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https://www.readbyqxmd.com/read/29779223/gene-editing-vectors-for-studying-nicotinic-acetylcholine-receptors-in-cholinergic-transmission
#1
Can Peng, Yijin Yan, Veronica J Kim, Staci E Engle, Jennifer N Berry, J Michael McIntosh, Rachael L Neve, Ryan M Drenan
Nicotinic acetylcholine receptors (nAChRs), prototype members of the cys-loop ligand gated ion channel family, are key mediators of cholinergic transmission in the central nervous system. Despite their importance, technical gaps exist in our ability to dissect the function of individual subunits in the brain. To overcome these barriers, we designed CRISPR/Cas9 small guide RNA sequences (sgRNAs) for production of loss-of-function alleles in mouse nAChR genes. These sgRNAs were validated in vitro via deep sequencing...
May 19, 2018: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29776328/recent-progress-and-considerations-for-aav-gene-therapies-targeting-the-central-nervous-system
#2
REVIEW
Erik Allen Lykken, Charles Shyng, Reginald James Edwards, Alejandra Rozenberg, Steven James Gray
BACKGROUND: Neurodevelopmental disorders, as a class of diseases, have been particularly difficult to treat even when the underlying cause(s), such as genetic alterations, are understood. What treatments do exist are generally not curative and instead seek to improve quality of life for affected individuals. The advent of gene therapy via gene replacement offers the potential for transformative therapies to slow or even stop disease progression for current patients and perhaps minimize or prevent the appearance of symptoms in future patients...
May 18, 2018: Journal of Neurodevelopmental Disorders
https://www.readbyqxmd.com/read/29775653/atomic-structure-of-a-rationally-engineered-gene-delivery-vector-aav2-5
#3
Matthew Burg, Claire Rosebrough, Lauren M Drouin, Antonette Bennett, Mario Mietzsch, Paul Chipman, Robert McKenna, Duncan Sousa, Mark Potter, Barry Byrne, R Jude Samulski, Mavis Agbandje-McKenna
AAV2.5 represents the first structure-guided in-silico designed Adeno-associated virus (AAV) gene delivery vector. This engineered vector combined the receptor attachment properties of AAV serotype 2 (AAV2) with the muscle tropic properties of AAV1, and exhibited an antibody escape phenotype because of a modified antigenic epitope. To confirm the design, the structure of the vector was determined to a resolution of 2.78 Å using cryo-electron microscopy and image reconstruction. The structure of the major viral protein (VP), VP3, was ordered from residue 219 to 736, as reported for other AAV structures, and the five AAV2...
May 15, 2018: Journal of Structural Biology
https://www.readbyqxmd.com/read/29774075/plectin-targeted-liposomes-enhance-the-therapeutic-efficacy-of-a-parp-inhibitor-in-the-treatment-of-ovarian-cancer
#4
Siva Sai Krishna Dasa, Galina Diakova, Ryo Suzuki, Anne M Mills, Michael F Gutknecht, Alexander L Klibanov, Jill K Slack-Davis, Kimberly A Kelly
Advances in genomics and proteomics drive precision medicine by providing actionable genetic alterations and molecularly targeted therapies, respectively. While genomic analysis and medicinal chemistry have advanced patient stratification with treatments tailored to the genetic profile of a patient's tumor, proteomic targeting has the potential to enhance the therapeutic index of drugs like poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors in breast and ovarian cancer patients with BRCA1/2 mutations have shown promise...
2018: Theranostics
https://www.readbyqxmd.com/read/29767307/virus-vector-mediated-genetic-modification-of-brain-tumor-stromal-cells-after-intravenous-delivery
#5
Adrienn Volak, Stanley G LeRoy, Jeya Shree Natasan, David J Park, Pike See Cheah, Andreas Maus, Zachary Fitzpatrick, Eloise Hudry, Kelsey Pinkham, Sheetal Gandhi, Bradley T Hyman, Dakai Mu, Dwijit GuhaSarkar, Anat O Stemmer-Rachamimov, Miguel Sena-Esteves, Christian E Badr, Casey A Maguire
The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively...
