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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
Introduction 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, we investigated effects of retronectin-mediated T cell activation for CD19-specific CART cell production...
July 19, 2018: Human Gene Therapy
Yan Jiang, Yuanyuan Zhao, Fuchu He, Haijian Wang
Hepatic stellate cell (HSC) is the primary cell type responsible for liver fibrogenesis. TGF-β1 and PDGF are key profibrotic cytokines that regulate HSCs activation and proliferation with functional convergence. Dual RNA interference against their receptors may achieve therapeutic effects. We have devised a novel RNAi strategy based on HSCs specific GFAP promoter driven and lentivirally expressed artificial microRNAs (amiRNAs) that consist of microRNA-30a backbone and effective shRNAs against mouse Pdgfrβ and Tgfbr2, and tested their antifibrotic efficacy in primary and cultured HSCs and in mice affected with CCl4-induced hepatic fibrosis...
July 19, 2018: Human Gene Therapy
Jessica Bobula Foster, Namrata Choudhari, Jessica Perezzelli, Julie Storm, Ted J Hofmann, Payal Jain, Phillip B Storm, Norbert Pardi, Drew Weissman, Angela J Waanders, Stephan A Grupp, Katalin Kariko, Adam C Resnick, David Maxwell Barrett
T cells made with messenger RNA (mRNA) encoding chimeric antigen receptor (CAR) offer a safe alternative to those transduced with viral CARs by mitigating the side effects of constitutively active T cells. Previous studies have shown that mRNA CAR T cells are transiently effective, but lack persistence and potency across tumor types. We hypothesized that the efficacy of mRNA CARs could be improved by utilizing recent advancements in RNA technology, such as incorporating a modified nucleoside, 1-methylpseudouridine, into the mRNA and applying a novel purification method using RNase III to eliminate dsRNA contaminants...
July 19, 2018: Human Gene Therapy
Dimosthenis Giamouridis, Mei Hua Gao, N Chin Lai, Zhen Tan, Young Chul Kim, Tracy Guo, Atsushi Miyanohara, Matthijs W Blankesteijn, Erik A L Biessen, H Kirk Hammond
BACKGROUND: Peptide infusions of the corticotropin releasing factor family, including urocortin 2, stresscopin, and urocortin 3 (UCn3) have favorable acute effects in clinical heart failure (HF), but their short half-lives make them unsuited for chronic therapy. Here we ask whether UCn3 gene transfer, which provides sustained elevation of plasma UCn3 levels, increases function of the failing heart. METHODS: HF was induced by transmural left ventricular (LV) cryoinjury in mice...
July 13, 2018: Human Gene Therapy
Shuo Shi, Min Zhang, Rui Guo, Ying Miao, Biao Li
Bone marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. However, the optimal treatment time post-BMSCs implantation and the assessment of the long-term fate of therapeutic BMSCs post-tumor treatment are critical if such promising therapies are to be translated into clinical practice. Here, we have developed an efficient BMSCs based therapeutic strategy that simultaneously allows killing of tumor cells, inhibiting of tumor angiogenesis and assessment and eradication of implanted BMSCs after treatment of glioblastoma...
July 11, 2018: Human Gene Therapy
Anne-Kathrin Herrmann, Stefanie Grosse, Kathleen Börner, Chiara Krämer, Ellen Wiedtke, Manuel Gunkel, Dirk Grimm
Over the last decade, others and we have started to dissect the role of the assembly-activating protein AAP for the formation of Adeno-associated virus (AAV) capsids based on different viral serotypes. Recently, our group has specifically studied AAP's relevance during production of AAV gene therapy vectors in mammalian or insect cells, and found AAP to be essential for capsid protein stabilization and generation of functional vector particles. Here, we additionally addressed the lingering question whether molecular AAV evolution via DNA family shuffling of viral capsid genes would perturb AAP functionality due to concurrent and inadvertent recombination of the AAP open reading frame...
July 6, 2018: Human Gene Therapy
Shijie Zhang, Shushu Zhao, Xiang Jin, Bin Wang, Gan Zhao
DNA vaccines can elicit both humoral and cellular immune responses in mice. However, their poor immunogenicity is a major obstacle toward clinical applications. Improving the efficiency of delivery of DNA vaccines has become a key issue. Vaccination via microneedles penetrating the epidermis can dramatically enhance the stimulation of immune responses. In this study, we showed that by using microneedles to deliver DNA vaccines gene expression and corresponding immune responses were greatly improved compared to conventional needle injection...
July 3, 2018: Human Gene Therapy
Caitlin VanLith, Rebekah Guthman, Clara T Nicolas, Kari Allen, Zeji Du, Dong Jin Joo, Scott L Nyberg, Joseph B Lillegard, Raymond D Hickey
Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). It has been previously shown that ex vivo hepatocyte-directed gene therapy using an integrating lentiviral vector to replace the defective Fah gene can cure liver disease in small- and large-animal models of HT1. This study hypothesized that ex vivo hepatocyte-directed gene editing using CRISPR/Cas9 could be used to correct a mouse model of HT1, in which a single point mutation results in loss of FAH function...
