Table 2.

Few highlights of iPSC-disease models and the investigated therapy. The example of therapeutic potential of iPSC towards personalized cell therapy and disease modelling, has extended the functionality of the pluripotency beyond laboratory tables as a research tool in murine and human models.

Disorder	iPSC Characteristic	Therapy	Reference
Chronic Granulomatous Disease (CGD)—Preclinical	CGD-iPS-cells which transformed to neutrophils lacked production of reactive oxygen species (ROS)	The zinc finger nuclease -mediated functional correction of the causative CYBB gene in the neutrophils restored ROS production.	[32]
Hemophilia A (HA)—Preclinical mice model	The HA-iPSC derived endothelial cells lacked F8 gene expression and secretory protein	Lentiviral-based vector with F8 transgene and driven by endothelial-specific promoter was used, and the derived endothelial cells exhibited restored F8 gene expression	[33]
Hemophilia B (HB)—Preclinical hemophilic mice model	HB-iPSC derived hepatocyte-like cell lacked secretion of clotting factor IX	The CRISPR/Cas9 gene editing system was used to correct the cDNA in the HB-iPSCs and the resultant hepatocyte-like cells exhibited restored synthesis ability for clotting factor IX.	[34]
Severe combined immunodeficiency (SCID)—Preclinical	SCID-iPSCs with JAK3 deficiency exhibited lack of early T cell development	Gene editing by CRISPR/Cas9—enhanced gene targeting was used to correct the JAK3 mutation, which restored normal T cell development along with production of mature T cells with a broad T cell receptor repertoire.	[35]
Thalassemia—Preclinical	The iPSC-derived erythroid cells from homozygous alpha thalassemia exhibited lack of expression of the alpha globin gene	Zinc finger nuclease-mediated insertion of the globin transgene was done in the safe harbor site; AAVS1 on human chromosome 19 for correction of alpha-thalassemia major hydrops fetalis. The homozygous insertion corrected the imbalance of the globin chain in the erythroid cells.	[36]
Young-onset Parkinson’s disease (YOPD)—Preclinical	YOPD-iPSCs were differentiated to midbrain dopaminergic neural culture that exhibited increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, and reduced abundance of the lysosomal membrane protein LAMP1	Activation of lysosomal-specific pathway by phorbol ester PEP005 reduced α-synuclein, and phosphorylated protein kinase Cα levels, and increasing LAMP1 levels.	[37]
Parkinson’s disease (PD)—Proof-of-concept rodent study	Human iPSC-derived midbrain dopaminergic neurons were subjected to sorting to enrich the ventral midbrain (VM) neurons and improve efficacy and safety of cell therapy	Sorting using NCAM(+)/CD29(low) enriched VM dopaminergic neurons better. Further, PiPSC-derived NCAM(+)/CD29(low) DA neurons were able to restore motor function of 6-hydroxydopamine (6-OHDA) lesioned rats 16 weeks after transplantation.	[10]
Alzheimer’s disease (AD)—Proof-of-concept preclinical study	AD patient-derived iPSCs were carriers of three copies of the amyloid precursor protein (APP) gene	Gene editing by CRISPR/Cas9 system enables generation of iPS-cell lines with monoallelic, biallelic, or triallelic knockout of APP. The corticol neurons generated from isogenically corrected iPSCs were found to exhibit gene-dosage correlation dependent disease-phenotype correlation.	[38]
Amyotrophic lateral sclerosis (ALS)—Preclinical	ALS-iPSCs from fibroblasts exhibited SOD1+/A272C and FUS+/G1566A mutations	The CRISPR/Cas-9 nickases was used to correct the mutation and the gene corrected ALS-iPSCs (FUS+/+ and SOD1+/+) exhibited all pluripotency markers including OCT4, NANOG, and SOX2.	[39]
Barth syndrome (BTHS)—Proof-of-concept preclinical study	The BTHS-iPSC-derived cardiomyocytes exhibited abnormalities associated with mutations in the TAZ gene. Further, the cardiomyocytes assembled sparsely, and exhibited irregular sarcomeres.	The CRISPR/Cas9 system was used to introduce TAZ gene mutation in healthy donor iPSC-derived cardiomyocytes to identify relationship. Further, administration of antioxidant mitoTEMPO in the BTHS-iPCs-derived cardiomyocytes exhibited suppression of excess ROS production and normalization of the sarcomere organization and contractility.	[40]
Long QT syndrome (LQTS)—Preclinical	The LQT15-iPSC with CALM2-N98S mutation were differentiated into cardiomyocytes exhibited significantly lower beating rates, prolonged AP durations, and impaired inactivation of LTCC currents	The CRISPR/Cas9 system was used to correct the mutation in CALM2 and the resultant gene corrected iPSC-derived cardiomyocytes showed reversal in electrophysiological abnormalities with successfully recapitulating the disease phenotype.	[41]
Cystic fibrosis (CF)—Preclinical	The CF-iPSCs were positive for the CFTR mutation involving homozygous deletion of F508	The CRISPR/Cas9 system was used to correct the CFTR mutation, in combination with a completely excisable selection system. The gene correct iPSCs successfully differentiated to mature airway epithelial cells and recovered normal CFTR expression.	[42]