TABLE 1.
List of therapeutic strategies applied in hiPSC-derived models to treat primary biochemical defects and secondary pathological dysfunctions in LSD.
| Therapeutic strategies | LSDs | Drugs/viral vectors | Cellular models | Therapeutic outcomes | References |
| Cyclodextrins | NPC1 | HPBCD (1 mM) or HPGCD (1 mM) | hiPS-NSC | • Reduction of cholesterol at physiological levels. • Restoration of ATP levels. • Partial rescue of impaired autophagy (p62 clearance). | Soga et al., 2015 |
| HPBCD (500 μM) or MBCD (300 μM) | hiPS-NSC | • Reduction of cholesterol at physiological level. • Partial restoration of lysosomal trafficking. • Synergistic effects with δ-tocopherol [lower doses of HPBCD (50 μM) or MBCD (20 μM) are required]. | Yu et al., 2014 | ||
| HPBCD (8 mM) or MBCD (300 μM) | hiPSC-derived neurons | • Reduction of cholesterol accumulation. | Yu et al., 2014 | ||
| NPA | HPBCD (1.5 – 6 mM) | hiPS-NSC | • 30–54% reduction of sphingomyelin storage. • Partial restoration of lysosomal trafficking. • Synergistic effects with δ-tocopherol [lower doses of HPBCD (30 μM) are required]. | Long et al., 2016 | |
| WD | HPBCD (300 – 600 μM) | hiPS-NSC | • Reduction of accumulation of cholesteryl esters • Partial restoration of lysosomal trafficking. | Aguisanda et al., 2017 | |
| TSD | HPBCD (500 μM) | hiPS-NSC | • 92–97% decrease of GM2 accumulation. • Synergistic effects with δ-tocopherol [lower doses of HPBCD (50 μM) are required]. | Vu et al., 2018 | |
| NCL | HPBCD (500 μM – 1 mM) | hiPS-NSC | • Partial recovery of lysosomal trafficking (40–50% decrease of enlarged lysosomes). • Synergistic effects with δ-tocopherol [lower doses of HPBCD (125 μM) are required]. | Sima et al., 2018 | |
| Tocopherols | NPC1 | δ-tocopherol (20 μM) | hiPS-NSC and neurons | • Partial restoration of lysosomal trafficking (in hiPS-NSC). • Reduction of cholesterol accumulation (in hiPS-NSC and neurons). | Yu et al., 2014 |
| NPA | δ-tocopherol (40 μM) or α-tocopherol (80 μM) | hiPS-NSC | • 30–50% reduction of sphingomyelin storage (highest effects with α-tocopherol). • Partial restoration of lysosomal trafficking. | Long et al., 2016 | |
| WD | δ-tocopherol (5–10 μM) | hiPS-NSC | • Reduction of accumulation of cholesteryl esters. • Partial restoration of lysosomal trafficking. | Aguisanda et al., 2017 | |
| TSD | δ-tocopherol (20 μM) | hiPS-NSC | • 75–83% decrease of GM2 accumulation. | Vu et al., 2018 | |
| NCL | δ-tocopherol (10–40 μM) | hiPS-NSC | • Partial recovery of lysosomal trafficking (10–60% decrease of enlarged lysosomes). | Sima et al., 2018 | |
| mTOR-independent enhancers | NPC1 | Carbamazepine (100 μM), verapamil (5 μM), trehalose (10 mM) | hiPSC-derived neurons | • Rescue of impaired autophagy (p62 clearance). • Increased survival in neuronal cultures. • No additive effects combining carbamazepine and HPBCD. | Maetzel et al., 2014 |
| Modulator of lipid metabolism and neurogenesis | NPC1 | Valproic Acid (1 mM) | NSC derived from direct reprogramming of fibroblasts | • Activation of LXR β pathway. • Reduction of cholesterol at physiological levels. • Partial restoration of lysosomal trafficking. • Recovery of self-renewal NSC potential. | Sung et al., 2017 |
| Modulators of calcium and WNT signals | NPC1 | Curcumin (10 μM), dantrolene (10 μM) or BIO (10 μM) | hiPSC-derived neurons | • Increased neuronal viability. | Hsieh et al., 2004 |
| Regulators of inflammasome | GM1 | Z-YVAD-FMK (10 μM) or IL1RA (1 mg/ml) | hiPS-NSC | • Downregulated expression of inflammasome factors. • Recovery of morphological abnormalities in neurospheres. • Reduced release of pro-inflammatory cytokines upon hiPS-NSC transplantation. | Son et al., 2015 |
| ERT | NPA | Human ASM (187.5 nM) | hiPS-NSC | • Partial reduction of sphingomyelin storage. | Long et al., 2016 |
| WD | rhLAL (0.3 – 2.7 μM) | hiPS-NSC | • Reduction of accumulation of cholesteryl esters. • Partial restoration of lysosomal trafficking. | Aguisanda et al., 2017 | |
| TSD | rhHEXA (100 nM) | hiPS-NSC | • Strong reduction of GM2 accumulation at physiological levels. | Vu et al., 2018 | |
| NCL | rhPPT1 (200 nM) or rhTPP1 (200 nM) | hiPS-NSC | • Restoration of lysosomal trafficking at physiological levels in hiPS-NSC derived from infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) NCL patients. | Sima et al., 2018 | |
| Gene Therapy | MPS IIIC | LV.pCMV.hHGSNAT | hiPSC-derived neurons | • Supraphysiological (50–150 fold higher) enzymatic activity. • Recovery of network connectivity in mature neurons. | Canals et al., 2015 |
| MLD | LV.pPGK.hARSA or bdLV.pPGK.hARSA.GFP | hiPSC-derived NSC, neurons, and glial cells | • Supraphysiological (5–40 fold higher) enzymatic activity, highest in differentiated cultures. • Recovery of sulfatide storage and composition in hiPS-NSC and differentiated progeny. • In hiPS-NSC: recovery of lysosomal trafficking and NSC differentiation potential; • In hiPS-NSC differentiated cultures: rescue of cellular stress and apoptosis. | Frati et al., 2018 | |
| NCL | AAVrh10.pCAG.hCLN2 or AAVrh10.pCAG.hCLN3 | hiPS-NSC | • Reduced subunit c storage at physiological levels. | Lojewski et al., 2014 | |
| GM1 | AAVrh9.pCAG.hGLB1 | Cerebral organoids | • 50% of physiological enzymatic activity. • Reduction (50–75%) of GM1 storage. | Latour et al., 2019 |
NPC1, Niemann–Pick disease type C 1; NPA, Niemann–Pick disease type A; WD, Wolman disease; TSD, Tay-Sachs disease; NCL, Neuronal Ceroid Lipofucinosis; GM1, GM1 ganglosidosis; MPS, Mucopolysaccharidosis; MLD, Metachromatic Leukodistrophy; HPBCD, 2-hydroxypropyl-β-cyclodextrin; HPGCD, 2-hydroxypropyl-δ-cyclodextrin; MBCD, methyl-β-cyclodextrin; LXR β, Liver X receptor β; ASM, Acid Sphingomyelinase; LAL, Lysosomal Acid Lipase; HEXA, Hexosaminidase A; PPT1, Palmitoyl-protein thioesterase 1; TTP1, Tripeptidyl-peptidase 1; HGSNAT, Heparan-α-glucosaminide N-acetyltransferase; ARSA, Arylsufatase A; CLN, ceroid lipofuscinosis; GLB1, β-galactosidase 1; pCMV, Cytomegalovirus promoter; pPGK, human Phosphoglycerate Kinase promoter; pCAG, composite of the CMV early enhancer and chicken beta-actin promoter.