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Adeno-associated virus

Ariana Jose, Mario Mietzsch, Kennon Smith, Justin Kurian, Paul Chipman, Robert McKenna, John Chiorini, Mavis Agbandje-McKenna
Adeno-associated virus serotype 5 (AAV5) is being developed as a gene delivery vector for several diseases, including hemophilia and Huntington's disease, and has a demonstrated efficient transduction in liver, lung, skeletal muscle, and the CNS. One limitation of AAV gene delivery are pre-existing neutralizing antibodies which present a significant challenge for vector effectiveness in therapeutic applications. Here we report the cryo-electron microscopy and image reconstructed (cryo-EM) structure of AAV5 in complex with a newly generated monoclonal antibody, HL2476, at 3...
October 17, 2018: Journal of Virology
Johanna E Wagner, Christian Schön, Elvir Becirovic, Martin Biel, Stylianos Michalakis
Gene therapy holds promise for treating previously untreatable retinal disorders. The most promising approaches use gene transfer vectors derived from adeno-associated virus (AAV) to supplement a gene function in the affected cell type. One example is gene therapy for achromatopsia which affects daylight vision. In this case, recombinant AAV (rAAV) vectors are being developed to specifically target cone photoreceptors. Development of rAAV vectors could be facilitated by the use of in vitro models. In this chapter we provide a protocol which utilizes mouse 661W cells, an in vitro model of cone photoreceptors for evaluation of the transduction efficacy of rAAV vectors...
2019: Methods in Molecular Biology
Carlos J Alméciga-Díaz, Adriana M Montaño, Luis A Barrera, Shunji Tomatsu
BACKGROUND: Targeting specific tissues remains a major challenge to the promise of gene therapy. For example, several strategies have failed to target adeno-associated virus 2 (AAV2) vectors, to bone. We have evaluated in vitro and in vivo the affinity of an AAV2 vector to bone matrix, hydroxyapatite (HA) to treat Mucopolysacccharidosis IVA. METHODS: To increase vector affinity to HA, an aspartic acid octapeptide (D8) was inserted immediately after the N-terminal region of the VP2 capsid protein...
October 15, 2018: Pediatric Research
Thomas Hiller, Johanna Berg, Laura Elomaa, Viola Röhrs, Imran Ullah, Katrin Schaar, Ann-Christin Dietrich, Munir A Al-Zeer, Andreas Kurtz, Andreas C Hocke, Stefan Hippenstiel, Henry Fechner, Marie Weinhart, Jens Kurreck
Bioprinting is a novel technology that may help to overcome limitations associated with two-dimensional (2D) cell cultures and animal experiments, as it allows the production of three-dimensional (3D) tissue models composed of human cells. The present study describes the optimization of a bioink composed of alginate, gelatin and human extracellular matrix (hECM) to print human HepaRG liver cells with a pneumatic extrusion printer. The resulting tissue model was tested for its suitability for the study of transduction by an adeno-associated virus (AAV) vector and infection with human adenovirus 5 (hAdV5)...
October 12, 2018: International Journal of Molecular Sciences
Fengtao Luo, Yangli Xie, Zuqiang Wang, Junlan Huang, Qiaoyan Tan, Xianding Sun, Fangfang Li, Can Li, Mi Liu, Dali Zhang, Meng Xu, Nan Su, Zhenhong Ni, Wanling Jiang, Jinhong Chang, Hangang Chen, Shuai Chen, Xiaoling Xu, Chuxia Deng, Zhugang Wang, Xiaolan Du, Lin Chen
Apert syndrome (AS), the most severe form of craniosynostosis, is caused by missense mutations including Pro253Arg(P253R) of fibroblast growth factor receptor 2 (FGFR2), which leads to enhanced FGF/FGFR2-signaling activity. Surgical correction of the deformed skull is the typical treatment for AS. Because of constant maldevelopment of sutures, the corrective surgery is often executed several times, resulting in increased patient challenge and complications. Biological therapies targeting the signaling of mutant FGFR2 allele, in combination with surgery, may bring better outcome...
September 22, 2018: Molecular Therapy. Nucleic Acids
Erica Mondo, Richard Moser, Guangping Gao, Christian Mueller, Miguel Sena-Esteves, Ellen Sapp, Edith Pfister, Denice O'Connell, Kendra Takle, Kirsten E Erger, Wanglin Liu, Thomas J Conlon, Marian DiFiglia, Matthew J Gounis, Neil Aronin
BACKGROUND: Transgenic sheep are currently the only large animal model of Huntington's disease expressing full-length mutant human huntingtin. These transgenic sheep provide an opportunity to test adeno associated virus (AAV) therapies directly targeting the huntingtin gene. A recent study demonstrated that self-complementary (sc) AAV with artificial miRNA against human huntingtin reduced mutant human huntingtin in caudate and putamen after a single injection near the internal capsule...
