Abstract
BackgroundTay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes β-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD.ResultsWe generated induced pluripotent stem cells (iPSCs) from two TSD patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. The Tay-Sachs disease NSCs were then used to evaluate the therapeutic effects of enzyme replacement therapy (ERT) with recombinant human Hex A protein and two small molecular compounds: hydroxypropyl-β-cyclodextrin (HPβCD) and δ-tocopherol. Using this disease model, we observed reduction of lipid accumulation by employing enzyme replacement therapy as well as by the use of HPβCD and δ-tocopherol.ConclusionOur results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. The enzyme replacement therapy with recombinant Hex A protein and two small molecules (cyclodextrin and tocopherol) significantly ameliorated lipid accumulation in the Tay-Sachs disease cell model.
Highlights
Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes β-hexosaminidase
A patient induced pluripotent stem cells (iPSCs) line HT134A was established from the fibroblast line GM00221, while another patient iPSC line HT151A was generated from GM00515 (Table 1)
The short tandem repeat (STR) profiling analysis confirmed the cell source of each iPSC line as all 11 checked Short tandem repeat (STR) loci matched with its parental Tay-Sachs patient fibroblasts (Additional file 1: Figure S2C)
Summary
Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes β-hexosaminidase. TSD and Sandhoff disease are caused by mutations in the HEXA and HEXB genes, respectively. The AB variant is caused by mutations in the GM2A gene encoding for the GM2 activator for β-hexosaminidase A [1]. Both TSD and Sandhoff disease are rare neurodegenerative disorders due to a deficiency in the enzyme β-hexosaminidase, which hydrolyzes GM2. Acute infantile TSD is the most common and harmful variant which shows progressive decline in muscle strength and loss of motor skills around six months to three years of age. The infant’s brain deteriorates which leads to seizures, blindness, loss of cognitive functions, and death [4]
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