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Adeno-associated virus

Nicole K Paulk, Katja Pekrun, Gregory W Charville, Katie Maguire-Nguyen, Michael N Wosczyna, Jianpeng Xu, Yue Zhang, Leszek Lisowski, Bryan Yoo, Jose G Vilches-Moure, Gordon K Lee, Joseph B Shrager, Thomas A Rando, Mark A Kay
Skeletal muscle is ideal for passive vaccine administration as it is easily accessible by intramuscular injection. Recombinant adeno-associated virus (rAAV) vectors are in consideration for passive vaccination clinical trials for HIV and influenza. However, greater human skeletal muscle transduction is needed for therapeutic efficacy than is possible with existing serotypes. To bioengineer capsids with therapeutic levels of transduction, we utilized a directed evolution approach to screen libraries of shuffled AAV capsids in pools of surgically resected human skeletal muscle cells from five patients...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Dongsheng Duan
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin gene mutation. Conceptually, replacing the mutated gene with a normal one would cure the disease. However, this task has encountered significant challenges due to the enormous size of the gene and the distribution of muscle throughout the body. The former creates a hurdle for viral vector packaging and the latter begs for whole-body therapy. To address these obstacles, investigators have invented the highly abbreviated micro-dystrophin gene and developed body-wide systemic gene transfer with adeno-associated virus (AAV)...
July 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Bettina Buchthal, Ursula Weiss, Hilmar Bading
Synaptic NMDA receptors activating nuclear calcium-driven adaptogenomics control a potent body-own neuroprotective mechanism, referred to as acquired neuroprotection. Viral vector-mediated gene transfer in conjunction with stereotactic surgery has previously demonstrated the proficiency of several nuclear calcium-regulated genes to protect in vivo against brain damage caused by toxic extrasynaptic NMDA receptor signaling following seizures or stroke. Here we used noninvasive nose-to-brain administration of Activin A and SerpinB2, two secreted nuclear calcium-regulated neuroprotectants, for post-injury treatment of brain damage following middle cerebral artery occlusion (MCAO) in C57BL/6N mice...
July 23, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Jianzhong Ai, Yong He, Mingxia Zheng, Yi Wen, Huan Zhang, Fangyang Huang, Ye Zhu
BACKGROUND/AIMS: Cardiovascular diseases (CVD) are the leading causes for human mortality. However, the effective treatment for these diseases are still lacking. Currently, gene therapy could be a potential way for efficiently treating heart diseases. The aim of our study is to analyze the transduction efficacy and safety profile of recombinant adeno associated virus (AAV) serotype 9 for cardiomyocytes in vivo and in vitro. METHODS: We produced rAAV serotype 9 expressing enhanced green fluorescence protein (EGFP) driven by a cardiac troponin T (cTNT) promoter, and characterized its transduction efficiency in primary cultured cardiomyocytes in vitro, and in wild-type mouse heart tissue in vivo...
August 9, 2018: Cellular Physiology and Biochemistry
Marie Reine Haddad, Eun-Young Choi, Patricia M Zerfas, Ling Yi, Diego Martinelli, Patricia Sullivan, David S Goldstein, Jose A Centeno, Lauren R Brinster, Martina Ralle, Stephen G Kaler
Menkes disease is a lethal neurodegenerative disorder of copper metabolism caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Based on our prior clinical and animal studies, we seek to develop a therapeutic approach suitable for application in affected human subjects, using the mottled-brindled ( mo-br ) mouse model that closely mimics the Menkes disease biochemical and clinical phenotypes. Here, we evaluate the efficacy of low-, intermediate-, and high-dose recombinant adeno-associated virus serotype 9 (rAAV9)-ATP7A delivered to the cerebrospinal fluid (CSF), in combination with subcutaneous administration of clinical-grade copper histidinate (sc CuHis, IND #34,166)...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
April R Giles, Lakshmanan Govindasamy, Suryanarayan Somanathan, James M Wilson
Recent clinical trials have demonstrated the potential of adeno-associated virus (AAV)-based vectors for treating rare diseases. However, significant barriers remain for the translation of these vectors into widely available therapies. In particular, exposure to the AAV capsid can generate an immune response of neutralizing antibodies. One approach to overcome this response is to map the AAV-specific neutralizing epitopes and rationally design an AAV capsid able to evade neutralization. To accomplish this, we isolated a monoclonal antibody against AAV9 following immunization of Balb/c mice and hybridoma screening...