September 29, 2018: Journal of Huntington's Disease
Katherine N Wright, Amanda M Dossat, Caroline E Strong, Lindsay L Sailer, Samantha M Pavlock, Mohamed Kabbaj
DNA methylation has been identified as a powerful and activity-dependent regulator of changes in the brain that may underlie neuroadaptations in response to various types of stimuli, including exposure to drugs of abuse. Indeed, the medial prefrontal cortex (mPFC) projections to the nucleus accumbens (NAc) are critically important for reinstated cocaine-seeking, a rodent model of cocaine relapse. This circuitry undergoes a number of epigenetic modifications following cocaine exposure, including changes in DNA methylation that are associated with drug-seeking behavior...
October 15, 2018: Integrative Zoology
Andrew Octavian Sasmita
Alzheimer's disease (AD) is the most common form of dementia and has affected millions of individuals worldwide. The hallmarks of AD include the amyloid beta plaque deposits, tau neurofibrillary tangles, altered neuronal signaling, alongside decline in memory and cognitive functions. Conventional drug therapies do exist, such as donepezil or aducanumab, but these drugs mostly focus on halting AD progression instead of causing a reversal within the disease. In an effort to ameliorate and ultimately cure AD, researchers have delved into viral-mediated gene therapy to fix this disease from its root molecular causes...
October 14, 2018: Biotechnology & Genetic Engineering Reviews
Linyu Zhang, Hao Dong, Youwen Si, Nan Wu, Hao Cao, Bing Mei, Bo Meng
MicroRNAs, small noncoding RNAs, not only regulate gene expression at the post-transcriptional level in a variety of physiological processes but also accompany the initiation and progression of a vast number of diseases, including dementia. While miR-125b has been shown to be aberrantly expressed in some dementia patients, its role in the pathological process remains ambiguous. Presenilin-1/2 conditional double knockout mice exhibit a range of symptoms, including impaired cognition and memory, increased tau phosphorylation, neuroinflammation, and apoptosis, and are therefore regarded as a useful dementia model...
September 18, 2018: Neurobiology of Aging
Jeong-Ryul Hwang, Sung-Gyoo Park
Hepatitis B virus (HBV) infection remains a major global health problem; indeed, there are 250 million carriers worldwide. The host range of HBV is narrow; therefore, few primates are susceptible to HBV infection. However, ethical constraints, high cost, and large size limit the use of primates as suitable animal models. Thus, in vivo testing of therapies that target HBV has been hampered by the lack of an appropriate in vivo research model. To address this, mouse model systems of HBV are being developed and several are used for studying HBV in vivo ...
September 2018: Laboratory Animal Research
M Dominik Fischer, G Alex Ochakovski, Benjamin Beier, Immanuel P Seitz, Yousof Vaheb, Constanze Kortuem, Felix F L Reichel, Laura Kuehlewein, Nadine A Kahle, Tobias Peters, Aniz Girach, Eberhart Zrenner, Marius Ueffing, Robert E MacLaren, KarlUlrich Bartz-Schmidt, Barbara Wilhelm
PURPOSE: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1). METHODS: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51-60 years) with CHM received AAV2-REP1, by a single 0...
October 9, 2018: Retina
Hod Dana, Ondrej Novak, Michael Guardado-Montesino, James W Fransen, Amy Hu, Bart G Borghuis, Caiying Guo, Douglas S Kim, Karel Svoboda
Calcium imaging is commonly used to measure the neural activity of large groups of neurons in mice. Genetically encoded calcium indicators (GECIs) can be delivered for this purpose using non-invasive genetic methods. Compared to viral gene transfer, transgenic targeting of GECIs provides stable long-term expression and obviates the need for invasive viral injections. Transgenic mice expressing the green GECI GCaMP6 are already widely used. Here we present the generation and characterization of transgenic mice expressing the sensitive red GECI jRGECO1a, driven by the Thy1 promoter...
2018: PloS One
Karim Mouzannar, Floriane Fusil, Benoît Lacombe, Anaïs Ollivier, Camille Ménard, Vincent Lotteau, François-Loïc Cosset, Christophe Ramière, Patrice André
Hepatitis B virus (HBV) infection and bile acid (BA) metabolism are interdependent: infection modifies the expression of the BA nuclear receptor farnesoid X receptor (FXR)-α, and modulation of FXRα activity by ligands alters HBV replication. Mechanisms of HBV control by FXRα remain to be unveiled. FXRα silencing in HBV-infected HepaRG cells decreased the viral covalently closed circular (ccc)DNA pool size and transcriptional activity. Treatment with the FXRα agonist GW4064 inhibited FXRα proviral effect on cccDNA similarly for wild-type and hepatitis B viral X protein (HBx)-deficient virus, whereas agonist-induced inhibition of pregenomic and precore RNA transcription and viral DNA secretion was HBx dependent...
