Large animal models for Huntington’s disease research

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder for which there is currently no effective treatment available. Thus, it is imperative to establish appropriate disease models to delve deeply into the comprehensive progression of the disease. The genetic cause of HD is the abnormal expansion of CAG repeats in the huntingtin (HTT) gene, which leads to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat becomes misfolded and aggregates in the brain, causing selective loss of neurons in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders, including HD, and identifying potential therapeutic targets. Given the considerable species differences between rodents and large animals, large animal models of HD have been established to investigate the HD pathogenesis. These should facilitate the discovery of novel therapeutic targets, effective drug delivery, and improve treatment outcomes. We have previously explored the advantages of utilizing large animal models, particularly pigs, in other review articles. Since then, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. The current review aims to provide a more comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. In this review, we also explore the utilization of large animal models in Huntington's disease (HD) research, specifically focusing on sheep, non-human primates, and pigs. Our objective is to provide valuable insights into the application of these large animal models for investigating and treating neurodegenerative disorders.

Topics & Concepts