脑疾病是全球范围内的重要公共卫生问题。然而，现有的啮齿类动物模型在脑结构复杂程度、社会行为特征以及疾病进程等方面与人类存在显著差异，难以支撑从基础研究到临床应用转化的实际需求。灵长类动物虽然在某些方面与人类更为接近，但由于其繁殖慢、价格昂贵，且被列入保护动物范围难以被广泛应用。相比之下，家犬因其脑结构与人类高度相似、社会认知能力突出且实验检测体系与人类临床检测兼容，因而是研究人类脑疾病的理想模型。随着CRISPR/Cas9等基因编辑技术的成熟，家犬遗传操作技术得以迅速发展。目前，国际上已成功建立了包括Shank3突变孤独症（autism
spectrum disorder，ASD）家犬模型和DJ-1缺失帕金森病（Parkinson’s disease，PD）家犬模型在内的多种脑疾病模型，为脑疾病的基础和转化研究提供了可靠的实验系统。本文系统总结了基因编辑家犬模型在人类脑疾病研究中的最新研究进展，重点阐述了其生物学优势、关键技术突破与未来应用前景，以及当前存在的技术挑战和可能的应对方案。未来，结合人类脑疾病致病基因建模、疗效评估及影像-电生理等多模态检测技术等方向的发展，家犬有望成为人类脑疾病基础和临床前研究的重要模式动物。
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.
