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Double strand DNA breaks response in Huntington´s disease transgenic minipigs
Vaškovičová, Michaela; Šmatlíková, Petra; Herbert, A.; Motlík, Jan; Šolc, Petr
2017 - English
Huntington’s disease (HD) is progressive neurodegenerative disorder caused by presence of CAG expansion in the huntingtin gene, which gives rise to mutated form of huntingtin protein (mHtt). There is a strong evidence that DNA damage response is compromised by presence of mHtt in cells and increase of double strand DNA breaks (DSBs) is an early event in HD pathology. It was shown, that level of γH2AX is significantly higher in R6/2 mice compared to wild-type animals. Moreover, level of γH2AX is higher also in striatal neurons and fibroblasts of human HD patients. Furthermore, protein p53, key player in DNA damage response, is hyperactivated in cells expressing mHtt and inhibition of p53 or ATM ameliorates phenotypes of HD animal models. However, exact mechanism of mHtt action is not clear and therefore further investigation of mHtt effects on DSBs response is very important for the understanding of HD pathology.
Keywords:
transgenic minipigs
Available at various institutes of the ASCR
Double strand DNA breaks response in Huntington´s disease transgenic minipigs
Huntington’s disease (HD) is progressive neurodegenerative disorder caused by presence of CAG expansion in the huntingtin gene, which gives rise to mutated form of huntingtin protein (mHtt). There is ...
AAV-mediated delivery in large animals
Blits, B.; De Haan, M.; Evers, M.; Spronck, E. A.; Motlík, Jan; Bohuslavová, Božena; Ellederová, Zdeňka; Lewis, O. T.; Johnson, D.; Woolley, M.; Gill, S.; van Deventer, S.; Konstantinová, P.; Petry, H.
2017 - English
Gene therapy is an attractive option for treatment of neurological diseases. Delivery of the therapeutic gene at the proper location is key for an effective treatment and remains challenging, especially in larger animals. For translation from smaller (rodents) to larger animals, dimensions are different, but also the immune system plays a more prominent role in larger animals. Direct intracranial parenchymal infusions usually result in local transduction of tissue, whereas intrathecal infusions result in a more widespread transduction in the brain. Depending on the indication, the desired expression pattern of the therapeutic gene is to be elucidated and is dictating the route of infusion.
Keywords:
large animals
Available at various institutes of the ASCR
AAV-mediated delivery in large animals
Gene therapy is an attractive option for treatment of neurological diseases. Delivery of the therapeutic gene at the proper location is key for an effective treatment and remains challenging, ...
Following the phenotype development of TgHD minipigs by invasive and noninvasive approach
Ellederová, Zdeňka; Baxa, Monika; Vidinská, Daniela; Bohuslavová, Božena; Vochozková, Petra; Šmatlíková, Petra; Klíma, Jiří; Valeková, Ivona; Ardan, Taras; Juhás, Štefan; Juhásová, Jana; Konvalinková, R.; Klempíř, J.; Pokorný, M.; Krupička, R.; Kauler, J.; Hansíková, H.; Motlík, Jan
2017 - English
Recent promising treatments for Huntington’s disease (HD) may require pre-clinical testing in large animals. In 2009, we generated HD transgenic (TgHD) minipigs with one copy encoding the N-terminal part (548 aa) of human huntingtin (HTT) with 124 CAG/CAA repeats integrated into chromosome 1 q24-q25. The successful germ line transmission occurred through four successive generations.
Keywords:
minipigs; Huntington´s disease
Available at various institutes of the ASCR
Following the phenotype development of TgHD minipigs by invasive and noninvasive approach
Recent promising treatments for Huntington’s disease (HD) may require pre-clinical testing in large animals. In 2009, we generated HD transgenic (TgHD) minipigs with one copy encoding the N-terminal ...
Evaluation of strategies for humanization of the entire porcine HTT locus
Vochozková, Petra; Klymiuk, N.; Wolf, E.; Ellederová, Zdeňka; Motlík, Jan
2017 - English
Because fully suitable large animal models are still lacking for Huntington´s disease, we would like to generate a new minipig model which will have an entirely humanized HTT locus. Given the large size of the HTT gene (approx. 160 kb) we will test two different approaches to humanize the porcine HTT locus in porcine kidney cells (PKCs).
Keywords:
minipig model; HTT locus
Available at various institutes of the ASCR
Evaluation of strategies for humanization of the entire porcine HTT locus
Because fully suitable large animal models are still lacking for Huntington´s disease, we would like to generate a new minipig model which will have an entirely humanized HTT locus. Given the large ...
Stimulating autophagy and reducing inclusions in mouse model of Huntington's disease via expression of transcription factor EB (TFEB)
Vodička, Petr; Chase, K.; Iulliano, M.; Tousley, A.; Valentine, D. T.; Sapp, E.; Kegel-Gleason, K. B.; Sena-Esteves, M.; Aronin, N.; DiFiglia, M.
2017 - English
Mutant huntingtin (mHTT) is encoded by the Huntington’s disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy. We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9.
Keywords:
mutant huntingtin
Available at various institutes of the ASCR
Stimulating autophagy and reducing inclusions in mouse model of Huntington's disease via expression of transcription factor EB (TFEB)
Mutant huntingtin (mHTT) is encoded by the Huntington’s disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the ...