May 16, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29766031/a-rationally-engineered-capsid-variant-of-aav9-for-systemic-cns-directed-and-peripheral-tissue-detargeted-gene-delivery-in-neonates
#6
Dan Wang, Shaoyong Li, Dominic J Gessler, Jun Xie, Li Zhong, Jia Li, Karen Tran, Kim Van Vliet, Lingzhi Ren, Qin Su, Ran He, Jason E Goetzmann, Terence R Flotte, Mavis Agbandje-McKenna, Guangping Gao
Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766030/cre-recombinase-mediates-the-removal-of-bacterial-backbone-to-efficiently-generate-rsv40
#7
Xiaoxia Shi, Matthew Ryan Ykema, Jaco Hazenoot, Lysbeth Ten Bloemendaal, Irene Mancini, Machteld Odijk, Peter de Haan, Piter J Bosma
Gene therapy has been shown to be a feasible approach to treat inherited disorders in vivo . Among the currently used viral vector systems, adeno-associated virus (AAV) vectors are the most advanced and have been applied in patients successfully. An important drawback of non-integrating AAV vectors is their loss of expression upon cell division, while repeating systemic administration lacks efficacy due to the induction of neutralizing antibodies. In addition, a significant percentage of the general population is not eligible for AAV-mediated gene therapy due to pre-existing immunity...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766027/efficacy-and-safety-of-glycosidic-enzymes-for-improved-gene-delivery-to-the-retina-following-intravitreal-injection-in-mice
#8
Jasmina Cehajic-Kapetanovic, Nina Milosavljevic, Robert A Bedford, Robert J Lucas, Paul N Bishop
Viral gene delivery is showing great promise for treating retinal disease. Although subretinal vector delivery has mainly been used to date, intravitreal delivery has potential advantages if low retinal transduction efficiency can be overcome. To this end, we investigated the effects of co-injection of glycosaminoglycan-degrading enzymes, singly or in combination, with AAV2 as a method of increasing retinal transduction. Experiments using healthy mice demonstrated that these enzymes enhance retinal transduction...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766026/development-of-intrathecal-aav9-gene-therapy-for-giant-axonal-neuropathy
#9
Rachel M Bailey, Diane Armao, Sahana Nagabhushan Kalburgi, Steven J Gray
An NIH-sponsored phase I clinical trial is underway to test a potential treatment for giant axonal neuropathy (GAN) using viral-mediated GAN gene replacement (https://clinicaltrials.gov/ct2/show/NCT02362438). This trial marks the first instance of intrathecal (IT) adeno-associated viral (AAV) gene transfer in humans. GAN is a rare pediatric neurodegenerative disorder caused by autosomal recessive loss-of-function mutations in the GAN gene, which encodes the gigaxonin protein. Gigaxonin is involved in the regulation, turnover, and degradation of intermediate filaments (IFs)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766023/adeno-associated-virus-genome-population-sequencing-achieves-full-vector-genome-resolution-and-reveals-human-vector-chimeras
#10
Phillip W L Tai, Jun Xie, Kaiyuen Fong, Matthew Seetin, Cheryl Heiner, Qin Su, Michael Weiand, Daniella Wilmot, Maria L Zapp, Guangping Gao
Recombinant adeno-associated virus (rAAV)-based gene therapy has entered a phase of clinical translation and commercialization. Despite this progress, vector integrity following production is often overlooked. Compromised vectors may negatively impact therapeutic efficacy and safety. Using single molecule, real-time (SMRT) sequencing, we can comprehensively profile packaged genomes as a single intact molecule and directly assess vector integrity without extensive preparation. We have exploited this methodology to profile all heterogeneic populations of self-complementary AAV genomes via bioinformatics pipelines and have coined this approach AAV-genome population sequencing (AAV-GPseq)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766022/influence-of-pre-existing-anti-capsid-neutralizing-and-binding-antibodies-on-aav-vector-transduction
