CELLULAR AND FUNCTIONAL ALTERATIONS IN HUMAN IPSC-DERIVED MODELS OF SANFILIPPO SYNDROME

Sanfilippo Syndrome is a rare monogenic lysosomal storage disorder characterized by impaired heparan sulfate (HS) degradation. It is caused by pathological mutations in genes encoding HS-degrading enzymes, resulting in intralysosomal HS accumulation which triggers cellular dysfunction and death. This process primarily impacts the central nervous system, causing progressive neurodegeneration and, consequently, severe cognitive decline. Given the absence of curative treatments, human-relevant disease models are urgently needed to elucidate pathogenic mechanisms and support therapeutic development.
Here, we generated induced pluripotent stem cell (iPSC)-derived models of Sanfilippo Syndrome using two complementary in vitro systems: 2D forebrain neuronal cultures and 3D cortical organoids. These models were systemically characterized to assess cellular and functional disease-associated phenotypes.
Both platforms exhibited significant pathological alterations, including disrupted lysosomal dynamics and synaptic dysfunction. Furthermore, functional analysis using calcium imaging demonstrated significant abnormalities in spontaneous neuronal activity in Sanfilippo cultures compared to healthy controls, indicating impaired network function.
Together, these findings demonstrate that human iPSC-derived 2D and 3D neural models effectively recapitulate key pathological hallmarks of Sanfilippo Syndrome. This integrated platform provides a valuable human-based framework for investigating disease mechanisms and hold significant promise for the evaluation of potential therapeutic strategies.