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Minipigs as a Large-Brained Animal Model for Huntington’s Disease: From Behavior and Imaging to Gene Therapy

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Huntington’s Disease

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1780))

Abstract

Large animal models offer novel opportunities in exploring safety, biology, and efficacy of novel therapeutic approaches for Huntington’s disease (HD). Challenges in the development of, for example, gene therapy, such as delivery, distribution, and persistence of virus vectors or oligo sense nucleotides, can be explored in large brains and organisms approaching human size. We here introduce the transgenic Libechov minipig as a large animal model of HD. Methods developed to assess motor, cognitive, and behavioral features expected to manifest in an HD model are described. We also outline established protocols for magnetic resonance imaging (MRI) including magnetic resonance spectroscopy (MRS) for minipigs. The successful conduct of long-term follow-up studies over several years with repeated behavioral testing and imaging is reported. We discuss the advantages and limitations of using this model with regard to translational reliability, homology to humans and with respect to feasibility, breeding, housing, handling, and finally ethical considerations. It is concluded that minipigs can fulfill an important role in preclinical development to bridge the gap between rodents and nonhuman primate research in the translation to humans.

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Acknowledgments

The work reported in this chapter was conducted between 2009 and 2017. The longitudinal phenotyping study including MRI protocol development was funded by the CHDI Foundation (www.chdifoundation.org) from 2012 to 2015; we particularly appreciate the continuous input and encouragement provided by David Howland from CHDI Foundation. Continuation of the work was supported by generous private donations of HD families who want to remain anonymous, but have no conflicts of interest in this project or biomedical research in general. HD families who supported the projects conducted at the George-Huntington -Institute provided additional funding for this work. We thank Jan Motlik, Zdenka Ellederova, Monika Baxa, and Stefan Juhas from the Research Center PIGMOD & Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Libechov, Czech Republic, for support of the project and for providing the wt and tgHD minipigs for this study. The imaging analysis performed with minipigs was supported by Hans J. Johnson from the University of Iowa. We are very grateful for the intense support this project has received for many years from the Faculty of Medicine at the University of Muenster, Germany, particularly (1) the Central Animal Facility represented by Stefan Schlatt, Jens Ehmcke, Sandra Stoeppeler, and the whole team at the facility; (2) Department of Clinical Radiology with Cornelius Faber, Walter Heindel, Nina Nagelmann, and Harald Kugel; (3) Martin Luecke from the Office for Animal Care; and (4) E. Bernd Ringelstein and Michael Deppe from the Department of Neurology. We also gratefully acknowledge the input provided by Nicole Kemper, Ute Radespiel, and Michael Wendt, University of Veterinary Medicine Hannover, Germany. Some elements of this chapter are part of the dissertations of Verena Schuldenzucker, Sarah Schramke, Lorena Rieke, Tamara Matheis, Maike Wirsig, Eva Hölzner, Robin Schubert, and Frauke Frank.

Author information

Authors and Affiliations

  1. George-Huntington-Institute, Muenster, Germany

    Ralf Reilmann & Verena Schuldenzucker

  2. Department of Clinical Radiology, University of Muenster, Muenster, Germany

    Ralf Reilmann

  3. Department of Neurodegenerative Diseases and The Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany

    Ralf Reilmann

  4. Institute of Zoology, University of Veterinary Medicine Hannover, Hannover, Germany

    Verena Schuldenzucker

Authors
  1. Ralf Reilmann
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  2. Verena Schuldenzucker
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Corresponding author

Correspondence to Ralf Reilmann .

Editor information

Editors and Affiliations

  1. Brain Repair Group, Cardiff University, Cardiff, United Kingdom

    Sophie V. Precious

  2. Brain Repair Group, Cardiff University, Cardiff, United Kingdom

    Anne E. Rosser

  3. Brain Repair Group, Cardiff University, Cardiff, United Kingdom

    Stephen B. Dunnett

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Reilmann, R., Schuldenzucker, V. (2018). Minipigs as a Large-Brained Animal Model for Huntington’s Disease: From Behavior and Imaging to Gene Therapy. In: Precious, S., Rosser, A., Dunnett, S. (eds) Huntington’s Disease. Methods in Molecular Biology, vol 1780. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7825-0_13

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  • DOI: https://doi.org/10.1007/978-1-4939-7825-0_13

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7824-3

  • Online ISBN: 978-1-4939-7825-0

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