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Adeno associated

Claudia Kathe, Thomas Haynes Hutson, Stephen Brendan McMahon, Lawrence David Falcon Moon
Brain and spinal injury reduce mobility and often impair sensorimotor processing in the spinal cord leading to spasticity. Here, we establish that complete transection of corticospinal pathways in the pyramids impairs locomotion and leads to increased spasms and excessive mono- and polysynaptic low threshold spinal reflexes in rats. Treatment of affected forelimb muscles with an adeno-associated viral vector (AAV) encoding human Neurotrophin-3 at a clinically-feasible time-point after injury reduced spasticity...
October 19, 2016: ELife
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
Dennis Wang, Nhu-An Pham, Jiefei Tong, Shingo Sakashita, Ghassan Allo, Lucia Kim, Naoki Yanagawa, Vibha Raghavan, Yuhong Wei, Christine To, Quang M Trinh, Maud H W Starmans, Michelle A Chan-Seng-Yue, Dianne Chadwick, Lei Li, Chang-Qi Zhu, Ni Liu, Ming Li, Sharon Lee, Vladimir Ignatchenko, Dan Strumpf, Paul Taylor, Nadeem Moghal, Geoffrey Liu, Paul C Boutros, Thomas Kislinger, Melania Pintilie, Igor Jurisica, Frances A Shepherd, John D McPherson, Lakshmi Muthuswamy, Michael F Moran, Ming-Sound Tsao
Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice...
October 17, 2016: International Journal of Cancer. Journal International du Cancer
G N Nguyen, L A George, J I Siner, R J Davidson, C B Zander, X L Zheng, V R Arruda, R M Camire, D E Sabatino
BACKGROUND: The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a Paired basic Amino acid Cleaving Enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function...
October 17, 2016: Journal of Thrombosis and Haemostasis: JTH
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
Amy M Lange, Ekaterina S Altynova, Giang N Nguyen, Denise E Sabatino
Factor VIII (FVIII) is a large glycoprotein that is challenging to express both in vitro and in vivo. Several studies suggest that high levels of FVIII expression can lead to cellular stress. After gene transfer, transgene expression is restricted to a subset of cells and the increased FVIII load per cell may impact activation of the unfolded protein response. We sought to determine whether increased FVIII expression in mice after adeno-associated viral liver gene transfer would affect the unfolded protein response and/or immune response to the transgene...
2016: Molecular Therapy. Methods & Clinical Development
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
Joshua I Siner, Benjamin J Samelson-Jones, Julie M Crudele, Robert A French, Benjamin J Lee, Shanzhen Zhou, Elizabeth Merricks, Robin Raymer, Timothy C Nichols, Rodney M Camire, Valder R Arruda
Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645-1648) in the design of B-domain-deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity...
October 6, 2016: JCI Insight
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
Weidong Shi, Chenyue Zhang, Zhen Chen, Hao Chen, Luming Liu, Zhiqiang Meng
Efficient inhibition of tumor metastasis after resection of primary tumors is critical for cancer therapy. We have recently shown that Cyr61 promotes growth of pancreatic ductal adenocarcinoma (PDAC) through PI3k/Akt signaling-enhanced nuclear exclusion of p27. Here, we report that administration of adeno-associated viral vectors carrying a short-hairpin interfering RNA (shRNA) for Cyr61 via pancreatic duct significantly decreased the distal tumor metastases after resection of primary pancreatic tumor in mice...
September 26, 2016: Oncotarget
Fernando R Carvalho, Débora A Lentini-Oliveira, Lucila Bf Prado, Gilmar F Prado, Luciane Bc Carvalho
BACKGROUND: Apnoea is a breathing disorder marked by the absence of airflow at the nose or mouth. In children, risk factors include adenotonsillar hypertrophy, obesity, neuromuscular disorders and craniofacial anomalies. The most common treatment for obstructive sleep apnoea syndrome (OSAS) in childhood is adeno-tonsillectomy. This approach is limited by its surgical risks, mostly in children with comorbidities and, in some patients, by recurrence that can be associated with craniofacial problems...
October 5, 2016: Cochrane Database of Systematic Reviews
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
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