## 6 Conclusions and Future Perspectives  
The development of gene engineering technology has enabled the generation of transgenic rabbits that have contributed to the progress of biomedical science as an animal model in several research fields where the mouse is unsuitable as a research model. To extrapolate results from animal experimentation to humans, we must focus on the appropriate species depending on the purpose of the study. Rabbits have some unique features such as a lipid metabolism system very close to humans and a medium body size (not too small like mouse and rat, and not too large like dog and monkey) that is easily handled and applied to experimental manipulation. Therefore, many transgenic rabbits have been produced as animal models for lipid metabolism and atherosclerosis, cardiac failure, immunology, and oncogenesis. For a long time, the transgenic efficiency of rabbits was low and production of knockout rabbits was difficult because of the lack of rabbit ES cells. However, these problems were solved by the emergence of novel genome editing technology in this decade. We can now easily produce both transgenic and knockout rabbit models to analyze gain or loss of functions, or both. In the future, it is \begin{table}
\begin{tabular}{l c c c} \hline \hline  & **Mouse** & **Rabbit** & **Human** \\ \hline Lipoprotein profile & HDL-rich & LDL-rich & LDL-rich \\ CETP & None & Abundant & Abundant \\ Hepatic apoB mRNA editing & Yes & No & No \\ apoB48 & VLDLs/LDLs and & & \\  & chylomicrons & Chylomicrons & Chylomicrons \\ Hepatic lipase & High, 70\% in & Low, liver-bound & Low, liver-bound \\  & circulation & & \\ Hepatic LDL receptor & Usually high & Down-regulated & Down-regulated \\ apoA-II & Monomer & Absent & Dimmer \\ Dietary cholesterol & Resistant & Sensitive & Sensitive \\ Atherosclerosis & Resistant & Susceptible & - \\ Myosin type of myocardium & \(\alpha\)-MyHC & \(\beta\)-MyHC & \(\beta\)-MyHC \\ Ion channel of myocardium & I\({}_{\text{to}}\) and I\({}_{\text{slow}}\) & I\({}_{\text{kr}}\) and I\({}_{\text{ls}}\) & I\({}_{\text{kr}}\) and I\({}_{\text{ls}}\) \\ ECG pattern & J-wave & T-wave & T-wave \\  & (Single lead) & (12 lead) & (12 lead) \\ \hline HDL, high density lipoprotein; LDL, low density lipoprotein; CETP, cholesteryl ester transfer protein; VLDL, very & \\  & low density lipoprotein; MyHC, myosin heavy chain; ECG, electrocardiogram. Modified from [PERSON] et al. [3; 5]. & \\ \end{tabular}
\end{table} 
Table 3: Comparison of lipid metabolism and cardiac characteristics between mice, rabbits, and humans. expected that the use of genetically modified rabbits will expand to various research fields including lipid metabolism, atherosclerosis, and cardiac failure. Genome editing technology may replace the traditional pronuclear microinjection method to produce transgenic rabbits because of the high efficiency of the knock-in (transgenic) rate. In knock-in rabbits produced by genome editing technology, one transgene is usually integrated at the DSB site in contrast to the pronuclear microinjection method that ranges from two to 100 copies or more. The transgene copy number should be considered when analyzing a target gene if it requires a high expression transgenic model. However, expression of a transgene may be out of proportion to the integrated transgene copy number. Moreover, extremely high expression beyond the physiological tolerance level may cause undesirable effects on animals and will not reflect the condition of the human disease. Additionally, complicated gene manipulation, such as conditional gene knockout in an organ-specific and time-controlled manner using the Cre/LoxP system, may be difficult in rabbits. As a result of that a long time is needed for a change in generation owing to the half year required for sexual maturation of rabbits, and there are no available inbred strains (a closed colony is common), brother-sister mating has difficulty to produce the homozyggote genotype needed for the experiment in a short period.