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Page 18 of 29 Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19

In current treatment approaches and clinical trials, HTT is lowered independently of the mutation or in an
[314]
allele-selective manner . Preclinical studies lowering HTT by micro-RNA (miRNA) have been performed
in genetic mouse models of HD, an acute rat model of HD, a large animal model, and non-human
primates [315-317] . Acute and local expression of HTT by lentiviral- or adenoviral vectors produces models that
replicate typical neuropathological features HD, like aggregation and neuronal dysfunction [315,318,319] . This rat
model can be used to evaluate the HTT lowering effects before a long preclinical trial is initiated, for
example, by investigating behavioral readouts. Most allele selective therapies utilize heterozygous single
nucleotide polymorphisms (SNPs) that are associated with the mutation-carrying allele. These therapeutic
targets are only found in fractions of a population, and accordingly, they are also not necessarily present in
the constructs that have been used to generate genetic models. Therefore, acute rat models can be used to
test combinations and variations of SNP targeting molecules to advance personalized therapies.

CONCLUSION
Huge strides have been made towards generating genetic rat models in the past 20 years. These genetic
models are an important asset for research on NDs to study physiological and pathophysiological
mechanisms. Rats add to the functional understanding of disease by allowing electrophysiological
measurements, harvesting of primary cell cultures and a wider range of surgical procedures. They offer the
possibility to evaluate therapeutic effects more precisely due to their genetic similarities to humans, larger
body size compared to mice, and the associated possibility of multiple sampling of biofluids over time.
Many behavioral tests have been developed in rats, enabling a more robust assessment of behavioral
phenotypes in rat models. Moreover, rats display a more complex behavioral repertoire than mice, allowing
more sophisticated extrapolation to the human condition. Often efforts are being made to provide a
complete characterization of the models, offering a good starting point to find an adequate fit for the
biological question to be answered. Despite the long list of advantages rats offer, they are less represented in
biomedical studies than mice. One reason for this is that genetic models have been generated with a delay
due to the technically challenging manipulation of the rat genome. This, economic reasons, and the
multifactorial etiology of many NDs have made phenotypic rat models commonly used models in
preclinical research. Still today, they fill a gap when genetic models cannot reproduce certain aspects of
disease, highlighting that in most cases only a combination of readouts, models, and model species can
answer biomedical questions adequately. New rat models have been developed and characterized recently
and can offer additional insight into disease mechanisms. Whether rats as models, combined with improved
study design, can increase the translational value of biomedical research remains to be seen.

DECLARATIONS
Authors’ contributions
Drafting, writing, revision of manuscript: Novati A, Singer-Mikosch E, Yu-Taeger L, Clemensson E,
Nguyen HP

Availability of data and materials
Not applicable.

Financial support and sponsorship
Not applicable.

Conflicts of interest
All authors declared that there are no conflicts of interest.