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https://read.qxmd.com/read/30766894/novel-chimeric-gene-therapy-vectors-based-on-adeno-associated-virus-and-four-different-mammalian-bocaviruses
#1
Julia Fakhiri, Marc A Schneider, Jens Puschhof, Megan Stanifer, Verena Schildgen, Stefan Holderbach, Yannik Voss, Jihad El Andari, Oliver Schildgen, Steeve Boulant, Michael Meister, Hans Clevers, Ziying Yan, Jianming Qiu, Dirk Grimm
Parvoviruses are highly attractive templates for the engineering of safe, efficient, and specific gene therapy vectors, as best exemplified by adeno-associated virus (AAV). Another candidate that currently garners increasing attention is human bocavirus 1 (HBoV1). Notably, HBoV1 capsids can cross-package recombinant (r)AAV2 genomes, yielding rAAV2/HBoV1 chimeras that specifically transduce polarized human airway epithelia (pHAEs). Here, we largely expanded the repertoire of rAAV/BoV chimeras, by assembling packaging plasmids encoding the capsid genes of four additional primate bocaviruses, HBoV2-4 and GBoV (Gorilla BoV)...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/30748001/viral-vector-mediated-cre-recombinase-expression-in-substantia-nigra-induces-lesions-of-the-nigrostriatal-pathway-associated-with-perturbations-of-dopamine-related-behaviors-and-hallmarks-of-programmed-cell-death
#2
Sara Rezai Amin, Carole Gruszczynski, Bruno P Guiard, Jacques Callebert, Jean-Marie Launay, Franck Louis, Catalina Betancur, Vincent Vialou, Sophie Gautron
Cre/loxP recombination is a widely used approach to study gene function in vivo, using mice models expressing the Cre recombinase under the control of specific promoters or through viral delivery of Cre-expressing constructs. A profuse literature on transgenic mouse lines points out the deleterious effects of Cre expression in various cell types and tissues, presumably by acting on illegitimate loxP-like sites present in the genome. However, most studies reporting the consequences of Cre-lox gene invalidation often omit adequate controls to exclude the potential toxic effects of Cre, compromising the interpretation of data...
February 12, 2019: Journal of Neurochemistry
https://read.qxmd.com/read/30740517/centrifugal-innervation-of-the-olfactory-bulb-a-reappraisal
#3
Estelle E In 't Zandt, Hillary L Cansler, Heather B Denson, Daniel W Wesson
The inter-regional connectivity of sensory structures in the brain allows for the modulation of sensory processing in manners important for perception. In the olfactory system, odor representations in the olfactory bulb (OB) are modulated by feedback centrifugal innervation from several olfactory cortices, including the piriform cortex (PCX) and anterior olfactory nucleus (AON). Previous studies reported that an additional olfactory cortex, the olfactory tubercle (OT), also centrifugally innervates the OB and may even shape the activity of OB output neurons...
January 2019: ENeuro
https://read.qxmd.com/read/30735971/sustained-somatostatin-gene-expression-reverses-kindling-induced-increases-in-the-number-of-dividing-type-1-neural-stem-cells-in-the-hippocampi-of-behaviorally-responsive-rats
#4
Jeffrey A Leibowitz, Gowri Natarajan, Junli Zhou, Paul R Carney, Brandi K Ormerod
Neurogenesis persists throughout life in the hippocampi of all mammals, including humans. In the healthy hippocampus, relatively quiescent Type-1 neural stem cells (NSCs) can give rise to more proliferative Type-2a neural progenitor cells (NPCs), which generate neuronal-committed Type-2b NPCs that mature into Type-3 neuroblasts. Many Type-3 neuroblasts survive and mature into functionally integrated granule neurons over several weeks. In kindling models of epilepsy, neurogenesis is drastically upregulated and many new neurons form aberrant connections that could support epileptogenesis and/or seizures...
January 11, 2019: Epilepsy Research
https://read.qxmd.com/read/30735101/bax-inhibitor-1-overexpression-in-prelimbic-cortex-protects-rats-against-depression-like-behavior-induced-by-olfactory-bulbectomy-and-reduces-apoptotic-and-inflammatory-signals
#5
Dao Li, Zhou Cai, Ji Wu, Yan Zhang
BACKGROUND AND PURPOSE: Depression is a mental disorder characterized by a pervasive low mood and loss of pleasure or interest in usual activities, and often results in the impairment of learning and memory. Bax inhibitor-1 (BI-1) has been reported to be involved in the pathological mechanisms for neurodegenerative disorders including depression. Here, we aimed to investigate the role of BI-1 in regulating depression-like behavior induced by olfactory bulbectomy (OB) in rats and the possible mechanism...
