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one to more efficiently generate pig models that can precisely mimic genetic mutations in neurological diseases. In
this review, we summarize recent advances in the use of pigs for modeling human neurological diseases, including
new approaches for generating genetically modified pig models.

Keywords: Pig models, neurological diseases, gene editing, genetic modification, genome editing tools, disease
models

INTRODUCTION
In vivo experiments using laboratory animals are essential for the verification of important findings from in
vitro studies. In addition, animal models of human diseases are critical in revealing pathological changes
and disease pathogenesis, which provide the theoretical basis for the development of treatments and
therapeutic strategies. Small animal models such as mice and rats have been widely used in biomedical
research, and animal models generated from mice have greatly advanced our understanding of the
pathology and mechanisms of diseases. Small animals can partially mimic the symptoms and pathologic
phenotypes of human disease, especially in extremely complex neurodegenerative diseases. That may be due
to the considerable differences in development, aging, and fine structures between mouse and human
brains. For example, the full development time for mouse brains is 21 days while primates’ brains need
more than 150 days to reach full maturation . The short lifespan of rodents is another major difference that
[1]
may cause the different presentation of the neuropathology, since mice can only live for a little over two
years, which is much shorter than the human’s average of 70 years. Therefore, the rapid development of the
brain and the short lifespan of mice may cause neuronal cells to respond less strongly to the production of
misfolded toxic proteins than do human neuronal cells. Differences in neural circuits and anatomical and
physiological features between rodent and human brains suggest that we should explore other animal
models to develop neurodegenerative diseases.

Undoubtedly, non-human primates (NHP) are ideal animal models that can closely mimic human diseases
due to the high similarities between NHP and humans in genetics, physiology, development, social
behaviors, and cognition. However, it is difficult to create a genetically modified NHP model when
compared with small animals due to various factors, including long breeding cycles, lack of effective
methods for genetic manipulations, high costs, community concerns, and high ethical standards. As a result,
[2]
the first transgenic mouse model was generated as early as 1974 , but the first genetically modified monkey
[3]
model did not appear until 2001 .
Considering the shortcomings of small animals and non-human primates in modeling human neurological
diseases, pigs have some advantages over other species. Pig models have several unique features that make
them a promising alternative animal model . Pigs can produce larger litters and have a shorter maturation
[4]
and reproduction time with fewer concerns about ethical issues and lower costs than non-human
primates . In regards to the similarity of pigs to humans, pigs are also highly close to humans in terms of
[5,6]
[5]
anatomy, physiology, and metabolism . As for the brain, the central nervous system of pigs is very similar
to that of humans. For example, both human and pig brains have many sulci and gyri. Anatomically, the
dorsal striata of the pig and human brains are both split into two distinct structures of the caudate nucleus
and putamen, compared with a single structure in the rodent brain. In addition, the hippocampus in the pig
brain more structurally resembles the human hippocampus than that in rodents. The timing of myelin
[6]
formation in pig brains is also similar to that of humans during brain development [Figure 1]. These
similarities make the pig a better animal model for studying neurological diseases. In addition, pigs have the
advantages of early sexual maturity (5-8 months), a short reproduction cycle between generations, and a