#11
Zachary Fitzpatrick, Christian Leborgne, Elena Barbon, Elisa Masat, Giuseppe Ronzitti, Laetitia van Wittenberghe, Alban Vignaud, Fanny Collaud, Séverine Charles, Marcelo Simon Sola, Fabienne Jouen, Olivier Boyer, Federico Mingozzi
Pre-existing immunity to adeno-associated virus (AAV) is highly prevalent in humans and can profoundly impact transduction efficiency. Despite the relevance to AAV-mediated gene transfer, relatively little is known about the fate of AAV vectors in the presence of neutralizing antibodies (NAbs). Similarly, the effect of binding antibodies (BAbs), with no detectable neutralizing activity, on AAV transduction is ill defined. Here, we delivered AAV8 vectors to mice carrying NAbs and demonstrated that AAV particles are taken up by both liver parenchymal and non-parenchymal cells; viral particles are then rapidly cleared, without resulting in transgene expression...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766021/transduction-patterns-of-adeno-associated-viral-vectors-in-a-laser-induced-choroidal-neovascularization-mouse-model
#12
Si Hyung Lee, Ye Seul Kim, Seung Kwan Nah, Hee Jong Kim, Ha Yan Park, Jin Young Yang, Keerang Park, Tae Kwann Park
Adeno-associated virus (AAV) vector is a promising platform technology for ocular gene therapy. Recently clinical successes to treat choroidal neovascularization (CNV) in wet type age-related macular degeneration have been reported. However, because pathologic conditions of the retina may alter the tropism of viral vectors, it is necessary to evaluate the transduction efficiency of different serotypes of AAV vectors in the retinas with CNVs. Here, we show the patterns and efficacy of transduction of AAV2, -5, and -8 vectors in a laser-induced CNV mouse model...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766020/amelioration-of-muscle-and-nerve-pathology-in-lama2-muscular-dystrophy-by-aav9-mini-agrin
#13
Chunping Qiao, Yi Dai, Viktoriya D Nikolova, Quan Jin, Jianbin Li, Bin Xiao, Juan Li, Sheryl S Moy, Xiao Xiao
LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin α2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno-associated viral (AAV) vector carrying the mini-agrin, which is a non-homologous functional substitute for the mutated laminin α2. A significant therapeutic effect in skeletal muscle was observed in our previous study using AAV serotype 1 (AAV1)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29765786/nasal-septal-perforation-in-propylthiouracil-induced-anti-neutrophil-cytoplasmic-antibody-associated-vasculitis
#14
Yusho Ishii, Tsuyoshi Shirai, Yousuke Hoshi, Yoko Fujita, Yuko Shirota, Hiroshi Fujii, Tomonori Ishii, Hideo Harigae
Here, we present the case of a 29-year-old woman with nasal septal perforation and positive myeloperoxidase- (MPO-) anti-neutrophil cytoplasmic antibody (ANCA). She had been diagnosed with Graves' disease and had been treated with propylthiouracil (PTU) for 14 months. A biopsy of the nasal septum revealed an infiltration of inflammatory cells, with no evidence of malignancy or granulomatous change. Because of the use of PTU, destructive nasal lesion, and positive MPO-ANCA, she was diagnosed with drug-induced ANCA-associated vasculitis (AAV) and was treated with prednisolone and methotrexate after the cessation of PTU...
2018: Case Reports in Rheumatology
https://www.readbyqxmd.com/read/29765083/adeno-associated-virus-vector-mediated-interleukin-10-induction-prevents-vascular-inflammation-in-a-murine-model-of-kawasaki-disease
#15
Jun Nakamura, Sachiko Watanabe, Hiroaki Kimura, Motoi Kobayashi, Tadayoshi Karasawa, Ryo Kamata, Fumitake Usui-Kawanishi, Ai Sadatomo, Hiroaki Mizukami, Noriko Nagi-Miura, Naohito Ohno, Tadashi Kasahara, Seiji Minota, Masafumi Takahashi
Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis...
