Abstract
ABSTRACTHuntington's disease (HD) is an inherited devastating neurodegenerative disease with no known cure to date. Several therapeutic treatments for HD are in development, but their safety, tolerability and efficacy need to be tested before translation to bedside. The monogenetic nature of this disorder has enabled the generation of transgenic animal models carrying a mutant huntingtin (mHTT) gene causing HD. A large animal model reflecting disease progression in humans would be beneficial for testing the potential therapeutic approaches. Progression of the motor, cognitive and behavioral phenotype was monitored in transgenic Huntington's disease minipigs (TgHD) expressing the N-terminal part of human mHTT. New tests were established to investigate physical activity by telemetry, and to explore the stress-induced behavioral and cognitive changes in minipigs. The longitudinal study revealed significant differences between 6- to 8-year-old TgHD animals and their wild-type (WT) controls in a majority of the tests. The telemetric study showed increased physical activity of 4.6- to 6.5-year-old TgHD boars compared to their WT counterparts during the lunch period as well as in the afternoon. Our phenotypic study indicates progression in adult TgHD minipigs and therefore this model could be suitable for longstanding preclinical studies of HD.This article has an associated First Person interview with the first author of the paper.
Highlights
The clinical symptoms of neurodegenerative Huntington’s disease (HD) are motor, cognitive and behavioral impairments manifesting typically in the mid-30s (Nance, 1998)
The decrease in walking score was significant in transgenic Huntington’s disease minipigs (TgHD) boars at 6-7.9 years (P=0.013), and in TgHD sows at 4-5.9 years (P=0.015), compared with their agematched WT controls
Significant sex-related differences were observed between TgHD boars and TgHD sows at younger (4-5.9 years) and older (6-7.9 years) age (P=0.003 and P=0.024, respectively)
Summary
The clinical symptoms of neurodegenerative Huntington’s disease (HD) are motor, cognitive and behavioral impairments manifesting typically in the mid-30s (Nance, 1998). Large animal models can provide better preclinical outcomes – including safety, biodistribution, longitudinal assessment and efficacy of novel therapeutic approaches – compared to rodents (Howland and Munoz-Sanjuan, 2014). Largeanimal models, such as non-human primates (Kocerha et al, 2013; Yang et al, 2008), sheep (Jacobsen et al, 2010), and pigs or minipigs (Baxa et al, 2013; Uchida et al, 2001; Yan et al, 2018; Yang et al, 2010), have been generated. Their similar metabolism, body weight, longevity of 15-20 years and high reproduction make them suitable for translational research (Vodicǩ a et al, 2005)
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