June 22, 2018: Human Gene Therapy
Tristan McCaughey, David Mark Budden, Paul G Sanfilippo, George E C Gooden, Li Fan, Eva Fenwick, Gwyneth Rees, Casimir MacGregor, Lei Si, Christine Chen, Helena Hai Liang, Alice Pebay, Timothy Baldwin, Alex W Hewitt
BACKGROUND: The CRISPR/Cas system could provide an efficient and reliable means of editing the human genome and has the potential to revolutionise modern medicine; however, rapid developments are raising complex ethical issues. There has been significant scientific debate regarding the acceptability of some applications of CRISPR/Cas, with leaders in the field highlighting the need for the lay public's views to shape expert discussion. As such, we sought to determine the factors that influence public opinion on gene editing...
June 21, 2018: Human Gene Therapy
Ron Ofri, Edward Averbukh, Raaya Ezra-Elia, Maya Ross, Hen Honig, Alexey Obolensky, Alexander Rosov, William W Hauswirth, Elisha Gootwine, Eyal Banin
Achromatopsia causes severely reduced visual acuity, photoaversion and inability to discern colors due to cone photoreceptor dysfunction. In 2010, we reported on day blindness in sheep caused by a stop codon mutation of the ovine CNGA3 gene, and began gene augmentation therapy trials in this naturally occurring large animal model of CNGA3 achromatopsia. The purpose of this study was to evaluate long-term efficacy and safety results of treatment, findings that hold great relevance for clinical trials in CNGA3 achromatopsia patients that started recently...
June 21, 2018: Human Gene Therapy
Xintao Hu, Antonio Valentin, Yanhui Cai, Frances Dayton, Margherita Rosati, Eric G Ramírez-Salazar, Viraj Kulkarni, Kate E Broderick, Niranjan Y Sardesai, Linda S Wyatt, Patricia L Earl, Bernard Moss, James I Mullins, George N Pavlakis, Barbara K Felber
DNA-based vaccines able to induce efficient cytotoxic T-cell responses targeting conserved elements (CE) of human immunodeficiency virus type 1 (HIV-1) Gag have been developed. These CE were selected by stringent conservation, the ability to induce T-cell responses with broad human leukocyte antigen coverage, and the association between recognition of CE epitopes and viral control in HIV-infected individuals. Based on homology to HIV, a simian immunodeficiency virus p27gag CE DNA vaccine has also been developed...
June 21, 2018: Human Gene Therapy
Ahmet Hazini, Markian Pryshliak, Vanessa Brückner, Karin Klingel, Martina Sauter, Sandra Pinkert, Jens Kurreck, Henry Fechner
Coxsackievirus B3 (CVB3), a single-stranded RNA virus of the picornavirus family, has been described as a novel oncolytic virus. However, the CVB3 strain used induced hepatitis and myocarditis in vivo. It was hypothesized that oncolytic activity and safety of CVB3 depends on the virus strain and its specific receptor tropism. Different laboratory strains of CVB3 (Nancy, 31-1-93, and H3), which use the coxsackievirus and adenovirus receptor (CAR), and the strain PD, which uses N- and 6-O-sulfated heparan sulfate (HS) for entry into the cells, were investigated for their potential to lyse tumor cells and for their safety profile...
June 20, 2018: Human Gene Therapy
Eva Lichtenegger, Florestan Koll, Helena Haas, Klaus Mantwill, Klaus-Peter Janssen, Melanie Laschinger, Jürgen Gschwend, Katja Steiger, Peter Black, Igor Moskalev, Roman Nawroth, Per Sonne Holm
Muscle-invasive bladder cancer represents approximately 25% of patients diagnosed with bladder cancer and carries a significant risk of death. Oncolytic viruses (OV) are novel antitumor agents with the ability to selectively replicate and lyse tumor cells while sparing healthy tissue. Thus, we explored the efficiency of the oncolytic, YB-1 selective adenovirus XVir-N-31 in vitro and in an orthotopic mouse model for bladder cancer by intramural injection under ultrasound guidance. We demonstrated that XVir-N-31 replicates in bladder cancer cells and induced a stronger immunogenic cell death than adenovirus wildtype by facilitating enhanced release of HMGB1 and exosomal Hsp70...
