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AAV OR Adeno-associated virus

Pavitra Ramachandran, Vivian Lee, Zhangyong Wei, Ji Yun Song, Giulia Casal, Therese Cronin, Keirnan Willett, Rachel Huckfeldt, Jessica I W Morgan, Tomas S Aleman, Albert M Maguire, Jean Bennett
Within the next decade, we will see many gene therapy clinical trials for eye diseases progress, which may lead to treatments for thousands of visually impaired people around the world. To target retinal diseases that affect specific cell types, several recombinant adeno-associated virus (AAV) serotypes have been generated and used successfully in pre-clinical mouse studies. Because there are numerous anatomic, and physiologic differences between the eyes of mice and 'men' and because surgical delivery approaches and immunologic responses also differ between these species, we evaluated the transduction characteristics of two promising new serotypes AAV7m8 and AAV8BP2, in retinas of animals that are most similar to those of humans: non-human primates (NHPs)...
October 18, 2016: Human Gene Therapy
Haiyan Lu, Xiaoyan Song, Feng Wang, Guodong Wang, Yuncheng Wu, Qiaoshu Wang, Yongting Wang, Guo-Yuan Yang, Zhijun Zhang
Endogenous Netrin-1 (NT-1) protein was significantly increased after cerebral ischemia, which may participate in the repair after transient cerebral ischemic injury. In this work, we explored whether NT-1 can be steadily overexpressed by adeno-associated virus (AAV) and the exogenous NT-1 can promote neural stem cells migration from the subventricular zone (SVZ) region after cerebral ischemia. Adult CD-1 mice were injected stereotacticly with AAV carrying NT-1 gene (AAV-NT-1). Mice underwent 60 min of middle cerebral artery (MCA) occlusion 1 week after injection...
2016: Frontiers in Cellular Neuroscience
Irene Zolotukhin, David M Markusic, Brett Palaschak, Brad E Hoffman, Meera A Srikanthan, Roland W Herzog
Hemophilia A and B are coagulation disorders resulting from the loss of functional coagulation factor VIII (FVIII) or factor IX proteins, respectively. Gene therapy for hemophilia with adeno-associated virus vectors has shown efficacy in hemophilia B patients. Although hemophilia A patients are more prevalent, the development of therapeutic adeno-associated virus vectors has been impeded by the size of the F8 cDNA and impaired secretion of FVIII protein. Further, it has been reported that over-expression of the FVIII protein induces endoplasmic reticulum stress and activates the unfolded protein response pathway both in vitro and in hepatocytes in vivo, presumably due to retention of misfolded FVIII protein within the endoplasmic reticulum...
2016: Molecular Therapy. Methods & Clinical Development
Patricia Moran Losada, Philippe Chouvarine, Marie Dorda, Silke Hedtfeld, Samira Mielke, Angela Schulz, Lutz Wiehlmann, Burkhard Tümmler
Chronic airway infections determine most morbidity in people with cystic fibrosis (CF). Herein, we present unbiased quantitative data about the frequency and abundance of DNA viruses, archaea, bacteria, moulds and fungi in CF lower airways. Induced sputa were collected on several occasions from children, adolescents and adults with CF. Deep sputum metagenome sequencing identified, on average, approximately 10 DNA viruses or fungi and several hundred bacterial taxa. The metagenome of a CF patient was typically found to be made up of an individual signature of multiple, lowly abundant species superimposed by few disease-associated pathogens, such as Pseudomonas aeruginosa and Staphylococcus aureus, as major components...
April 2016: ERJ Open Research
Giuseppe Ronzitti, Giulia Bortolussi, Remco van Dijk, Fanny Collaud, Severine Charles, Christian Leborgne, Patrice Vidal, Samia Martin, Bernard Gjata, Marcelo Simon Sola, Laetitia van Wittenberghe, Alban Vignaud, Philippe Veron, Piter J Bosma, Andres F Muro, Federico Mingozzi
Crigler-Najjar syndrome is a severe metabolic disease of the liver due to a reduced activity of the UDP Glucuronosyltransferase 1A1 (UGT1A1) enzyme. In an effort to translate to the clinic an adeno-associated virus vector mediated liver gene transfer approach to treat Crigler-Najjar syndrome, we developed and optimized a vector expressing the UGT1A1 transgene. For this purpose, we designed and tested in vitro and in vivo multiple codon-optimized UGT1A1 transgene cDNAs. We also optimized noncoding sequences in the transgene expression cassette...
