An induced pluripotent stem cell line (TRNDi009-C) from a Niemann-Pick disease type A patient carrying a heterozygous p.L302P (c.905 T>C) mutation in the SMPD1 gene.

Niemann-Pick disease type A (NPA) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for the protein acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 21-fetal-week-old female patient with NPA that has a heterozygous mutation of a p.L302P variant (c.905 T > C) using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPA.

Generation of an induced pluripotent stem cell line (TRNDi004-I) from a Niemann-Pick disease type B patient carrying a heterozygous mutation of p.L43_A44delLA in the SMPD1 gene.

Niemann-Pick disease type B (NPB) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 1-year old male patient with NPB that has a heterozygous mutation of a p.L43_A44delLA of SMPD1 using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPB.

Generation of an induced pluripotent stem cell line (TRNDi005-A) from a Mucopolysaccharidosis Type IVA (MPS IVA) patient carrying compound heterozygous p.R61W and p.WT405del mutations in the GALNS gene.

Mucopolysaccharidosis type IVA (MPS IVA) is a rare genetic disease caused by mutations in the GALNS gene and is inherited in an autosomal recessive manner. GALNS encodes N-acetylgalactosamine-6-sulfatase that breaks down certain complex carbohydrates known as glycosaminoglycans (GAGs). Deficiency in this enzyme causes accumulation of GAGs in lysosomes of body tissues. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a MPS IVA patient that has compound heterozygous mutations (p.R61W and p.WT405del) in the GALNS gene. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for drug development.

An induced pluripotent stem cell line (TRNDi006-A) from a MPS IIIB patient carrying homozygous mutation of p.Glu153Lys in the NAGLU gene.

Mucopolysaccharidosis type III B (MPS IIIB) is a lysosomal storage disorder caused by mutations in the NAGLU gene encoding N-acetylglucosaminidase. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line from dermal fibroblasts of a MPS IIIB patient. The iPSC line has homozygous mutations of G>A transversion at nucleotide 457 of the NAGLU gene (457G>A), resulting in the substitution of lysine for glutamic acid at codon 153 (Glu153Lys). This iPSC line allows for the study of disease phenotypes and pathophysiology as well as disease modeling in human cells.

A human induced pluripotent stem cell line (TRNDi007-B) from an infantile onset Pompe patient carrying p.R854X mutation in the GAA gene.

Pompe disease is an autosomal inherent genetic disease caused by mutations in the GAA gene that encodes acid alpha-glucosidase. The disease affects patients in heart, skeletal muscles, liver, and central nervous system. A human induced pluripotent stem cell (iPSC) line was generated from the skin dermal fibroblasts of a Pompe patient with homozygosity for a c.2560C > T (p.R854X) mutation in exon 18 of the GAA gene. This human iPSC line provides a useful resource for disease modeling and drug discovery.

Generation of an induced pluripotent stem cell line (TRNDi002-B) from a patient carrying compound heterozygous p.Q208X and p.G310G mutations in the NGLY1 gene.

NGLY1 deficiency is a rare genetic disease caused by mutations in the NGLY1 gene that encodes N-glycanase 1. The disease phenotype in patient cells is unclear. A human induced pluripotent stem cell (iPSC) line was generated from skin dermal fibroblasts of a patient with NGLY1 deficiency that has compound heterozygous mutations of a p.Q208X variant (c.622C > T) in exon 4 and a p.G310G variant (c.930C > T) in exon 6 of the NGLY1 gene. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for drug development to treat NGLY1 deficiency.

Generation of an induced pluripotent stem cell line (TRNDi003-A) from a Noonan syndrome with multiple lentigines (NSML) patient carrying a p.Q510P mutation in the PTPN11 gene.

Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD Syndrome, is a rare autosomal dominant disorder. Approximately 90% of NSML cases are caused by missense mutations in the PTPN11 gene which encodes the protein tyrosine phosphatase SHP2. A human induced pluripotent stem cell (iPSC) line was generated using peripheral blood mononuclear cells (PBMCs) from a patient with NSML that carries a gene mutation of p.Q510P on the PTPN11 gene using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for drug development to treat NSML.

Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease.

BACKGROUND: Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes ß-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD. RESULTS: We 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-ß-cyclodextrin (HPßCD) 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 HPßCD and δ-tocopherol. CONCLUSION: Our 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.