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Human Gene Therapy

Caitlin VanLith, Rebekah Guthman, Clara T Nicolas, Kari Allen, Zeji Du, Dong Jin Joo, Scott L Nyberg, Joseph B Lillegard, Raymond Daniel 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. In this study, we 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...
May 15, 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 used CVB3 strain induced hepatitis and myocarditis in vivo. We hypothesized that oncolytic activity and safety of CVB3 depends on the virus strain and its specific receptor tropism. We investigated different laboratory strains of CVB3 (Nancy, 31-1-93, H3) which use the coxsackievirus and adenovirus receptor (CAR) and the strain PD which uses N- and 6-O-sulfated heparin sulfate (HS) for entry into the cells, for their potential to lyse tumor cells and for their safety profile...
May 9, 2018: Human Gene Therapy
Christina Schug, Wolfgang Sievert, Sarah Urnauer, Andrea Maria Müller, Kathrin Alexandra Schmohl, Alexandra Wechselberger, Nathalie Schwenk, Kirsten Lauber, Markus Schwaiger, Gabriele Multhoff, Ernst Wagner, Peter J Nelson, Christine Spitzweg
The tumor-homing properties of mesenchymal stem cells (MSC) have led to their development as delivery vehicles for the targeted delivery of therapeutic genes such as the sodium iodide symporter (NIS) to solid tumors. External beam radiation therapy (EBRT) may represent an ideal setting for the application of engineered MSC-based gene therapy as tumor irradiation may enhance MSC recruitment into irradiated tumors through the increased production of select factors linked to MSC migration. In the present study, the irradiation of human liver cancer cells (HuH7) (1-10 Gy) showed a strong dose-dependent increase in steady state mRNA levels of CXCL8, CXCL12/SDF-1, FGF2, PDGFβ, TGFβ1, TSP-1 and VEGF (0-48 h), which was verified for most factors at the protein level (after 48 h)...
May 4, 2018: Human Gene Therapy
Jagadeesh Kumar 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. Here, we evaluated the effect of genetically modifying concentrated human mesenchymal stem cells from bone marrow to induce chondrogenesis by recombinant adeno-associated viral (rAAV) vector gene transfer of the sex-determining region Y-type high-mobility group box 9 (SOX9) factor upon seeding in three-dimensional (3D) woven poly(ε-caprolactone) (PCL) scaffolds that provide mechanical properties mimicking those of native articular cartilage...
May 2, 2018: Human Gene Therapy
Bian Hu, Yan Zou, Linlin Zhang, Jiaxing Tang, Gabriele Niedermann, Elke Firat, Xingxu Huang, Xuekai Zhu
CRISPR/Cas9-mediated PD-1 disruption in chimeric antigen receptor (CAR) T cells could be an appealing choice to improve the therapeutic efficacy of CAR T cells in an immunosuppressive tumor microenvironment. In most of the reported cases, Cas9 was delivered into T cells by way of electroporation with RNA or protein. However, transient expression of Cas9 by transfection with a plasmid encoding its gene is apparently simpler, as it avoids the steps of <i>in vitro</i> transcription of DNA or protein production...
April 28, 2018: Human Gene Therapy
Lijuan Yin, Siqi Hu, Shan Mei, Hong Sun, Fengwen Xu, Jian Li, Weijun Zhu, Xiaoman Liu, Fei Zhao, Di Zhang, Shan Cen, Chen Liang, Fei Guo
CRISPR/Cas9 is an adaptive immune system that bacteria and archaea have evolved to resist the invading viruses and plasmid DNA by creating site-specific double-strand breaks in DNA. In this study, we have tested this gene editing system in inhibiting HIV-1 infection by targeting the viral long terminal repeat and the gene coding sequences. We observed strong inhibition of HIV-1 infection by Cas9/gRNA, which resulted not only from insertions and deletions (indels) that were introduced into viral DNA due to Cas9 cleavage, but also from the marked decrease in the levels of the late viral DNA products and the integrated viral DNA...
April 12, 2018: Human Gene Therapy
Lvxia Dai, Qu Pan, Yanjuan Peng, Sizhou Huang, Jianmin Liu, Tian Chen, Xin Wang, Dengbang Chen, Jiandong Wang, Yanfeng Zhu, Hui Wang, Yilun Liu, Yu Ou, Xiaoping Yu, Kang Cao
Cross-reacting material 197 (CRM197) is a mutant form of the diphtheria toxin. Recent studies have found that CRM197 exerts an experimental antitumor effect on several types of tumors. This study applied a novel treatment of adenovirus-mediated CRM197 (AdCRM197) to human ovarian cancer cells. Interestingly, it was found that A2780 cells were sensitive to AdCRM197, but SKOV3 cells were resistant to it. Since SKOV3 cells are p53 deletion cells, while A2780 cells are p53 wild-type cells, it was postulated that p53 might play a key role in AdCRM197-induced apoptosis...
