A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder

TLDR

Inherited defects in glycosphingolipid degradation cause severe GSL storage disorders, for which no effective treatments currently exist. The study investigates substrate deprivation therapy for GSL storage disorders by creating a genetic mouse model. The model was generated by crossing Sandhoff disease mice with mice deficient in GSL synthesis. Mice with simultaneous defects in GSL synthesis and degradation did not accumulate GSLs, showed improved neurologic function and extended lifespan, but eventually developed late‑onset neurologic disease due to oligosaccharide accumulation, supporting the therapy’s validity while highlighting limitations.

Abstract

Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations.