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Statements

Subject Item
n2:RIV%2F67985904%3A_____%2F13%3A00391811%21RIV14-TA0-67985904
rdf:type
n14:Vysledek skos:Concept
dcterms:description
Background: Some promising treatments for Huntington's disease (HD) may require pre-clinical testing in large animals. Minipig is a suitable species because of its large gyrencephalic brain and long lifespan. Objective: To generate HD transgenic (TgHD) minipigs encoding huntingtin (HTT)1–548 under the control of human HTT promoter. Methods: Transgenesis was achieved by lentiviral infection of porcine embryos. PCR assessment of gene transfer, observations of behavior, and postmortem biochemical and immunohistochemical studies were conducted. Results: One copy of the human HTT transgene encoding 124 glutamines integrated into chromosome 1 q24-q25 and successful germ line transmission occurred through successive generations (F0, F1, F2 and F3 generations). No developmental or gross motor deficits were noted up to 40 months of age. Mutant HTT mRNA and protein fragment were detected in brain and peripheral tissues. No aggregate formation in brain up to 16 months was seen by AGERA and filter retardation or by immunostaining. DARPP32 labeling in WT and TgHD minipig neostriatum was patchy. Analysis of 16 month old sibling pairs showed reduced intensity of DARPP32 immunoreactivity in neostriatal TgHD neurons compared to those of WT. Compared to WT, TgHD boars by one year had reduced fertility and fewer spermatozoa per ejaculate. In vitro analysis revealed a significant decline in the number of WT minipig oocytes penetrated by TgHD spermatozoa. Conclusions: The findings demonstrate successful establishment of a transgenic model of HD in minipig that should be valuable for testing long term safety of HD therapeutics. The emergence of HD-like phenotypes in the TgHD minipigs will require more study. Background: Some promising treatments for Huntington's disease (HD) may require pre-clinical testing in large animals. Minipig is a suitable species because of its large gyrencephalic brain and long lifespan. Objective: To generate HD transgenic (TgHD) minipigs encoding huntingtin (HTT)1–548 under the control of human HTT promoter. Methods: Transgenesis was achieved by lentiviral infection of porcine embryos. PCR assessment of gene transfer, observations of behavior, and postmortem biochemical and immunohistochemical studies were conducted. Results: One copy of the human HTT transgene encoding 124 glutamines integrated into chromosome 1 q24-q25 and successful germ line transmission occurred through successive generations (F0, F1, F2 and F3 generations). No developmental or gross motor deficits were noted up to 40 months of age. Mutant HTT mRNA and protein fragment were detected in brain and peripheral tissues. No aggregate formation in brain up to 16 months was seen by AGERA and filter retardation or by immunostaining. DARPP32 labeling in WT and TgHD minipig neostriatum was patchy. Analysis of 16 month old sibling pairs showed reduced intensity of DARPP32 immunoreactivity in neostriatal TgHD neurons compared to those of WT. Compared to WT, TgHD boars by one year had reduced fertility and fewer spermatozoa per ejaculate. In vitro analysis revealed a significant decline in the number of WT minipig oocytes penetrated by TgHD spermatozoa. Conclusions: The findings demonstrate successful establishment of a transgenic model of HD in minipig that should be valuable for testing long term safety of HD therapeutics. The emergence of HD-like phenotypes in the TgHD minipigs will require more study.
dcterms:title
A transgenic minipig model of Hungtington´s disease A transgenic minipig model of Hungtington´s disease
skos:prefLabel
A transgenic minipig model of Hungtington´s disease A transgenic minipig model of Hungtington´s disease
skos:notation
RIV/67985904:_____/13:00391811!RIV14-TA0-67985904
n14:predkladatel
n15:ico%3A67985904
n3:aktivita
n10:I n10:P
n3:aktivity
I, P(ED2.1.00/03.0124), P(TA01011466)
n3:cisloPeriodika
1
n3:dodaniDat
n5:2014
n3:domaciTvurceVysledku
n4:4536096 n4:8893012 n4:8486891 n4:7205120 n4:8103283 n4:8905029 n4:3762874 n4:5434505 n4:1947788
n3:druhVysledku
n12:J
n3:duvernostUdaju
n16:S
n3:entitaPredkladatele
n13:predkladatel
n3:idSjednocenehoVysledku
59164
n3:idVysledku
RIV/67985904:_____/13:00391811
n3:jazykVysledku
n18:eng
n3:klicovaSlova
Huntington´s disease; mutant huntingtin; minipigs; large animal model
n3:klicoveSlovo
n6:mutant%20huntingtin n6:Huntington%C2%B4s%20disease n6:large%20animal%20model n6:minipigs
n3:kodStatuVydavatele
NL - Nizozemsko
n3:kontrolniKodProRIV
[C3306D3D2225]
n3:nazevZdroje
Journal of Huntington´s Disease
n3:obor
n17:EB
n3:pocetDomacichTvurcuVysledku
9
n3:pocetTvurcuVysledku
24
n3:projekt
n7:TA01011466 n7:ED2.1.00%2F03.0124
n3:rokUplatneniVysledku
n5:2013
n3:svazekPeriodika
2
n3:tvurceVysledku
Pavlok, Antonín Vrtel, R. Nejime, T. Hansíková, H. Marsala, M. Mačáková, Monika Baxa, Monika Marsala, S. Musilová, P. Kubíčková, S. Juhásová, Jana Miyanohara, A. Thompson, L. M. Sontag, E. M. Hruška-Plocháň, Marian Schier, Jan Cattaneo, E. Weiss, A. Howland, D. S. Vodička, Petr Juhás, Štefan DiFiglia, M. Motlík, Jan Klíma, Jiří
s:issn
1879-6397
s:numberOfPages
22
n19:doi
10.3233/JHD-130001