2016: Molecular Therapy. Methods & Clinical Development
Bi-Jhen Syu, Chia-En Loh, Yu-Hsin Hsueh, M Eric Gershwin, Ya-Hui Chuang
Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease with a long natural history. The pathogenesis of PBC is thought to be orchestrated by Th1 and/or Th17. In this study, we investigated the role of CD4(+) helper T subsets and their cytokines on PBC using our previous established murine model of 2-OA-OVA immunization. We prepared adeno-associated virus (AAV)-IFN-γ and AAV-IL-4 and studied their individual influences on the natural history of autoimmune cholangitis in this model. Administration of IFN-γ significantly promotes recruitment and lymphocyte activation in the earliest phases of autoimmune cholangitis but subsequently leads to downregulation of chronic inflammation through induction of the immunosuppressive molecule IL-30...
October 10, 2016: Scientific Reports
D Gowanlock R Tervo, Bum-Yeol Hwang, Sarada Viswanathan, Thomas Gaj, Maria Lavzin, Kimberly D Ritola, Sarah Lindo, Susan Michael, Elena Kuleshova, David Ojala, Cheng-Chiu Huang, Charles R Gerfen, Jackie Schiller, Joshua T Dudman, Adam W Hantman, Loren L Looger, David V Schaffer, Alla Y Karpova
Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential...
October 6, 2016: Neuron
Steven F Merkel, Allison M Andrews, Evan M Lutton, Dakai Mu, Eloise Hudry, Bradley T Hyman, Casey A Maguire, Servio H Ramirez
Developing therapies for central nervous system (CNS) diseases is exceedingly difficult due to the blood-brain barrier (BBB). Notably, emerging technologies may provide promising new options for the treatment of CNS disorders. Adeno-associated virus serotype 9 (AAV9) has been shown to transduce cells in the CNS following intravascular administration in rodents, cats, pigs, and non-human primates. These results suggest that AAV9 is capable of crossing the BBB. However, mechanisms that govern AAV9 transendothelial trafficking at the BBB remain unknown...
October 8, 2016: Journal of Neurochemistry
Jeremy S Francis, Ireneusz Wojtas, Vladimir Markov, Steven J Gray, Thomas J McCown, R Jude Samulski, Larissa T Bilaniuk, Dah-Jyuu Wang, Darryl C De Vivo, Christopher G Janson, Paola Leone
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression...
October 4, 2016: Neurobiology of Disease
Martin J Hicks, Maria J Chiuchiolo, Douglas Ballon, Jonathan P Dyke, Eric Aronowitz, Kosuke Funato, Viviane Tabar, David Havlicek, Fan Fan, Dolan Sondhi, Stephen M Kaminsky, Ronald G Crystal
Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh...
2016: PloS One
Francesco Lodola, Diego Morone, Marco Denegri, Rossana Bongianino, Hiroko Nakahama, Lucia Rutigliano, Rosanna Gosetti, Giulia Rizzo, Alessandra Vollero, Michelangelo Buonocore, Carlo Napolitano, Gianluigi Condorelli, Silvia G Priori, Elisa Di Pasquale
Catecholaminergic Polymorphic Ventricular Tachycardia type 2 (CPVT2) is a highly lethal recessive arrhythmogenic disease caused by mutations in the calsequestrin-2 (CASQ2) gene. We have previously demonstrated that viral transfer of the wild-type (WT) CASQ2 gene prevents the development of CPVT2 in a genetically induced mouse model of the disease homozygous carrier of the R33Q mutation. In the present study, we investigated the efficacy of the virally mediated gene therapy in cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs) obtained from a patient carrying the homozygous CASQ2-G112+5X mutation...
October 6, 2016: Cell Death & Disease
S-S Jiao, L-L Shen, C Zhu, X-L Bu, Y-H Liu, C-H Liu, X-Q Yao, L-L Zhang, H-D Zhou, D G Walker, J Tan, J Götz, X-F Zhou, Y-J Wang
Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established...
October 4, 2016: Translational Psychiatry
Sandra Motas, Virginia Haurigot, Miguel Garcia, Sara Marcó, Albert Ribera, Carles Roca, Xavier Sánchez, Víctor Sánchez, Maria Molas, Joan Bertolin, Luca Maggioni, Xavier León, Jesús Ruberte, Fatima Bosch
Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal storage disease characterized by severe neurologic and somatic disease caused by deficiency of iduronate-2-sulfatase (IDS), an enzyme that catabolizes the glycosaminoglycans heparan and dermatan sulphate. Intravenous enzyme replacement therapy (ERT) currently constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier (BBB) limits ERT efficacy in treating neurological symptoms...
June 16, 2016: JCI Insight
Mei Hua Gao, Dimosthenis Giamouridis, N Chin Lai, Evelyn Walenta, Vivian Almeida Paschoal, Young Chul Kim, Atsushi Miyanohara, Tracy Guo, Min Liao, Li Liu, Zhen Tan, Theodore P Ciaraldi, Simon Schenk, Aditi Bhargava, Da Young Oh, H Kirk Hammond
Using mice rendered insulin resistant with high fat diets (HFD), we examined blood glucose levels and insulin resistance after i.v. delivery of an adeno-associated virus type 8 encoding murine urocortin 2 (AAV8.UCn2). A single i.v. injection of AAV8.UCn2-normalized blood glucose and glucose disposal within weeks, an effect that lasted for months. Hyperinsulinemic-euglycemic clamps showed reduced plasma insulin, increased glucose disposal rates, and increased insulin sensitivity following UCn2 gene transfer...