February 8, 2019: Neurological Research
https://read.qxmd.com/read/30734931/pink1-regulates-fkbp5-interaction-with-akt-phlpp-and-protects-neurons-from-neurotoxin-stress-induced-by-mpp
#6
Wassamon Boonying, Alvin Joselin, En Huang, Dianbo Qu, Farzaneh Safarpour, Grace O Iyirhiaro, Yasmilde Rodriguez Gonzalez, Steve M Callaghan, Ruth S Slack, Daniel Figeys, Young-Hwa Chung, David S Park
Loss of function mutations in the PTEN-induced putative kinase 1 (Pink1) gene have been linked with an autosomal recessive familial form of early onset Parkinson's disease (PD). However, the underlying mechanism(s) responsible for degeneration remains elusive. Presently, using co-immunoprecipitation in HEK (Human embryonic kidney) 293 cells, we show that Pink1 endogenously interacts with FK506-binding protein 51 (FKBP51) FKBP5 and directly phosphorylates FKBP5 at Serine in an in vitro kinase assay. Both FKBP5 and Pink1 have been previously associated with protein kinase B (AKT) regulation...
February 8, 2019: Journal of Neurochemistry
https://read.qxmd.com/read/30734456/glutamatergic-neurons-in-the-medial-prefrontal-cortex-mediate-the-formation-and-retrieval-of-cocaine-associated-memories-in-mice
#7
Tong Zhang, Junko Yanagida, Hironori Kamii, Shintaro Wada, Masaki Domoto, Hitoki Sasase, Satoshi Deyama, Takeshi Takarada, Eiichi Hinoi, Kenji Sakimura, Akihiro Yamanaka, Takashi Maejima, Michihiro Mieda, Takeshi Sakurai, Naoya Nishitani, Kazuki Nagayasu, Shuji Kaneko, Masabumi Minami, Katsuyuki Kaneda
In drug addiction, environmental stimuli previously associated with cocaine use readily elicit cocaine-associated memories, which persist long after abstinence and trigger cocaine craving and consumption. Although previous studies suggest that the medial prefrontal cortex (mPFC) is involved in the expression of cocaine-addictive behaviors, it remains unclear whether excitatory and inhibitory neurons in the mPFC are causally related to the formation and retrieval of cocaine-associated memories. To address this issue, we used the designer receptors exclusively activated by designer drugs (DREADD) technology combined with a cocaine-induced conditioned place preference (CPP) paradigm...
February 7, 2019: Addiction Biology
https://read.qxmd.com/read/30733670/transduction-of-adeno-associated-virus-vectors-targeting-hair-cells-and-supporting-cells-in-the-neonatal-mouse-cochlea
#8
Xi Gu, Renjie Chai, Luo Guo, Biao Dong, Wenyan Li, Yilai Shu, Xinsheng Huang, Huawei Li
Adeno-associated virus (AAV) is the preferred vector for gene therapy of hereditary deafness, and different viral serotypes, promoters and transduction pathways can influence the targeting of AAV to different types of cells and the expression levels of numerous exogenous genes. To determine the transduction and expression patterns of AAV with different serotypes or promoters in hair cells and supporting cells in the neonatal mouse cochlea, we examined the expression of enhanced green fluorescent protein (eGFP) for five different types of AAV vectors [serotypes 2, 9, and Anc80L65 with promoter cytomegalovirus (CMV)-beta-Globin and serotypes 2 and 9 with promoter chicken beta-actin (CBA)] in in vitro cochlear explant cultures and we tested the transduction of AAV2/2-CBA, AAV2/9-CBA, and AAV2/Anc80L65-CMV by in vivo microinjection into the scala media of the cochlea...
2019: Frontiers in Cellular Neuroscience
https://read.qxmd.com/read/30719486/trans-ocular-electric-current-in-vivo-enhances-aav-mediated-retinal-gene-transduction-after-intravitreal-vector-administration
#9
Hongman Song, Ronald A Bush, Yong Zeng, Haohua Qian, Zhijian Wu, Paul A Sieving
Adeno-associated virus (AAV) vector-mediated gene delivery is a promising approach for therapy, but implementation in the eye currently is hampered by the need for delivering the vector underneath the retina, using surgical application into the subretinal space. This limits the extent of the retina that is treated and may cause surgical injury. Vector delivery into the vitreous cavity would be preferable because it is surgically less invasive and would reach more of the retina. Unfortunately, most conventional, non-modified AAV vector serotypes penetrate the retina poorly from the vitreous; this limits efficient transduction and expression by target cells (retinal pigment epithelium and photoreceptors)...
June 14, 2019: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/30713782/mannan-binding-lectin-suppresses-growth-of-hepatocellular-carcinoma-by-regulating-hepatic-stellate-cell-activation-via-the-erk-cox-2-pge-2-pathway
#10
Junru Li, Huifang Li, Yu Yu, Yan Liu, Yunzhi Liu, Qiang Ma, Liyun Zhang, Xiao Lu, Xiang-Yang Wang, Zhengliang Chen, Daming Zuo, Jia Zhou
Mannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain largely unknown. Here, using a murine hepatocellular carcinoma (HCC) model, we showed that MBL was a component of liver microenvironment and MBL-deficient (MBL-/- ) mice exhibited an enhanced tumor growth compared with wild-type (WT) mice...