August 8, 2018: Journal of Virology
Niansheng Ju, Rundong Jiang, Stephen L Macknik, Susana Martinez-Conde, Shiming Tang
Whereas optogenetic techniques have proven successful in their ability to manipulate neuronal populations-with high spatial and temporal fidelity-in species ranging from insects to rodents, significant obstacles remain in their application to nonhuman primates (NHPs). Robust optogenetics-activated behavior and long-term monitoring of target neurons have been challenging in NHPs. Here, we present a method for all-optical interrogation (AOI), integrating optical stimulation and simultaneous two-photon (2P) imaging of neuronal populations in the primary visual cortex (V1) of awake rhesus macaques...
August 8, 2018: PLoS Biology
Tsukasa Ohmori
Hemophilia is a congenital hemorrhagic disease caused by genetic abnormalities in coagulation factor VIII or factor IX. Current conventional therapy to prevent bleeding requires frequent intravenous injections of coagulation factor concentrates from early childhood. Accordingly, gene therapy for hemophilia remains an exciting future prospect for patients and their families, due to its potential to cure the disease through a one-time treatment. After a series of successes in basic research, recent clinical trials have demonstrated clear efficacy of gene therapy for hemophilia using adeno-associated virus (AAV) vectors...
August 6, 2018: International Journal of Hematology
Cynthia X He, Erica D Arroyo, Daniel A Cantu, Anubhuti Goel, Carlos Portera-Cailliau
The first three postnatal weeks in rodents are a time when sensory experience drives the maturation of brain circuits, an important process that is not yet well understood. Alterations in this critical period of experience-dependent circuit assembly and plasticity contribute to several neurodevelopmental disorders, such as autism, epilepsy, and schizophrenia. Therefore, techniques for recording network activity and tracing neuronal connectivity over this time period are necessary for delineating circuit refinement in typical development and how it deviates in disease...
2018: Frontiers in Neural Circuits
Christopher A Reid, Emily R Nettesheim, Thomas B Connor, Daniel M Lipinski
Vascular endothelial growth factor (VEGF) is a key mediator in the development and progression of choroidal neovascularization (CNV) in patients with wet age-related macular degeneration (AMD). As a consequence, current treatment strategies typically focus on the administration of anti-VEGF agents, such as Aflibercept (Eylea), that inhibit VEGF function. While this approach is largely successful at counteracting CNV progression, the treatment can require repetitive (i.e. monthly) intravitreal injections of the anti-VEGF agent throughout the patient's lifetime, imposing a substantial financial and medical burden on the patient...
August 6, 2018: Scientific Reports
Еlena V Mitroshina, Tatiana A Mishchenko, Alexandra V Usenko, Ekaterina A Epifanova, Roman S Yarkov, Maria S Gavrish, Alexey A Babaev, Maria V Vedunova
Brain-derived neurotrophic factor (BDNF) is one of the key signaling molecules that supports the viability of neural cells in various brain pathologies, and can be considered a potential therapeutic agent. However, several methodological difficulties, such as overcoming the blood⁻brain barrier and the short half-life period, challenge the potential use of BDNF in clinical practice. Gene therapy could overcome these limitations. Investigating the influence of viral vectors on the neural network level is of particular interest because viral overexpression affects different aspects of cell metabolism and interactions between neurons...
August 5, 2018: International Journal of Molecular Sciences
John R Counsell, Rajvinder Karda, Juan Antinao Diaz, Louise Carey, Tatiana Wiktorowicz, Suzanne M K Buckley, Shima Ameri, Joanne Ng, Julien Baruteau, Filipa Almeida, Rohan de Silva, Roberto Simone, Eleonora Lugarà, Gabriele Lignani, Dirk Lindemann, Axel Rethwilm, Ahad A Rahim, Simon N Waddington, Steven J Howe
Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs. In our investigations, systemic PFV vector delivery to neonatal mice gave transgene expression in the heart, xiphisternum, liver, pancreas, and gut, whereas intracranial administration produced brain expression until animals were euthanized 49 days post-transduction...
August 2, 2018: Molecular Therapy. Nucleic Acids
Weiwei Xi, Xuming Zhao, Meijun Wu, Wenjuan Jia, Hua Li
Although microRNA-155 (miR-155) is implicated in the pathogenesis of several fibrotic diseases, information regarding its functional role in renal fibrosis is limited. The current study aims to investigate the effects of miR-155 on renal fibrosis in unilateral ureteral occlusion (UUO) mice. MiR-155 level was significantly increased in renal tissues of UUO mice and TGF-β1-treated HK2 cells. Masson's trichrome staining showed that delivery of adeno-associated virus encoding miR-155 inhibitor led to a decrease in renal fibrosis induced by UUO...