May 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29764210/curative-ex-vivo-hepatocyte-directed-gene-editing-in-a-mouse-model-of-hereditary-tyrosinemia-type-1
#16
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
https://www.readbyqxmd.com/read/29763913/intraventricular-injection-of-lkb1-inhibits-the-formation-of-diet-induced-obesity-in-rats-by-activating-the-ampk-pomc-neurons-sympathetic-nervous-system-axis
#17
Pengjiao Xi, Jianying Du, Huimin Liang, Jie Han, Zhaoxia Wu, Haomin Wang, Lu He, Qiming Wang, Haize Ge, Yongmei Li, Jie Xue, Derun Tian
BACKGROUND/AIMS: Obesity is increasingly becoming a major public health problem worldwide. Peripheral LKB1 inhibits white fat generation, but the effect of central LKB1 on diet-induced obesity (DIO) is unknown. Therefore, we examined whether LKB1 over-expression in the hypothalamus can inhibit the development of obesity. METHODS: Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic apparatus. LKB1-AAV-EGFP (2.0 × 108 or 2.0 × 1010 vector genomes) or Control-AAV-EGFP (2...
May 9, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29760925/methimazole-induced-anca-associated-vasculitis-with-diffuse-alveolar-haemorrhage
#18
Naoki Arai, Kenji Nemoto, Shuji Oh-Ishi, Mizu Nonaka, Kenji Hayashihara, Takefumi Saito
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) caused by methimazole (MMI) is known to be relatively rare; therefore, the optimal therapeutic approach for these cases remains to be established. A 59-year-old man who was treated with MMI for a diagnosis of Graves' disease was referred to our hospital because of progressive haemoptysis. The patient was diagnosed with diffuse alveolar haemorrhage (DAH) secondary to AAV based on increased inflammatory reactions with positive myeloperoxidase-ANCA in the serum and the results of bronchoalveolar lavage fluid...
July 2018: Respirology Case Reports
https://www.readbyqxmd.com/read/29759820/clustered-regularly-interspaced-short-palindromic-repeats-based-genome-surgery-for-the-treatment-of-autosomal-dominant-retinitis-pigmentosa
#19
Yi-Ting Tsai, Wen-Hsuan Wu, Ting-Ting Lee, Wei-Pu Wu, Christine L Xu, Karen S Park, Xuan Cui, Sally Justus, Chyuan-Sheng Lin, Ruben Jauregui, Pei-Yin Su, Stephen H Tsang
PURPOSE: To develop a universal gene therapy to overcome the genetic heterogeneity in retinitis pigmentosa (RP) resulting from mutations in rhodopsin (RHO). DESIGN: Experimental study for a combination gene therapy that uses both gene ablation and gene replacement. PARTICIPANTS: This study included 2 kinds of human RHO mutation knock-in mouse models: RhoP23H and RhoD190N . In total, 23 RhoP23H/P23H , 43 RhoP23H/+ , and 31 RhoD190N/+ mice were used for analysis...
May 5, 2018: Ophthalmology
https://www.readbyqxmd.com/read/29754775/in-situ-gene-therapy-via-aav-crispr-cas9-mediated-targeted-gene-regulation
#20
Ana M Moreno, Xin Fu, Jie Zhu, Dhruva Katrekar, Yu-Ru V Shih, John Marlett, Jessica Cabotaje, Jasmine Tat, John Naughton, Leszek Lisowski, Shyni Varghese, Kang Zhang, Prashant Mali
Development of efficacious in vivo delivery platforms for CRISPR-Cas9-based epigenome engineering will be critical to enable the ability to target human diseases without permanent modification of the genome. Toward this, we utilized split-Cas9 systems to develop a modular adeno-associated viral (AAV) vector platform for CRISPR-Cas9 delivery to enable the full spectrum of targeted in situ gene regulation functionalities, demonstrating robust transcriptional repression (up to 80%) and activation (up to 6-fold) of target genes in cell culture and mice...
April 25, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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