2019: Oncoimmunology
https://read.qxmd.com/read/30706391/aav-production-using-baculovirus-expression-vector-system
#11
Quentin Sandro, Karima Relizani, Rachid Benchaouir
Gene transfer and gene therapy are powerful approaches for many biological research applications and promising avenues for the treatment of many genetic or cancer diseases. The most efficient gene transfer tools are currently derived from viruses. Among them, the recombinant adeno-associated viruses (AAVs) are vectors of choice for many fundamental and therapeutic applications. The increasing number of clinical trials involving AAVs demonstrates the need to implement production and purification processes to meet the quantitative and qualitative demands of regulatory agencies for the use of these vectors in clinical trials...
2019: Methods in Molecular Biology
https://read.qxmd.com/read/30705921/preclinical-development-of-an-aav8-hugt1a1-vector-for-the-treatment-of-crigler-najjar-syndrome
#12
Fanny Collaud, Giulia Bortolussi, Laurence Guianvarc'h, Sem J Aronson, Thierry Bordet, Philippe Veron, Severine Charles, Patrice Vidal, Marcelo Simon Sola, Stephanie Rundwasser, Delphine G Dufour, Florence Lacoste, Cyril Luc, Laetitia V Wittenberghe, Samia Martin, Christine Le Bec, Piter J Bosma, Andres F Muro, Giuseppe Ronzitti, Matthias Hebben, Federico Mingozzi
Adeno-associated viruses (AAVs) are among the most efficient vectors for liver gene therapy. Results obtained in the first hemophilia clinical trials demonstrated the long-term efficacy of this approach in humans, showing efficient targeting of hepatocytes with both self-complementary (sc) and single-stranded (ss) AAV vectors. However, to support clinical development of AAV-based gene therapies, efficient and scalable production processes are needed. In an effort to translate to the clinic an approach of AAV-mediated liver gene transfer to treat Crigler-Najjar (CN) syndrome, we developed an (ss)AAV8 vector carrying the human UDP-glucuronosyltransferase family 1-member A1 (hUGT1A1) transgene under the control of a liver-specific promoter...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/30705425/sirt1-in-forebrain-excitatory-neurons-produces-sexually-dimorphic-effects-on-depression-related-behaviors-and-modulates-neuronal-excitability-and-synaptic-transmission-in-the-medial-prefrontal-cortex
#13
Yun Lei, Jiangong Wang, Dan Wang, Chen Li, Bin Liu, Xing Fang, Jingjing You, Ming Guo, Xin-Yun Lu
Sirtuin 1 (SIRT1), an NAD+ -dependent deacetylase, is a key regulator of cellular metabolism. Recent genome-wide association studies identified genetic variants of SIRT1 linked to major depressive disorders. SIRT1 is widely expressed in the brain; however, neuronal substrates that mediate SIRT1 action on depressive behaviors remain largely unknown. Here we show that selective deletion of SIRT1 in forebrain excitatory neurons causes depression-like phenotypes in male but not female mice. AAV-Cre-mediated SIRT1 knockdown in the medial prefrontal cortex (mPFC) of adult male mice induces depressive-like behaviors...
January 31, 2019: Molecular Psychiatry
https://read.qxmd.com/read/30696954/cancer-therapy-with-a-crispr-assisted-telomerase-activating-gene-expression-system
#14
Wei Dai, Xinhui Xu, Danyang Wang, Jian Wu, Jinke Wang
Cancer is caused by a series of alterations in genome and epigenome and exists in multiple complex forms, making it difficult to be prevented and/or treated. Telomerase, an enzyme responsible for the maintenance of telomere, is silent in most normal somatic cells but activated in 90% of cancer cells, making it an excellent target for cancer therapy. Therefore, various telomerase activity inhibitors have been developed to treat cancer but all failed due to side effects. Here we acted oppositely to develop a cancer gene therapy named telomerase-activating gene expression (Tage) system by utilizing the telomerase activity in cancer cells...
January 29, 2019: Oncogene
https://read.qxmd.com/read/30692604/safety-and-efficacy-evaluations-of-an-adeno-associated-virus-variant-for-preparing-il10-secreting-human-neural-stem-cell-based-therapeutics
#15
Mira Cho, Kwangsoo Jung, Seung-Hyun Kim, Il-Sun Kim, Miri Kim, Mikyung Shin, Haeshin Lee, Kook In Park, Jae-Hyung Jang
Gene therapy technologies are inevitably required to boost the therapeutic performance of cell therapies; thus, validating the efficacy of gene carriers specifically used for preparing cellular therapeutics is a prerequisite for evaluating the therapeutic capabilities of gene and cell combinatorial therapies. Herein, the efficacy of a recombinant adeno-associated virus derivative (rAAVr3.45) was examined to evaluate its potential as a gene carrier for genetically manipulating interleukin-10 (IL10)-secreting human neural stem cells (hNSCs) that can potentially treat ischemic injuries or neurological disorders...