Body fluid exosomes as potential carriers of Huntington’s disease biomarkers
Kupcová Skalníková, Helena; Červenka, Jakub; Bohuslavová, Božena; Turnovcová, Karolína; Vodička, Petr
2017 - English
Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by a progressive motor, behavioural, and cognitive decline, ending in death. The cause of HD is an abnormal expansion of CAG repeats in HTT gene resulting in prolonged polyglutamine (polyQ) sequence in huntingtin protein (HTT). Huntingtin is a large protein (348 kDa) expressed ubiquitously through the body, with highest expression in the brain and testes. To study HD pathophysiology and to test experimental therapies, a transgenic HD minipig (TgHD) model expressing N-terminal part (N548-124Q) of human mutated huntingtin (mHTT) under the control of human huntingtin promoter was created in Libechov. Beside the mild neurological impairment, the TgHD boars show decreased fertility after 13th month of age.
Keywords:
Huntington´s disease
Available at various institutes of the ASCR
Body fluid exosomes as potential carriers of Huntington’s disease biomarkers
Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by a progressive motor, behavioural, and cognitive decline, ending in death. The cause of HD is an abnormal expansion ...
The effect of WNT5A and WNT7A on cartilage formation and anterior-posterior patterning of the limb
Killinger, Michael; Buchtová, Marcela
2017 - English
Growth and patterning of the vertebrate limb is controlled by signals produced in the appical ectodermal ridge (AER) and by the zone of polarizing aktivity (ZPA). limb development requires tight interactions between these signalling centers to keep asymmetrical arrangement of all skeletal elements and their growth.
Keywords:
limb
Available at various institutes of the ASCR
The effect of WNT5A and WNT7A on cartilage formation and anterior-posterior patterning of the limb
Growth and patterning of the vertebrate limb is controlled by signals produced in the appical ectodermal ridge (AER) and by the zone of polarizing aktivity (ZPA). limb development requires tight ...
Potent anti-spasticity and anti-nociceptive effect of subpial GAD65 and VGAT gene delivery in rat and mice
Maršala, M.; Tadokoro, T.; Hernandez, M. B.; Navarro, M.; Maršala, S.; Miyanohara, A.; Juhás, Štefan; Juhásová, Jana; Platoshyn, O.
2017 - English
In previous studies we have developed a novel spinal subpial (SP) AAV delivery technique in adult mice, rats and minipigs. Using this technique we have demonstrated potent and wide-spread transgene (GFP) expression in spinal white and gray matter after a single SP bolus of AAV9-UBI-GFP.
Keywords:
rat; mouse
Available at various institutes of the ASCR
Potent anti-spasticity and anti-nociceptive effect of subpial GAD65 and VGAT gene delivery in rat and mice
In previous studies we have developed a novel spinal subpial (SP) AAV delivery technique in adult mice, rats and minipigs. Using this technique we have demonstrated potent and wide-spread transgene ...
Evaluation of efficacy and bio-distribution of AAV5-miHTT in HD minipig brain
Bohuslavová, Božena; Juhás, Štefan; Juhásová, Jana; Ellederová, Zdeňka; Motlík, Jan
2016 - English
Healthy minipigs (n=29) were pre-screened for serum AAV5 neutralizing antibodies (NABs) in serum by uniQure. Conclusions: Intrastriatal/intrathalamic bilateral application of AAV5-CAG-miHtt(3e13/1e13gctotal) or PBS/Sucrose (54μl/216μl) similarly to AA5-CAG-GFP didn´t cause any neurological deficit in transgenic as well as wild type animals. The body weight increased in all animals 84 days after AAV5-CAG-miHtt/PBS-Sucroseintrastriatal/intrathalamic delivery with two exceptions TGanimal L616 (AAV5-CAG-miHtt1e 13g ctotal) and WTanimal L485 (AAV5-CAG-miHtt3e13gc total). The TG boar N176 from group VII (PBS/Sucrose) died during narcosis 56 days after IP/IT application), shortly after CSF and blood collection.The boar breathed heavily and intermittently, then the heart stopped beat and resuscitation failed. We immediately flushed them by 20 L of PBS with heparin and collect all tissues. All animals had normal food consumption. Inflammatory proces in AAV5-CAG-miHtt (1e13 gc total) seems to be similar to PBS/Sucrose injected animals accompanied with no detectable histological pathologies.
Keywords:
minipig; Huntington´s disease
Available at various institutes of the ASCR
Evaluation of efficacy and bio-distribution of AAV5-miHTT in HD minipig brain
Healthy minipigs (n=29) were pre-screened for serum AAV5 neutralizing antibodies (NABs) in serum by uniQure. Conclusions: Intrastriatal/intrathalamic bilateral application of ...
Phenotypic Analyses of the HD transgenic Minipig Model
Motlík, Jan; Ellederová, Zdeňka
2016 - English
The transgenic model of Huntington’s disease in minipig (TgHD) was created in 2009 and information coding the sequence of N-terminal part of human mutated huntingtin was transferred to subsequent generations from both female and male sides. In each litter, transgenic (TgHD) and wild-type (WT) piglets were born in approximately equal ratio. At present, the Laboratory of Cell Regeneration and Plasticity keeps sets of animals in F2 and F3 generations with identical genetic background and bred in identical conditions of feeding and housing. The present research project was focused on a complex of non-invasive and invasive approaches to WT and TgHD minipigs to achieve the entire phenotypic analysis of HD progression in this large animal model.
Keywords:
minipig
Available at various institutes of the ASCR
Phenotypic Analyses of the HD transgenic Minipig Model
The transgenic model of Huntington’s disease in minipig (TgHD) was created in 2009 and information coding the sequence of N-terminal part of human mutated huntingtin was transferred to subsequent ...
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