September 22, 2016: JCI Insight
Benjamin Steines, David D Dickey, Jamie Bergen, Katherine J D A Excoffon, John R Weinstein, Xiaopeng Li, Ziying Yan, Mahmoud H Abou Alaiwa, Viral S Shah, Drake C Bouzek, Linda S Powers, Nicholas D Gansemer, Lynda S Ostedgaard, John F Engelhardt, David A Stoltz, Michael J Welsh, Patrick L Sinn, David V Schaffer, Joseph Zabner
The physiological components that contribute to cystic fibrosis (CF) lung disease are steadily being elucidated. Gene therapy could potentially correct these defects. CFTR-null pigs provide a relevant model to test gene therapy vectors. Using an in vivo selection strategy that amplifies successful capsids by replicating their genomes with helper adenovirus coinfection, we selected an adeno-associated virus (AAV) with tropism for pig airway epithelia. The evolved capsid, termed AAV2H22, is based on AAV2 with 5 point mutations that result in a 240-fold increased infection efficiency...
September 8, 2016: JCI Insight
Giridhar Murlidharan, Andrew Crowther, Rebecca A Reardon, Juan Song, Aravind Asokan
Adeno-associated viruses (AAV) are currently being evaluated in clinical trials for gene therapy of CNS disorders. However, host factors that influence the spread, clearance, and transduction efficiency of AAV vectors in the brain are not well understood. Recent studies have demonstrated that fluid flow mediated by aquaporin-4 (AQP4) channels located on astroglial end feet is essential for exchange of solutes between interstitial and cerebrospinal fluid. This phenomenon, which is essential for interstitial clearance of solutes from the CNS, has been termed glial-associated lymphatic transport or glymphatic transport...
September 8, 2016: JCI Insight
Rachael A Powis, Evangelia Karyka, Penelope Boyd, Julien Côme, Ross A Jones, Yinan Zheng, Eva Szunyogova, Ewout J N Groen, Gillian Hunter, Derek Thomson, Thomas M Wishart, Catherina G Becker, Simon H Parson, Cécile Martinat, Mimoun Azzouz, Thomas H Gillingwater
The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA...
July 21, 2016: JCI Insight
Lichan Tao, Yihua Bei, Ping Chen, Zhiyong Lei, Siyi Fu, Haifeng Zhang, Jiahong Xu, Lin Che, Xiongwen Chen, Joost Pg Sluijter, Saumya Das, Dragos Cretoiu, Bin Xu, Jiuchang Zhong, Junjie Xiao, Xinli Li
Dysregulation of microRNAs has been implicated in many cardiovascular diseases including fibrosis. Here we report that miR-433 was consistently elevated in three models of heart disease with prominent cardiac fibrosis, and was enriched in fibroblasts compared to cardiomyocytes. Forced expression of miR-433 in neonatal rat cardiac fibroblasts increased proliferation and their differentiation into myofibroblasts as determined by EdU incorporation, α-SMA staining, and expression levels of fibrosis-associated genes...
2016: Theranostics
Naoki Yamawaki, Benjamin A Suter, Ian R Wickersham, Gordon M G Shepherd
A set of methods is described for channelrhodopsin-2 (ChR2)-based synaptic circuit analysis that combines photostimulation of virally transfected presynaptic neurons' axons with whole-cell electrophysiological recordings from retrogradely labeled postsynaptic neurons. The approach exploits the preserved photoexcitability of ChR2-expressing axons in brain slices and can be used to assess either local or long-range functional connections. Stereotaxic injections are used both to express ChR2 selectively in presynaptic axons of interest (using rabies virus [RV] or adeno-associated virus [AAV]) and to label two types of postsynaptic projection neurons of interest with fluorescent retrograde tracers...
October 3, 2016: Cold Spring Harbor Protocols
Carlos B Mantilla
Breathing is a life-sustaining behavior that in mammals is accomplished by activation of dedicated muscles responsible for inspiratory and expiratory forces acting on the lung and chest wall. Motor control is exerted by specialized pools of motoneurons in the medulla and spinal cord innervated by projections from multiple centers primarily in the brainstem that act in concert to generate both the rhythm and pattern of ventilation. Perturbations that prevent the accomplishment of the full range of motor behaviors by respiratory muscles commonly result in significant morbidity and increased mortality...
September 30, 2016: Experimental Neurology
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