January 28, 2019: Gene Therapy
https://read.qxmd.com/read/30675284/crispr-cas9-mediated-cervical-cancer-treatment-targeting-human-papillomavirus-e6
#16
Takahiro Yoshiba, Yasushi Saga, Masashi Urabe, Ryosuke Uchibori, Shigeki Matsubara, Hiroyuki Fujiwara, Hiroaki Mizukami
High-risk human papillomavirus (HPV) is a common cause of cervical cancer. HPV E6 oncoprotein promotes the degradation of host tumor suppressor gene p53 , leading to the development of tumors. Therapeutic strategies that specifically target E6, which is constitutively expressed in tumors and is not present in normal tissues, may be highly effective and safe. CRISPR-CRISPR associated protein 9 (Cas9) is one of the genome editing technologies that has recently garnered attention, and is used to knockout target gene expression...
February 2019: Oncology Letters
https://read.qxmd.com/read/30671314/evaluation-of-aav-dj-vector-for-retinal-gene-therapy
#17
Yusaku Katada, Kenta Kobayashi, Kazuo Tsubota, Toshihide Kurihara
Purpose: The most common virus vector used in gene therapy research for ophthalmologic diseases is the adeno-associated virus (AAV) vector, which has been used successfully in a number of preclinical and clinical studies. It is important to evaluate novel AAV vectors in animal models for application of clinical gene therapy. The AAV-DJ (type 2/type 8/type 9 chimera) was engineered from shuffling eight different wild-type native viruses. In this study, we investigated the efficiency of gene transfer by AAV-DJ injections into the retina...
2019: PeerJ
https://read.qxmd.com/read/30666318/recombinant-aav-cea-tumor-vaccine-in-combination-with-an-immune-adjuvant-breaks-tolerance-and-provides-protective-immunity
#18
Jonathan A Hensel, Vinayak Khattar, Reading Ashton, Selvarangan Ponnazhagan
Carcinoembryonic antigen (CEA) is a human glycoprotein involved in cellular adhesion and expressed during human fetal development. Although expression of CEA largely ceases prior to birth, several human epithelial cancers, including colorectal, gastric, squamous esophageal, and breast carcinomas have been known to overexpress CEA, suggesting its potential as an immunotherapeutic target. Using a transgenic mouse model constitutively expressing human CEA in a spatiotemporal manner as a self-protein and a syngeneic mouse colon cancer cell line, MC38-CEA, overexpressing CEA, we tested the potential of a novel genetic immunotherapy approach against CEA-expressing tumors, using recombinant adeno-associated virus vector encoding CEA (rAAV-CEA) and appropriately timed immune adjuvant application...
March 29, 2019: Molecular Therapy Oncolytics
https://read.qxmd.com/read/30666309/adeno-associated-viral-vector-2-and-9-transduction-is-enhanced-in-streptozotocin-induced-diabetic-mouse-retina
#19
Si Hyung Lee, Jin Young Yang, Sanjar Madrakhimov, Ha Yan Park, Keerang Park, Tae Kwann Park
Adeno-associated viruses (AAVs) are currently the most popular vector platform technology for ocular gene therapy. While transduction efficiency and tropism of intravitreally administered AAV has been fairly well established in various retinal conditions, its transduction pattern in diabetic retinas has not previously been characterized. Here, we describe the transduction efficiencies of four different AAV serotypes, AAV2, 5, 8, and 9, in streptozotocin (STZ)-induced diabetic mouse retinas after intravitreal injections, which differed according to the duration of diabetic induction...
June 14, 2019: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/30654371/the-hpv16-e1-carboxyl-domain-provides-a-helper-function-for-adeno-associated-virus-replication
#20
Maohua Cao, Sarmistha Bandyopadhyay, Hongqing Zhu, Hong You, Paul L Hermonat
BACKGROUND/AIMS: Recombinant adeno-associated virus (rAAV) is now in the clinic, yet production of rAAV remains problematic. We previously determined that human papillomavirus type 16 (HPV16) E1 protein boosts rAAV yields and E1 enhances AAV Rep78's replication-related biochemistries. Here, we deletion-mapped the helper domain within E1 to help glean its mechanism of action. METHODS: Rep78-E1 interaction was analyzed by Gal4-based yeast two-hybrid (Y2H)-cDNA assay...
January 17, 2019: Intervirology
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