October 11, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Tsukasa Ohmori
Hemophilia is congenital hemorrhagic disease due to genetic abnormality of blood coagulation factor VIII or factor IX. Hemophilia appears suitable for gene therapy because it is caused by a single gene abnormality, and therapeutic coagulation factor levels vary across a broad range. Since the success of gene therapy eliminates the need for regular administration of factor concentrates, the development has been met with great expectation from patients and their families. In fact, several clinical trials using adeno-associated virus (AAV) vectors have been started in Western countries, and long-term therapeutic effect could be obtained by single injection...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Yunlong Liu, Li Lv, Lianzhang Wang, Yi Zhong
Social isolation (SI) has detrimental effects on human and animal cognitive functions. In particular, acute isolation in adult mice impairs social recognition memory (SRM). Previous accounts of this impairment have focused primarily on memory consolidation. However, the current study suggests that impaired SRM results from enhanced forgetting. SI accelerates SRM decay without affecting memory formation. The impairment is caused by elevated Rac1 activity in the hippocampus. Using adeno-associated-virus-based genetic manipulation, we found that inhibition of Rac1 activity blocked forgetting of SRM in isolated adult mice, whereas activation of Rac1 accelerated forgetting in group-housed mice...
October 9, 2018: Cell Reports
Lukas Villiger, Hiu Man Grisch-Chan, Helen Lindsay, Femke Ringnalda, Chiara B Pogliano, Gabriella Allegri, Ralph Fingerhut, Johannes Häberle, Joao Matos, Mark D Robinson, Beat Thöny, Gerald Schwank
CRISPR-Cas-based genome editing holds great promise for targeting genetic disorders, including inborn errors of hepatocyte metabolism. Precise correction of disease-causing mutations in adult tissues in vivo, however, is challenging. It requires repair of Cas9-induced double-stranded DNA (dsDNA) breaks by homology-directed mechanisms, which are highly inefficient in nondividing cells. Here we corrected the disease phenotype of adult phenylalanine hydroxylase (Pah)enu2 mice, a model for the human autosomal recessive liver disease phenylketonuria (PKU)1 , using recently developed CRISPR-Cas-associated base editors2-4 ...
October 2018: Nature Medicine
Basel T Assaf, Laurence O Whiteley
Progress in understanding the molecular bases of human health and disease in recent decades has flourished making it possible for the field of gene therapy (GT) to offer new possibilities for treating, and even curing, a plethora of medical conditions such as monogenic disorders and metabolic diseases. GT is a therapeutic intervention to genetically alter or modify living cells by means of gene delivery achieved using either viral vectors or nonviral vectors, with adeno-associated virus (AAV) vectors constituting market-share majority...
October 7, 2018: Toxicologic Pathology
Yoichiro Shinohara, Ayumu Konno, Keisuke Nitta, Yasunori Matsuzaki, Hiroyuki Yasui, Junya Suwa, Keiju Hiromura, Hirokazu Hirai
Adeno-associated virus (AAV)-PHP.B, a capsid variant of AAV serotype 9, is highly permeable to the blood-brain barrier. A major obstacle to the systemic use of AAV-PHP.B is the generation of neutralizing antibodies (NAbs); however, temporal profiles of NAb production after exposure to AAV-PHP.B, and the influence on later AAV-PHP.B administration, remains unknown. To address these, AAV-PHP.Bs expressing either GFP or mCherry by neuron-specific or astrocyte-specific promoters were intravenously administered to mice at various intervals, and brain expression was examined...
October 5, 2018: Molecular Neurobiology
Amine Meliani, Florence Boisgerault, Romain Hardet, Solenne Marmier, Fanny Collaud, Giuseppe Ronzitti, Christian Leborgne, Helena Costa Verdera, Marcelo Simon Sola, Severine Charles, Alban Vignaud, Laetitia van Wittenberghe, Giorgia Manni, Olivier Christophe, Francesca Fallarino, Christopher Roy, Alicia Michaud, Petr Ilyinskii, Takashi Kei Kishimoto, Federico Mingozzi
Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. However, vector immunogenicity represents a major limitation to gene transfer with AAV vectors, particularly for vector re-administration. Here, we demonstrate that synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cell-mediated responses. This allows successful vector re-administration in mice and nonhuman primates...
October 5, 2018: Nature Communications
Suzie Buono, Jacob A Ross, Hichem Tasfaout, Yotam Levy, Christine Kretz, Leighla Tayefeh, John Matson, Shuling Guo, Pascal Kessler, Brett P Monia, Marc Bitoun, Julien Ochala, Jocelyn Laporte, Belinda S Cowling
Centronuclear myopathies (CNM) are a group of severe muscle diseases for which no effective therapy is currently available. We have previously shown that reduction of the large GTPase DNM2 in a mouse model of the X-linked form, due to loss of myotubularin phosphatase MTM1, prevents the development of the skeletal muscle pathophysiology. As DNM2 is mutated in autosomal dominant forms, here we tested whether DNM2 reduction can rescue DNM2 -related CNM in a knock-in mouse harboring the p.R465W mutation ( Dnm2 RW/+ ) and displaying a mild CNM phenotype similar to patients with the same mutation...
October 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
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