Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses
Abstract
1. Introduction
2. Approved Therapies and Ongoing Drug Discovery Efforts for the NCLs
3. NCL Animal Models
4. NCL Cellular Models
5. iPSC-Based Phenotypic Modeling for Drug Discovery in The NCLs
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Disease | GENE/Protein | Age of Onset | Known Function | Refs. |
---|---|---|---|---|
CLN1 | PPT1 (palmitoyl protein thioesterase 1) | 6–18 months | Palmitoy-protein thioesterase activity plays a critical role in the degradation of lipid-modified proteins via removing fatty acid residues from cysteine residues | [16] |
CLN2 | TPP1 (tripeptidyl peptidase 1) | 2–4 years | Serine protease activity prevents intralysosomal accumulation of storage material and neuronal loss | [17,18] |
CLN3 | CLN3, lysosomal/endosomal transmembrane protein | 4–10 years | Predicted function as a pH regulator and modulator of vesicular trafficking and fusion that promotes cellular homeostasis and neuronal survival | [19] |
CLN4 | DNAJC5/CSPα (cysteine string protein α) | Adult | Involvement in exocytosis and endocytosis functions plays a regulatory role in ATPase activity and assists in folding proteins in synaptic vesicles | [20] |
CLN5 | Soluble lysosomal protein | 4–7 years | Glycoside hydrolase activity modulates vesicular trafficking | [21,22] |
CLN6 | Transmembrane protein of endoplasmic reticulum | 18 months to 6 years | Precise function remains unclear but is linked with intracellular trafficking and lysosomal function | [23] |
CLN7 | MFSD8 (major facilitator superfamily domain-containing 8), lysosomal transmembrane protein | 2–6 years | Predicted transmembrane transporter function plays a role in preventing neuronal loss, robust accumulation of lipofuscin, reactive gliosis, and degeneration and storage accumulation in the retina | [24] |
CLN8 | Transmembrane protein of endoplasmic reticulum | 2–7 years (Turkish variant late-infantile NCL), 5–10 (northern epilepsy) | Aids in lysosomal biogenesis through transportation from the ER to the Golgi complex and in the regulation of lipid metabolism | [25,26] |
CLN10 | CTSD (cathepsin D) | In utero | Aspartic protease functions in an unknown neuroprotective mechanism | [27,28] |
CLN11 | PRGN (progranulin) | Early to mid-twenties | Known roles in inflammation, embryogenesis, cell motility and tumorigenesis | [29] |
CLN12 | ATP13A2 | 13–16 years | Regulation of ion homeostasis | [30] |
CLN13 | CTSF (cathepsin F) | Adult | Loss of lysosomal cysteine protease activity leads to deterioration of motor function and reduced brain function | [31] |
CLN14 | KCTD7 (potassium channel tetramerization domain-containing protein 7) | 8–24 months | Modulation of potassium ion channel activity | [32,33] |
Name | NCL | Controls | Treatment | Summary | Refs. |
---|---|---|---|---|---|
New York Stem Cell Foundation (Multiple) | CLN3 | Parent cells available | - | - | https://nyscf.org/ |
Cedars Sinai iPSC Core (Multiple) | CLN6 | Parent cells available | - | - | https://biomanufacturing.cedars-sinai.org/ |
LEli004-A | CLN3 | Isogenic (LEli004-A-1) | - | - | [101] |
Sima et al. | CLN1 & CLN2 | WT control | δ-Tocopherol (DT) and hydroxypropyl-β-cyclodextrin (HPBCD) | Treatment reduced lipid accumulation and lysosomal enlargement | [105] |
Lojewski et al. | CLN2 & CLN3 | WT control | Fenofibrate, gemfibrozil and PTC124 | Fenofibrate and gemfibrozil failed to increase TPP1 activity. While PTC124 resulted in an increase of TPP1 activity and attenuation of neuropathology in patient iPSC-derived neural progenitor cells | [106] |
Wiley et al. | CLN3 | IMR90 control | Adeno-associated adenovirus serotype 2 (AAV2) carrying human CLN3 | AAV2-CLN3 restored CLN3 patient-specific transcript and protein in fibroblasts and iPSC-derived retinal neurons | [74] |
Kinarivala et al. | CLN3 | IMR90 control | Flupirtine derivatives | Neuroprotective molecules upregulated Bcl-2, modulatedautophagy, enhanced clearance of subunit c and rescued mitochondrial dysfunction | [63] |
Tang et al. | CLN3 | WT control | CLN3 gene supplementation | Gene therapy rescued phagocytosis of photoreceptor outer segment in CLN3 disease iPSC-RPE cells | [107] |
Uusi-Rauva et al. | CLN5 | WT control | - | Phenotypic characterization of CLN5 patient-derived iPSCs showed accumulation of autofluorescent storage material and subunit c of the mitochondrial ATP synthase | [108] |
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Morsy, A.; Carmona, A.V.; Trippier, P.C. Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses. Molecules 2021, 26, 6235. https://doi.org/10.3390/molecules26206235
Morsy A, Carmona AV, Trippier PC. Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses. Molecules. 2021; 26(20):6235. https://doi.org/10.3390/molecules26206235
Chicago/Turabian StyleMorsy, Ahmed, Angelica V. Carmona, and Paul C. Trippier. 2021. "Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses" Molecules 26, no. 20: 6235. https://doi.org/10.3390/molecules26206235
APA StyleMorsy, A., Carmona, A. V., & Trippier, P. C. (2021). Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses. Molecules, 26(20), 6235. https://doi.org/10.3390/molecules26206235