June 19, 2018: Human Gene Therapy
Chen Xu, Dongning Liu, Zhixin Chen, Fan Zhuo, Huankui Sun, Jiaping Hu, Taiyuan Li
Colorectal cancer (CRC) is among cancers with highest incidence globally and currently ranks fourth as the leading cause of cancer-related deaths worldwide. It remains an urgent need for novel strategies in the management of patients with advanced CRC. Adoptive transfer of allogeneic natural killer (NK) cells represent an attractive option in the treatment of patients with CRC. In this study, we successfully expanded NK cells from umbilical cord blood (UCB) with membrane-bound IL-21, termed eUCB-NK cells. eUCB-NK cells efficiently lysed CRC cell lines in vitro and secreted significantly higher levels of IFN-γ, TNF-α, GM-CSF and CCL3 compared with IL-2 stimulated NK cells...
June 19, 2018: Human Gene Therapy
Allison May Keeler, Marina Zieger, Sophia Todeasa, Angela Mccall, Jennifer Gifford, Samantha Bircsak, Sourav Roy Choudhury, Barry J Byrne, Miguel Sena-Esteves, Mai K ElMallah
Pompe disease is an autosomal recessive glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption in muscle and central nervous system (CNS). Adeno-associated virus (AAV) gene therapy is ideal for Pompe disease since a single systemic injection may correct both muscle and CNS pathologies. Using the Pompe mouse, we sought to explore if AAVB1, a newly engineered vector with a high affinity for muscle and CNS, reduces systemic weakness and improves survival in adult mice...
June 14, 2018: Human Gene Therapy
Xiao Zhao, Juan Long, Fei Liang, Nan Liu, Yuying Sun, Yongzhi Xi
Antigen-specific tolerizing DNA vaccines are one of the most promising strategies for rheumatoid arthritis (RA) treatment, and act by inducing potent immune tolerance instead of generalized immunosuppression. Recently, we developed a novel antigen-specific tolerizing DNA vaccine coding for chicken type II collagen (pcDNA-CCOL2A1), and confirmed its potent therapeutic efficacy in an established rat model of collagen-induced arthritis (CIA). Here we report the prophylactic vaccination efficacy of a single 300ug/kg dose of pcDNA-CCOL2A1 against CIA incidence, severity, and onset...
June 14, 2018: Human Gene Therapy
Wenjie Hou, Min Mao, Zongji Shen, Youguo Chen, Chi Chi
Long non-coding RNAs are generally regarded as important regulators in various human diseases. As a lncRNA, HOXD-AS1 has been found to be a tumor promoter in ovarian cancer, glioma and lung cancer. However, the specific effects of HOXD-AS1 on the chemoresistance of cervical cancer cells are still not fully explored. Firstly, the level of HOXD-AS1 was tested in non-malignant tissues and CC tissues as well as in CC cells and cisplatin-resistant CC cells. As a result, HOXD-AS1 was overexpressed in CC tissues and cisplatin-resistant CC cells...
June 13, 2018: Human Gene Therapy
Xiao Liang, Li Liu, Yu-Quan Wei, Guangping Gao, Xiawei Wei
Considerable efforts have been devoted in the development of safe and efficient gene therapy for life-threatening or inherited diseases. The delivery alternatives play key roles in enhancing the therapeutic effect of nucleic cargo. To date, both the viral vectors and non-viral vectors were utilized and evaluated in clinical trials. With the improvement of material science and nanotechnologies, positively charged nanoparticles have emerged as potential gene delivery systems. In this review, we highlighted the clinical trials concerned with cationic nanocarrier mediated gene therapy...
June 12, 2018: Human Gene Therapy
Jenny Greig, Jayme Nordin, John White, Qiang Wang, Erin Bote, Tamara Goode, Roberto Calcedo, Samuel Wadsworth, Lili Wang, James M Wilson
Hemophilia A is a common hereditary bleeding disorder that is characterized by a deficiency of human blood coagulation factor VIII (hFVIII). Previous studies with adeno-associated viral (AAV) vectors identified two liver-specific promoter and enhancer combinations (E03.TTR and E12.A1AT) that drove high level expression of a codon-optimized, B-domain-deleted hFVIII transgene in a mouse model of the disease. Here, we further evaluated these enhancer/promoter combinations in cynomolgus macaques using two different AAV capsids (AAVrh10 and AAVhu37)...
June 11, 2018: Human Gene Therapy
Jagadeesh K Venkatesan, Franklin T Moutos, Ana Rey-Rico, Bradley T Estes, Janina Frisch, Gertrud Schmitt, Henning Madry, Farshid Guilak, Magali Cucchiarini
Combining gene therapy approaches with tissue engineering procedures is an active area of translational research for the effective treatment of articular cartilage lesions, especially to target chondrogenic progenitor cells such as those derived from the bone marrow. This study evaluated the effect of genetically modifying concentrated human mesenchymal stem cells from bone marrow to induce chondrogenesis by recombinant adeno-associated virus (rAAV) vector gene transfer of the sex-determining region Y-type high-mobility group box 9 (SOX9) factor upon seeding in three-dimensional-woven poly(ɛ-caprolactone; PCL) scaffolds that provide mechanical properties mimicking those of native articular cartilage...
June 11, 2018: Human Gene Therapy
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