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Sökning: onr:"swepub:oai:lup.lub.lu.se:2bac8ee7-ab26-4a25-8f23-533ebd554c17" > A novel adeno-assoc...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00006024naa a2200733 4500
001oai:lup.lub.lu.se:2bac8ee7-ab26-4a25-8f23-533ebd554c17
003SwePub
008180917s2018 | |||||||||||000 ||eng|
0247 a https://lup.lub.lu.se/record/2bac8ee7-ab26-4a25-8f23-533ebd554c172 URI
0247 a https://doi.org/10.1093/brain/awy1262 DOI
040 a (SwePub)lu
041 a engb eng
042 9 SwePub
072 7a art2 swepub-publicationtype
072 7a ref2 swepub-contenttype
1001 a Tordo, Julieu King's College London4 aut
2451 0a A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency
264 c 2018-05-16
264 1b Oxford University Press (OUP),c 2018
300 a 18 s.
520 a Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Cell- och molekylärbiologi0 (SwePub)301082 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Cell and Molecular Biology0 (SwePub)301082 hsv//eng
653 a adeno-associated virus
653 a capsid engineering
653 a lysosomal transmembrane enzyme
653 a mucopolysaccharidosis
653 a neurotropism
7001 a O'Leary, Claireu University of Manchester4 aut
7001 a Antunes, André S.L.M.u King's College London4 aut
7001 a Palomar, Nuriau King's College London4 aut
7001 a Aldrin-Kirk, Patricku Lund University,Lunds universitet,Molekylär neuromodulering,Forskargrupper vid Lunds universitet,Molecular Neuromodulation,Lund University Research Groups4 aut0 (Swepub:lu)med-pca
7001 a Basche, Marku University College London4 aut
7001 a Bennett, Antonetteu Florida Museum Natural History4 aut
7001 a D'Souza, Zelphau University of Manchester4 aut
7001 a Gleitz, Hélèneu University of Manchester4 aut
7001 a Godwin, Annieu University of Manchester4 aut
7001 a Holley, Rebecca J.u University of Manchester4 aut
7001 a Parker, Helenu University of Manchester4 aut
7001 a Liao, Ai Yinu University of Manchester4 aut
7001 a Rouse, Paulu University of Manchester4 aut
7001 a Youshani, Amir Saamu University of Manchester4 aut
7001 a Dridi, Larbiu Centre Hospitalier Universitaire Sainte-Justine4 aut
7001 a Martins, Carlau Centre Hospitalier Universitaire Sainte-Justine4 aut
7001 a Levade, Thierryu Toulouse University Hospital4 aut
7001 a Stacey, Kevin B.u University of Manchester4 aut
7001 a Davis, Daniel M.u University of Manchester4 aut
7001 a Dyer, Adamu King's College London4 aut
7001 a Clément, Nathalieu Florida Museum Natural History4 aut
7001 a Björklund, Tomasu Lund University,Lunds universitet,Molekylär neuromodulering,Forskargrupper vid Lunds universitet,Molecular Neuromodulation,Lund University Research Groups4 aut0 (Swepub:lu)mphy-tbj
7001 a Ali, Robin R.u University College London4 aut
7001 a Agbandje-McKenna, Mavisu Florida Museum Natural History4 aut
7001 a Rahim, Ahad A.u University College London4 aut
7001 a Pshezhetsky, Alexeyu Centre Hospitalier Universitaire Sainte-Justine4 aut
7001 a Waddington, Simon N.u University College London,University of the Witwatersrand4 aut
7001 a Linden, R. Michaelu King's College London4 aut
7001 a Bigger, Brian W.u University of Manchester4 aut
7001 a Henckaerts, Elsu King's College London4 aut
7102 a King's College Londonb University of Manchester4 org
7730 t Braind : Oxford University Press (OUP)g 141:7, s. 2014-2031q 141:7<2014-2031x 0006-8950x 1460-2156
8564 u http://dx.doi.org/10.1093/brain/awy126x freey FULLTEXT
8564 u https://academic.oup.com/brain/article-pdf/141/7/2014/25137174/awy126.pdf
8564 8u https://lup.lub.lu.se/record/2bac8ee7-ab26-4a25-8f23-533ebd554c17
8564 8u https://doi.org/10.1093/brain/awy126

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