jean-Marc Hoffmann, Maria-Luisa Schubert, Lei Wang, Sanmei Wang, Wenjie Gong, Brigitte Neuber, Ulrike Gern, Anita Schmitt, Carsten Müller-Tidow, Peter Dreger, Michael Schmitt, Leopold Sellner
Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin-mediated T-cell activation for CD19-specific CART cell production...
September 5, 2018: Human Gene Therapy
Chen Xu, Dongning Liu, Zhixin Chen, Fan Zhuo, Huankui Sun, Jiaping Hu, Taiyuan Li
Colorectal cancer (CRC) is among the cancers with the highest incidence globally, and it currently ranks as the fourth leading cause of cancer-related deaths worldwide. Novel strategies for the treatment of advanced CRC are urgently needed, and adoptive transfer of allogeneic natural killer (NK) cells represents an attractive option. In this study, we successfully expanded NK cells from umbilical cord blood (UCB) with membrane-bound interleukin (IL)-21, termed eUCB-NK cells. eUCB-NK cells efficiently lysed CRC cell lines in vitro and secreted significantly higher levels of interferon-γ, tumor necrosis factor-α, granulocyte-macrophage colony stimulating factor, and chemokine ligand 3 compared with IL-2-stimulated NK cells...
September 5, 2018: Human Gene Therapy
Chi Chi, Min Mao, Zongji Shen, Youguo Chen, Jie Chen, Wenjie Hou
Long noncoding RNAs (lncRNAs) are important regulators in various human diseases. The lncRNA HOXD-AS1 is a tumor promoter in ovarian cancer, glioma, and lung cancer, but the specific effects of HOXD-AS1 on cervical cancer (CC) chemoresistance remain unclear. Here, the level of HOXD-AS1 in nonmalignant and CC tissues as well as in CC cells and cisplatin-resistant CC cells was determined. qRT-PCR indicated that HOXD-AS1 was overexpressed in CC tissues and cisplatin-resistant CC cells. Loss-of-function assays showed that downregulation of HOXD-AS1 expression suppressed chemoresistance of cisplatin-resistant CC cells...
September 5, 2018: Human Gene Therapy
Xiao Liang, Li Liu, Yu-Quan Wei, Guang-Ping Gao, Xia-Wei Wei
Considerable efforts have been devoted to develop safe and efficient gene therapies for life-threatening or inherited diseases. The choice of gene delivery vehicle plays key roles in enhancing the therapeutic effect of nucleic acid cargo. To date, gene therapy approaches involving both viral vectors and nonviral vectors have been evaluated in clinical trials. With improvements in material science and nanotechnologies, positively charged nanoparticles have emerged as potential gene delivery vehicles. In this review, we highlight clinical trials that examined cationic nanocarrier-mediated gene therapy as well as discuss both the toxicity and efficacy of nanocarrier-based therapeutics...
September 5, 2018: Human Gene Therapy
Christopher B Doering, Gabriela Denning, Jordan Shields, Eli J Fine, Ernest T Parker, Alok Srivastava, Pete Lollar, H Trent Spencer
Genetically-modified, autologous hematopoietic stem and progenitor cells (HSPCs) represent a new class of genetic medicine. Following this therapeutic paradigm, we are developing a product candidate, designated CD68-ET3-LV CD34<sup>+</sup>, for the treatment of the severe bleeding disorder, hemophilia A. The product consists of autologous CD34<sup>+</sup> cells transduced with a human immunodeficiency virus-1-based, monocyte lineage-restricted, self-inactivating lentiviral vector (LV), termed CD68-ET3-LV, encoding a bioengineered coagulation factor VIII (fVIII) transgene, termed ET3, designed for enhanced expression...
August 30, 2018: Human Gene Therapy
Michael A Morgan, Axel Schambach
Successful translation of chimeric antigen receptor (CAR) T cells designed to target and eradicate CD19+ lymphomas has emboldened scientists and physicians worldwide to explore the possibility of applying CAR T-cell technology to other tumor entities, including solid tumors. Next-generation strategies such as fourth-generation CARs (CAR T cells redirected for universal cytokine killing, also known as TRUCKs) designed to deliver immunomodulatory cytokines to the tumor microenvironment, dual CAR designs to improve tumor control, inclusion of suicide genes as safety switches, and precision genome editing are currently being investigated...
August 29, 2018: Human Gene Therapy
Patricia Mercier-Letondal, Chrystel Marton, Marina Deschamps, Christophe Ferrand, Charline Vauchy, Clément Chenut, Aurélie Baguet, Olivier Adotévi, Christophe Borg, Jeanne Galaine, Yann Godet
High risk human papillomavirus (HPV) infection is a causal factor in oropharyngeal and gynecological malignancies, enabling HPV-targeted immunotherapy development to treat patients suffering from these cancers. T cell-mediated adoptive immunotherapy targeting E6 and E7, two HPV16 proteins consistently expressed in tumor cells, appears to be both attractive and safe. However, isolation of HPV-specific T cells is difficult due to the low frequency of these cell precursors in the peripheral blood, and HPV-positive cancer cells often down-regulate major histocompatibility complex (MHC) class I expression <i>ex vivo</i> limiting the efficacy of MHC class I-restricted approaches...
August 23, 2018: Human Gene Therapy
Francesco Galli, Laricia Bragg, Linda Meggiolaro, Maira Rossi, Miriam Caffarini, Naila Naz, Sabrina Santoleri, Giulio Cossu
In the last few years there has been significant advance in pre-clinical and clinical work of gene and cell therapy for muscular dystrophy. At the time of writing several trials are ongoing and more are expected to start. It is thus a time of expectation, even though many hurdles remain and it is unclear now whether they will be solved by current strategies or further improvements will be necessary.
August 22, 2018: Human Gene Therapy
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