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Orphanet J Rare Dis. 2018 Apr 10;13(1):54. doi: 10.1186/s13023-018-0798-2.

Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses.

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD, 20892, USA.
2
Department of Gynecologic Oncology, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
3
iPSC core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
4
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD, 20892, USA. wzheng@mail.nih.gov.

Abstract

BACKGROUND:

Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs.

RESULTS:

We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of δ-tocopherol (DT) and hydroxypropyl-β-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of δ-tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy.

CONCLUSION:

The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development.

KEYWORDS:

Cyclodextrin; Enzyme replacement therapy; INCL; Induced pluripotent stem cells; LINCL; Lysosomal storage disease; Neural stem cells; Neuronal ceroid lipofuscinosis; δ-tocopherol

PMID:
29631617
PMCID:
PMC5891977
DOI:
10.1186/s13023-018-0798-2
[Indexed for MEDLINE]
Free PMC Article

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