Use iPS cells to model diseases
|
Diseases modelled with iPS cells |
||||
|
Disease |
Molecular defect of donor cell |
Cell type differentiated from iPS cells |
Disease phenocopied in differentiated cells |
Drug or functional tests |
|
Neurological |
||||
|
Amyotrophic lateral sclerosis (ALS)1 |
Heterozygous Leu144Phe mutation in SOD1 |
Motor neurons and glial cells |
ND |
No |
|
Spinal muscular atrophy (SMA)2 |
Mutations in SMN1 |
Neurons and astrocytes, and mature motor neurons |
Yes |
VPA and tobramycin ameliorate phenotype |
|
Parkinson’s disease3–6 |
Multifactorial; mutations in LRRK2 and/or SNCA |
Dopaminergic neurons |
No |
Transplanted Parkinson’s disease iPS-cell-derived neurons ameliorate phenotype in rats with Parkinson’s disease |
|
Huntington’s disease3 |
72 CAG repeats in the huntingtin gene |
None |
NA |
No |
|
Down’s syndrome3 |
Trisomy 21 |
Teratoma with tissue from each of the three germ layers |
Yes |
No |
|
Fragile X syndrome7 |
CGG triplet repeat expansion resulting in the silencing of FMR1 |
None |
NA |
No |
|
Familial dysautonomia8 |
Mutation in IKBKAP |
Central nervous-system lineage, peripheral neurons, haematopoietic cells, endothelial cells and endodermal cells |
Yes |
Kinetin ameliorates phenotype |
|
Rett’s syndrome9,10 |
Heterozygous mutation in MECP2 |
Neural progenitor cells |
Yes |
IGF1 and high dose gentamicin treatment ameliorates phenotype |
|
Mucopolysaccharidosis type IIIB (MPS IIIB)11 |
Homozygous mutation in NAGLU |
Neural stem cells and differentiated neurons |
Partially |
Exogenous NAGLU enzyme replacement is sufficient to prevent pathology |
|
Schizophrenia12 |
Complex trait |
Neurons |
Yes |
Treatment with loxapine improves neuronal connectivity; no improvement with clozapine, olanzapine, risperidone or thioridazine |
|
X-linked adrenoleukodystrophy (X-ALD)13, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN) |
Mutation in ABCD1 |
Oligodendrocytes and neurons |
Partially |
Treatment with lovastatin or 4-phenylbutyrate ameliorates phenotype |
|
Haematological |
||||
|
ADA SCID3 |
Mutation or deletion in ADA |
None |
ND |
No |
|
Fanconi’s anaemia14 |
FAA and FAD2 corrected |
Haematopoietic cells |
No (corrected) |
No |
|
Schwachman–Bodian–Diamond syndrome3 |
Multifactorial |
None |
NA |
No |
|
Sickle-cell anaemia15,16 |
Homozygous HbS mutation |
None |
NA |
No |
|
-Thalassaemia17 |
Homozygous deletion in the -globin gene |
Haematopoietic cells |
ND |
No |
|
Polycythaemia vera18 |
Heterozygous Val617Phe mutation in JAK2 |
Haematopoietic progenitors (CD34+CD35+) |
Partially |
No |
|
Primary myelofibrosis18 |
Heterozygous mutation in JAK2 |
None |
NA |
No |
|
Metabolic |
||||
|
Lesch–Nyhan syndrome (carrier)3,4,19 |
Heterozygous mutation in HPRT1 |
None |
NA |
No |
|
Type 1 diabetes3,20 |
Multifactorial; unknown |
-Cell-like cells (express somatostatin, glucagon and insulin; glucose-responsive) |
ND |
No |
|
Gaucher’s disease, type III3 |
Mutation in GBA |
None |
NA |
No |
|
1-Antitrypsin deficiency (A1ATD)15,21 |
Homozygous mutation in the 1-antitrypsin gene |
Hepatocyte-like cells (fetal) |
Yes |
No |
|
Glycogen storage disease Ia (GSD1a)21,22 |
Defect in glucose-6-phosphate gene |
Hepatocyte-like cells (fetal) |
Yes |
No |
|
Familial hypercholesterolaemia21 |
Autosomal dominant mutation in LDLR |
Hepatocyte-like cells (fetal) |
Yes |
No |
|
Crigler–Najjar syndrome21,22 |
Deletion in UGT1A1 |
Hepatocyte-like cells (fetal) |
ND |
No |
|
Hereditary tyrosinaemia, type 121,22 |
Mutation in FAHD1 |
Hepatocyte-like cells (fetal) |
ND |
No |
|
Pompe disease23 |
Knockout of Gaa |
Skeletal muscle cells |
Yes |
No |
|
Progressive familial cholestasis22 |
Multifactorial |
Hepatocyte-like cells (fetal) |
ND |
No |
|
Hurler syndrome (MPS IH)24 |
Genetic defect in IDUA |
Haematopoietic cells |
No |
No |
|
Cardiovascular |
||||
|
LEOPARD syndrome25 |
Heterozygous mutation in PTPN11 |
Cardiomyocytes |
Yes |
No |
|
Type 1 long QT syndrome26 |
Dominant mutation in KCNQ1 |
Cardiomyocytes |
Yes |
No |
|
Type 2 long QT syndrome27 |
Missense mutation in KCNH2 |
Cardiomyocytes |
Yes |
E-4031 and cisapride aggravate disease phenotype; nifedipine, pinacidil and ranolazine ameliorate some aspects of disease phenotype |
|
Primary immunodeficiency |
||||
|
SCID28 or leaky SCID |
Mutation in RAG1 |
None |
NA |
No |
|
Omenn syndrome (OS)28 |
Mutation in RAG1 |
None |
NA |
No |
|
Cartilage-hair hypoplasia (CHH)28 |
Mutation in RMRP |
None |
NA |
No |
|
Herpes simplex encephalitis (HSE)28 |
Mutation in STAT1 or TLR3 |
Mature cell types of the central nervous system |
No |
No |
|
Other category |
||||
|
Duchenne muscular dystrophy3,29 |
Deletion in the dystrophin gene |
None |
NA |
No |
|
Becker muscular dystrophy3 |
Unidentified mutation in dystrophin |
None |
NA |
No |
|
Dyskeratosis congenita (DC)30 |
Deletion in DKC1 |
None |
NA |
No |
|
Cystic fibrosis15,31 |
Homozygous deletion in CFTR |
None |
NA |
No |
|
Friedreich’s ataxia (FRDA)32 |
Trinucleotide GAA repeat expansion in FXN |
Sensory and peripheral neurons, and cardiomyocytes |
Partially |
No |
|
Retinitis pigmentosa33 |
Heterogeneity in causative genes and mutations: mutations in RP9, RP1, PRPH2 or RHO |
Retinal progenitors, photoreceptor precursors, retinal-pigment epithelial cells and rod photoreceptor cells |
Yes |
-Tocopherol ameliorates disease phenotype in a mutated RP9 background but not in mutated RP1, PRPH2 or RHO backgrounds; ascorbic acid and -carotene treatment has no effect on phenotype |
|
Recessive dystrophic epidermolysis bullosa (RDEB)34 |
Mutation in COL7A1 |
Haematopoietic cells, and epidermis-like keratinocytes that differentiate into cells of all three germ layers in vivo |
Partially |
Gene correction with Col7a1 expression plasmid increases COL7A1 protein expression compared with wild-type cells |
|
Scleroderma15 |
Unknown |
None |
NA |
No |
|
Osteogenesis imperfecta19 |
Mutation in COL1A2 |
None |
NA |
No |
|
ABCD1, ATP-binding cassette, sub-family D, member 1; ADA, adenine deaminase; CFTR, cystic fibrosis transmembrane conductance regulator; COL1A2, 2-chain of type I collagen; COL7A1, 1-chain of type VII collagen; DKC1, dyskerin; FAA, Fanconi’s anaemia, complementation group A; FAD2, Fanconi’s anaemia, complementation group D2; FAHD1, fumarylacetoacetate hydrolase; FMR1, fragile X mental retardation 1; FXN, frataxin; Gaa, acid α-glucosidase; GBA, acid -glucosidase; HbS, sickle haemoglobin; HPRT1, hypoxanthine phosphoribosyltransferase 1; IDUA, -l-iduronidase; IGF1, insulin-like growth factor 1; JAK2, Janus kinase 2; KCNH2, potassium voltage-gated channel, subfamily H (eag-related), member 2; KCNQ1, potassium voltage-gated channel, KQT-like subfamily, member 1; LDLR, low-density lipoprotein receptor; LRRK2, leucine-rich repeat kinase 2; MECP2, methyl CpG binding protein 2; NA, not applicable; NAGLU , -N-acetylglucosaminidase; ND not determined; PRPH2, peripherin 2; PTPN11, protein tyrosine phosphatase, non-receptor type 11; RAG1, recombination activating gene 1; RHO, rhodopsin; RMRP, RNA component of mitochondrial-RNA-processing endoribonuclease; RP, retinitis pigmentosa; SCID, severe combined immunodeficiency; SMN1, survival of motor neuron 1; SNCA, -synuclein; SOD1, superoxide dismutase 1; STAT1, signal transducer and activator of transcription 1; TLR3, Toll-like receptor 3; UGT1A1, UDP glucuronosyltransferase 1 family, polypeptide A1; VPA, valproic acid. |
||||
Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008).
Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457 , 277–280 (2009).
Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).
Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009).
Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc. Natl Acad. Sci USA 107,
Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 28,
Cell Stem Cell 6,
Phil. Trans. R. Soc. B 366,
Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nature Methods 6, 370–376 (2009).
A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells. Hum. Mol. Genet . 20,
Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011).
Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Ann. Neurol . 70,
Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460, 53–59 (2009).
Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells 28, 1728–1740 (2010).
Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells 28,
Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases. Proc. Natl Acad. Sci. USA 106,
Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114, 5473–5480 (2009).
Engineering of human pluripotent stem cells by AAV-mediated gene targeting. Mol. Ther. 18, 1192–1199 (2010).
Generation of pluripotent stem cells from patients with type 1 diabetes. Proc. Natl Acad. Sci. USA 106, 15768–15773 (2009).
Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120,
Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev. 6, 622–632 (2010).
Generation of induced pluripotent stem (iPS) cells derived from a murine model of Pompe disease and differentiation of Pompe-iPS cells into skeletal muscle cells. Mol. Genet. Metab. 104,
Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome). Blood 117, 839–847 (2011).
Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465, 808–812 (2010).
Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010).
Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011).
Induced pluripotent stem cells: a novel frontier in the study of human primary immunodeficiencies. J. Allergy Clin. Immunol. 127, 1400–1407 (2011).
Female human iPSCs retain an inactive X chromosome. Cell Stem Cell 7,
Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464, 292–296 (2010).
Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7,
Generation of induced pluripotent stem cell lines from Friedreich ataxia patients. Stem Cell Rev. 7, 703–713 (2011).
Modeling retinal degeneration using patient-specific induced pluripotent stem cells. PLoS ONE 6, e17084 (2011).
Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa. J. Invest. Dermatol. 131, 848–856 (2011).