August 6, 2018: Cell Biology International
Nadia L Mitchell, Katharina N Russell, Martin P Wellby, Hollie E Wicky, Lucia Schoderboeck, Graham K Barrell, Tracy R Melzer, Steven J Gray, Stephanie M Hughes, David N Palmer
Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are neurodegenerative lysosomal storage diseases predominantly affecting children. Single administration of brain-directed lentiviral or recombinant single-stranded adeno-associated virus 9 (ssAAV9) vectors expressing ovine CLN5 into six pre-clinically affected sheep with a naturally occurring CLN5 NCL resulted in long-term disease attenuation. Treatment efficacy was demonstrated by non-invasive longitudinal in vivo monitoring developed to align with assessments used in human medicine...
July 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Clayton P Santiago, Casey J Keuthan, Sanford L Boye, Shannon E Boye, Aisha A Imam, John D Ash
Retinal degenerations are a large cluster of diseases characterized by the irreversible loss of light-sensitive photoreceptors that impairs the vision of 9.1 million people in the US. An attractive treatment option is to use gene therapy to deliver broad-spectrum neuroprotective factors. However, this approach has had limited clinical translation because of the inability to control transgene expression. To address this problem, we generated an adeno-associated virus vector named RPF2 that was engineered to express domains of leukemia inhibitory factor fused to the destabilization domain of bacterial dihydrofolate reductase...
July 19, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Maarten M G van den Hoogenhof, Ingeborg van der Made, Nina E de Groot, Amin Damanafshan, Shirley C M van Amersfoorth, Lorena Zentilin, Mauro Giacca, Yigal M Pinto, Esther E Creemers
The RNA-binding protein Rbm24 has recently been identified as a pivotal splicing factor in the developing heart. Loss of Rbm24 in mice disrupts cardiac development by governing a large number of muscle-specific splicing events. Since Rbm24 knockout mice are embryonically lethal, the role of Rbm24 in the adult heart remained unexplored. Here, we used adeno-associated viruses (AAV9) to investigate the effect of increased Rbm24 levels in adult mouse heart. Using high-resolution microarrays, we found 893 differentially expressed genes and 1102 differential splicing events in 714 genes in hearts overexpressing Rbm24...
August 3, 2018: Scientific Reports
Rui Xu, Ying Jia, Deborah A Zygmunt, Megan L Cramer, Kelly E Crowe, Guohong Shao, Agatha E Maki, Haley N Guggenheim, Benjamin C Hood, Danielle A Griffin, Ellyn Peterson, Brad Bolon, John P Cheatham, Sharon L Cheatham, Kevin M Flanigan, Louise R Rodino-Klapac, Louis G Chicoine, Paul T Martin
Recombinant adeno-associated virus (rAAV)rh74.MCK. GALGT2 is a muscle-specific gene therapy that is being developed to treat forms of muscular dystrophy. Here we report on an isolated limb infusion technique in a non-human primate model, where hindlimb blood flow is transiently isolated using balloon catheters to concentrate vector in targeted leg muscles. A bilateral dose of 2.5 × 1013 vector genomes (vg)/kg/limb was sufficient to induce GALGT2-induced glycosylation in 10%-60% of skeletal myofibers in all leg muscles examined...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Juliette Hordeaux, Christian Hinderer, Tamara Goode, Nathan Katz, Elizabeth L Buza, Peter Bell, Roberto Calcedo, Laura K Richman, James M Wilson
Mucopolysaccharidosis type I is a recessive genetic disease caused by deficiency of the lysosomal enzyme α-L-iduronidase, which leads to a neurodegenerative and systemic disease called Hurler syndrome in its most severe form. Several clinical trials are evaluating adeno-associated virus serotype 9 (AAV9) for the treatment of neurodegenerative diseases. Although these trials focus on systemic or lumbar administration, intrathecal administration via suboccipital puncture into the cisterna magna has demonstrated remarkable efficacy in large animals...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Juliette Hordeaux, Christian Hinderer, Tamara Goode, Elizabeth L Buza, Peter Bell, Roberto Calcedo, Laura K Richman, James M Wilson
Hunter syndrome is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. The severe form of this progressive, systemic, and neurodegenerative disease results in loss of cognitive skills and early death. Several clinical trials are evaluating adeno-associated virus 9 for the treatment of neurodegenerative diseases using systemic or intrathecal lumbar administration. In large animals, administration via suboccipital puncture gives better brain transduction than lumbar administration...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Sean M Crosson, Peter Dib, J Kennon Smith, Sergei Zolotukhin
Adeno-associated virus (AAV) is one of the most promising gene therapy vectors and is widely used as a gene delivery vehicle for basic research. As AAV continues to become the vector of choice, it is increasingly important for new researchers to have access to a simplified production and purification protocol for laboratory grade recombinant AAV. Here we report a detailed protocol for serotype independent production of AAV using a helper-free HEK293 cell system followed by iodixanol gradient purification, a method described earlier...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
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