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Page 8 of 13 Li et al. Ageing Neur Dis 2022;2:13 https://dx.doi.org/10.20517/and.2022.13

The above advanced technologies have already been used to generate many genome editing models,
[80]
[81]
[79]
[82]
especially in small animals and plants, such as mouse [76,77] , rat , rabbit , sheep , rice , and wheat .
[78]
Some groups have also succeeded in applying this tool to large animals [83,84] .
As for pigs, Li et al. first established pig models created via BE3, which separately targeted the TWIST2 gene
and the TYR gene . These pig models were able to reproduce the phenotypes of human diseases, which
[85]
indicates that base editing systems provide a safer and more efficient approach to generating pig models that
can precisely mimic point mutations of human diseases. Another study also indicated that using base
editing technology was able to precisely introduce three gene (GGTA1, B4galNT2, and CMAH) base
conversions into the pig genome with high efficiency . In summary, there is enormous potential for
[71]
establishing pig disease models of neurological disease through base editing because of its significant
advantages compared with the traditional CRISPR/Cas9 system.

POTENTIAL LIMITATIONS OF USE OF PIG MODELS
Currently, pig models for neurodegenerative diseases provide considerable support for the analysis and
treatment of such diseases in humans. In general, pig models have great potential to advance the study of
human neurodegenerative diseases, from pathogenesis research to the development of drugs, and even as
donors of tissues and organs.

In addition, while pig disease models have greatly accelerated advances in studying genetic diseases and
testing drugs and treatments, there are still some problems. First, pigs require more space than rodents in
animal facilities and, thus, higher maintenance costs. Second, due to their large size, surgical operations
need to be performed by trained personnel, and because its brain is wrapped in a thick skull, the collection
of brain tissue requires a high degree of proficiency of the operator, which increases the experimental cost to
a certain extent. Third, because of their large size, behavioral tests will be more difficult. However, at
present, various behavioral studies of pigs have been gradually improved, for instance, learning and memory
study using novel object recognition tests; anxiety and depression measurement using open field ;
[86]
neuropsychological screening for executive function, anxiety, willingness to explore a new environment,
[87]
and locomotion using the open field test ; and motor ability measurement using a 3D kinematic gait
analysis system .
[87]
CONCLUSION
A critical step in studying neurological diseases is to establish suitable animal models. Due to the complexity
of neurological diseases, such as AD and PD, as well as the species differences between mice and humans,
selective and overt neurodegeneration is not well modeled using mouse models. Pig models have great
potential in modeling neurological diseases due to their close resemblance to the human nervous system,
and several genetically modified pig models have been established for investigating neurodegenerative
diseases [Table 1].

Pigs have very similar brain structure and function to humans. More importantly, pigs have sulci and gyri,
and their brain volume is similar to that of humans, offering advantages over small animals for studying
important brain diseases. Given their short reproductive cycle (5-6 months of sexual maturity) and multiple
litter sizes (average of 7-8 piglets) as well as the availability of techniques for generating specific models of
human diseases, pigs also have distinct advantages over non-human primates. Pigs can also be ethically used
for translational research. For example, scientists and doctors recently successfully transplanted a pig heart
[88]
into a patient with end-stage heart disease . This work opened up a new avenue in the study of
xenotransplantation.