April 5, 2018: Human Gene Therapy
Dongsheng Duan
Whole-body systemic gene therapy is likely the most effective way to reduce greatly the disease burden of Duchenne muscular dystrophy (DMD), an X-linked inherited muscle disease that leads to premature death in early adulthood. Genetically, DMD is due to null mutation of the dystrophin gene, one of the largest genes in the genome. Recent studies have shown highly promising improvements in animal models with intravascular delivery of the engineered micro-dystrophin gene by adeno-associated virus (AAV). Several human trials are now started to advance AAV micro-dystrophin therapy to DMD patients...
April 5, 2018: Human Gene Therapy
Qian Liu, Jianpeng Wang, Hongye Yang, Hua Gao, Chuzhong Li, Xiaolei Lan, Yazhuo Zhang
Invasiveness of growth hormone-producing pituitary adenomas (GHPAs) causes difficulties in safe and complete adenoma removal during surgery and often leads to high recurrence. Epidermal growth factor-like domain 7 (EGFL7) has been shown to be able to promote tumor angiogenesis, growth, invasiveness, and metastasis through the Notch signaling pathway. It was previously demonstrated that EGFL7 was overexpressed in GHPAs. This study reports that EGFL7 and Notch2 (positive correlation with EGFL7) are overexpressed in invasive GHPA...
April 2, 2018: Human Gene Therapy
Andrew Osborne, Aiden X Z Wang, Alessia Tassoni, Peter S Widdowson, Keith R Martin
Brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related receptor-B (TrkB) is an important signaling system for the maintenance and survival of neurons. Gene therapy using either recombinant adeno-associated virus (AAV) or lentiviral vectors can provide sustained delivery of BDNF to tissues where reduced BDNF signaling is hypothesized to contribute to disease pathophysiology. However, elevation in BDNF at target sites has been shown to lead to a downregulation of TrkB receptors, thereby reducing the effect of chronic BDNF delivery over time...
April 2, 2018: Human Gene Therapy
Chien-Fu Hung, Xuequn Xu, Linhong Li, Ying Ma, Qiu Jin, Angelia Viley, Cornell Allen, Pachai Natarajan, Rama Shivakumar, Madhusudan V Peshwa, Leisha A Emens
CD19-targeted chimeric antigen receptor (CAR) engineered T/natural killer (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to "on-target off-tumor" toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK cells may permit prospective control of "on-target off-tumor" toxicity...
April 2, 2018: Human Gene Therapy
Miaojin Zhou, Zhiqing Hu, Liyan Qiu, Tao Zhou, Mai Feng, Qian Hu, Baitao Zeng, Zhuo Li, Qianru Sun, Yong Wu, Xionghao Liu, Lingqian Wu, Desheng Liang
Spinal muscular atrophy (SMA) is a kind of neuromuscular disease characterized by progressive motor neuron loss in the spinal cord. It is caused by mutations in the survival motor neuron 1 (SMN1) gene. SMN1 has a paralogous gene, survival motor neuron 2 (SMN2), in humans that is present in almost all SMA patients. The generation and genetic correction of SMA patient specific induced pluripotent stem cells (iPSCs) is a viable, autologous therapeutic strategy for the disease. Here, we generated c-Myc-free and non-integrating iPSCs from the urine cells of an SMA patient using an episomal iPSC reprogramming vector and designed a unique crRNA that does not have similar sequences (≤3 mismatches) anywhere in the human reference genome...
March 29, 2018: Human Gene Therapy
Fumio Kurosaki, Ryosuke Uchibori, Yoshihide Sehara, Yasushi Saga, Masashi Urabe, Hiroaki Mizukami, Koichi Hagiwara, Akihiro Kume
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder with limited therapeutic options. An aberrant wound healing process in response to repetitive lung injury has been suggested for its pathogenesis, and a number of cytokines including transforming growth factor (TGF)-β1 play pivotal roles in the induction and progression of fibrosis. Thus, the regulation of these pro-inflammatory conditions may reduce the progression of IPF and ameliorate its symptoms in patients. Interleukin-10 (IL-10), a pleiotropic cytokine, exerts anti-inflammatory and anti-fibrotic effects in numerous biological settings...
