Tay-Sachs disease models: From cellular and animal models to treatment perspectives

Tay-Sachs disease (TSD) is a lysosomal storage disorder caused by pathogenic variants in the HEXA gene, resulting in deficient activity of β-hexosaminidase A (Hex-A). Loss of Hex-A function leads to the intralysosomal accumulation of GM2 ganglioside, disrupting lysosomal homeostasis and triggering neurodegenerative processes, including neuronal death, demyelination, neuroinflammation, gliosis, and microglial activation. Current understanding of TSD pathophysiology, as well as the development and preclinical evaluation of therapeutic strategies, has relied heavily on a wide range of cellular and animal models. This review summarizes and critically discusses the main experimental models of TSD and their applications. Cellular models include patient-derived skin fibroblasts and induced pluripotent stem cells (iPSCs), which have been instrumental for mechanistic studies and therapeutic screening; however, their limited capacity to recapitulate tissue-level complexity highlights the need for advanced systems such as organoids and three-dimensional tissues. Animal models encompass naturally occurring TSD in species such as dogs, sheep, and deer, as well as genetically engineered mouse models, including single- and double-knockout strains. Given that mice partially bypass the Hex-A deficiency through neuraminidase-mediated GM2 degradation, double-knockout models have been crucial for dissecting the role of neuraminidases in disease modulation. Although no model fully reproduces the human disease phenotype, these systems have provided a robust foundation for pre-clinical testing and the translation of experimental therapies into clinical trials. Continued refinement and integration of these models will be essential for advancing effective treatments for Tay-Sachs disease.