Abstract: Human brain disorders represent a significant global public health challenge. However, existing rodent models display profound limitations due to marked differences from humans in brain structural complexity, social behavioral characteristics, and disease progression, thereby impeding the effective translation of basic research into clinical applications. Although non-human primates are closer to humans in certain aspects, their widespread use is severely constrained by high costs and strict ethical and conservation regulations. In contrast, domestic dogs possess brain structures highly similar to those of humans, exhibit advanced social cognitive abilities, and are compatible with clinical diagnostic and assessment systems used in humans, making them an increasingly attractive model for studying human brain disorders. With the advancement of genome-editing technologies such as CRISPR/Cas9, genetic manipulation in dogs has progressed rapidly. To date, multiple canine models of human brain diseases have been successfully established worldwide, including Shank3-mutant models for autism spectrum disorder (ASD) and DJ-1-deficient models for Parkinson’s disease (PD), providing powerful experimental systems for both fundamental research and translational applications. In this review, we systematically summarize recent advances in genetically modified canine models for human brain diseases, with a particular focus on their biological advantages, key technological breakthroughs, and future application prospects. In addition, we discuss current technical challenges and potential strategies to address them. Looking ahead, by integrating developments in modeling brain diseases, therapy efficacy assessment, and multimodal detection technologies like imaging-electrophysiology, domestic dogs hold promise as important model organisms for both basic and preclinical research on human brain disorders.

Key words: domestic dog, gene editing, brain disorder, translational research, CRISPR/Cas9