Large-Brained Animal Models of Huntington’s Disease: Sheep

Abstract

The limitations of using small-brained rodents to model diseases that affect large-brain humans are becoming increasingly obvious as novel therapies emerge. Huntington's disease (HD) is one such disease. In recent years, the desirability of a large-brained, long-lived animal model of HD for preclinical testing has changed into a necessity. Treatment involving gene therapy in particular presents delivery challenges that are currently unsolved. Models using long-lived, large-brained animals would be useful, not only for refining methods of delivery (particularly for gene and other therapies that do not involve small molecules) but also for measuring long-term "off-target" effects, and assessing the efficacy of therapies. With their large brains and convoluted cortices, sheep are emerging as feasible experimental subjects that can be used to bridge the gap between rodents and humans in preclinical drug development. Sheep are readily available, economical to use, and easy to care for in naturalistic settings. With brains of a similar size to a large rhesus macaque, they have much to offer. The only thing that was missing until recently was the means of testing their neurological function and behavior using approaches and methods that are relevant to HD. In this chapter, I will outline the present and future possibilities of using sheep and testing as large animal models of HD.

Behavioral phenotyping of minipigs transgenic for the Huntington gene

“…Notably, the tests proposed may also be transferred to other quadruped models of HD, e.g., sheep (Howland and MunozSanjuan, 2014;Morton and Howland, 2013) or models of other neurodegenerative disorders (Dolezalova et al, 2014).…”

“…We used female animals because they are easier to handle and could be rather held in groups than male minipigs, if they were not castrated (Morton and Howland, 2013). They were bred in the Institute of Animal Physiology and Genetics in Libechov, Czech Republic.…”

“…It was proposed that large animal models may have the potential to enhance translational reliability of preclinical research, e.g., by supplementing and confirming results obtained in rodents prior to translation into humans (Howland and Munoz-Sanjuan, 2014;Morton and Howland, 2013;Yang and Chan, 2011). Thus the development of large animal models for HD has recently been accelerated including the development of assessments for preclinical efficacy testing (Chang et al, 2015).…”

“…Minipigs exhibit a high genetic homology with humans, have similar metabolism, body weight and a fairly large gyrated brain with more structural similarities to the human brain than most models routinely used up-to-date (Baxa et al, 2013). Minipigs are easy to breed and house and maintenance of colonies is feasible at lower costs compared to monkeys (Morton and Howland, 2013;Schramke et al, 2015). Minipigs were thus proposed as a model that could play an important role in certain areas of translational preclinical research including HD (Dolezalova et al, 2014;Vodicka et al, 2005).…”

“…The monogenetic background of HD facilitated the development of a wide range of transgenic (tg) and knock-in animal models that have been used to investigate HD pathology and assess safety and efficacy of novel treatments, including nematodes, drosophila, mice, rats, sheep, monkeys and minipigs (Morton and Howland, 2013;Pouladi et al, 2013). A large body of preclinical research has been conducted using rodent models and the need for these models has been undisputed (e.g., Crook and Housman, 2011;Kim et al, 2011;William and Gray, 2011), even if critically challenged (Philips et al, 2014).…”