March 29, 2018: Human Gene Therapy
Chun-Qing Song, Dan Wang, Tingting Jiang, Kevin O'Connor, Qiushi Tang, Lingling Cai, Xiangrui Li, Zhiping Weng, Hao Yin, Guangping Gao, Christian Mueller, Terence R Flotte, Wen Xue
CRISPR genome editing holds promise in the treatment of genetic diseases that currently lack effective long-term therapies. Patients with Alpha-1 Antitrypsin (AAT) deficiency develop progressive lung disease due to the loss of AAT's antiprotease function and liver disease due to a toxic gain of function of the common mutant allele. However, it remains unknown whether CRISPR-mediated AAT correction in the liver, where AAT is primarily expressed, can correct either or both defects. Here we show that AAV delivery of CRISPR can effectively correct Z-AAT mutation in the liver of a transgenic mouse model...
March 29, 2018: Human Gene Therapy
Anai Gonzalez Cordero, Debbie Goh, Kamil Kruczek, Arifa Naeem, Milan Fernando, Sophia-Martha Kleine Holthaus, Matsuki Takaaki, Samuel J I Blackford, Magdalena Kloc, Leticia Agundez, Robert D Sampson, Shyamanga Borooah, Patrick Ovando-Roche, Manjit S Mehat, Emma L West, Alexander J Smith, Rachael A Pearson, Robin R Ali
Adeno-associated viral vectors are showing great promise as gene therapy vectors for a wide range of retinal disorders. To date, evaluation of therapeutic approaches has depended almost exclusively on the use of animal models. With recent advances in human stem cell technology, stem-cell derived retina now offers the possibility to assess efficacy in human organoids in vitro. Here we test 6 AAV serotypes (AAV2/2, AAV2/9, AAV2/8, AAV2/8T(Y733F), AAV2/5 and ShH10) to determine their efficiency in transducing mouse and human pluripotent stem cell (PSC)-derived RPE and photoreceptor cells in vitro...
March 26, 2018: Human Gene Therapy
Belinda Kramer, Radhika Singh, Jessica Wischusen, Rebecca Dent, Amanda Rush, Shiloh Middlemiss, Yu Wooi Ching, Ian E Alexander, Geoffrey McCowage
Gene transfer targeting hematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in severe combined immunodeficiencies affecting T-cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. HSCs are also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit...
March 23, 2018: Human Gene Therapy
Nalinda B Wasala, Jin-Hong Shin, Yi Lai, Yongping Yue, Federica Montanaro, Dongsheng Duan
Heart disease is a major health threat for Duchenne/Becker muscular dystrophy patients and carriers. Expression of a 6-8 kb mini-dystrophin gene in the heart holds promise to change the disease course dramatically. However, the mini-dystrophin gene cannot be easily studied with adeno-associated virus (AAV) gene delivery because the size of the minigene exceeds AAV packaging capacity. Cardiac protection of the ΔH2-R19 minigene was previously studied using the cardiac-specific transgenic approach. Although this minigene fully normalized skeletal muscle force, it only partially corrected electrocardiogram and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy...
March 22, 2018: Human Gene Therapy
Julian Clauß, Matthias Obenaus, Csaba Miskey, Zoltán Ivics, Zsuzsanna Izsvák, Wolfgang Uckert, Mario Bunse
Transposon-based vectors have entered clinical trials as an alternative to viral vectors for genetic engineering of T cells. However, transposon vectors require DNA transfection into T cells which we found to cause adverse effects. T cell viability was decreased in a dose-dependent manner and DNA-transfected T cells showed a delayed response upon T cell receptor (TCR) stimulation with regard to blast formation, proliferation and surface expression of CD25 and CD28. Gene expression analysis demonstrated a DNA-dependent induction of a type I interferon response and IFN-β upregulation...
March 21, 2018: Human Gene Therapy
Yi Zeng, Haibo Si, Yuangang Wu, Yong Li, Fei Cao, Canfeng Li, Zhi-Yao He, Zhuo Chen, Bin Shen
Numbers of previous studies indicated that genetic variation at the collage type I alpha 1 gene (COLIA1) locus influences susceptibility to osteoporosis. However, seldom study reported the effect of gene delivery using an adenoviral vector carrying human recombinant COLIA1 cDNA on stimulating osteogenic activity of osteoblast and enhancing fracture healing of ovariectomized rats. Our current study was performed to demonstrate whether direct gene delivery using an adenoviral vector carrying human recombinant COLIA1 cDNA could stimulate osteogenic activity of osteoblast in vitro and enhance fracture healing of ovariectomized rats in vivo...
March 20, 2018: Human Gene Therapy
Hale M Tasyurek, Hasan Ali Altunbas, Mustafa Kemal Balci, Thomas S Griffith, Salih Sanlioglu
Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon-like peptide-1 (GLP-1)-a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accompanied by a moderate reduction in GLP-1 secretion...
March 20, 2018: Human Gene Therapy
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