Abstract
BackgroundLarge animal models of Huntington’s disease (HD) may increase the reliability of translating preclinical findings to humans. Long live expectancy offers opportunities particularly for disease modifying approaches, but also challenges. The transgenic (tg) HD minipig model assessed in this study exhibits a high genetic homology with humans, similar body weight, and comparable brain structures. To test long-term safety, tolerability, and efficacy of novel therapeutic approaches in this model reliable assessments applicable longitudinally for several years are warranted for all phenotypical domains relevant in HD.ObjectiveTo investigate whether the tests proposed assessing motor, cognitive and behavioral domains can be applied repetitively over a 3-year period in minipigs with acceptable variability or learning effects and whether tgHD minipigs reveal changes in these domains compared to wildtype (wt) minipigs suggesting the development of an HD phenotype.MethodsA cohort of 14 tgHD and 18 wt minipigs was followed for three years. Tests applied every six months included a tongue coordination and hurdle test for the motor domain, a color discrimination test for cognition, and a dominance test for assessing behavior. Statistical analyses were performed using repeated ANOVA for longitudinal group comparisons and Wilcoxon-tests for intra-visit differences between tgHD and wt minipigs.ResultsAll tests applied demonstrated feasibility, acceptable variance and good consistency during the three-year period. No significant differences between tgHD and wt minipigs were detected suggesting lack of a phenotype before the age of four years.ConclusionsThe assessment battery presented offers measures in all domains relevant for HD and can be applied in long-term phenotyping studies with tgHD minipigs. The observation of this cohort should be continued to explore the timeline of phenotype development and provide information for future interventional studies.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an extended (!36) CAG repeat in the Huntingtin (HTT) gene [1], which varies in length between individuals [2]
No significant differences between tgHD and wt minipigs were detected suggesting lack of a phenotype before the age of four years
The results have been indispensable for research, but none of the disease modifying treatments suggesting efficacy pre-clinically were successfully translated into humans so far [5]
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an extended (!36) CAG repeat in the Huntingtin (HTT) gene [1], which varies in length between individuals [2]. The results have been indispensable for research, but none of the disease modifying treatments suggesting efficacy pre-clinically were successfully translated into humans so far [5]. Large animal (LA) models may have the potential to fill a gap between rodents and humans [6,7,8] and increase translational reliability, since they have a more similar metabolism, body weight and distribution, and more human like brain volume and anatomy [9]. Large animal models of Huntington’s disease (HD) may increase the reliability of translating preclinical findings to humans. The transgenic (tg) HD minipig model assessed in this study exhibits a high genetic homology with humans, similar body weight, and comparable brain structures. To test long-term safety, tolerability, and efficacy of novel therapeutic approaches in this model reliable assessments applicable longitudinally for several years are warranted for all phenotypical domains relevant in HD
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