Drug Discovery


Table 2: Examples of ‘disease phenotypes in a dish’ by iPS-derived terminal cell types DISEASE PHENOTYPES IN A DISH


Cardiac Disease Long QT Type 1 Source Patient iPS cells Expressed phenotype


Prolonged action potential, reduced IKs current


LEOPARD Syndrome Patient iPS cells


Enlarged cell size, greater sarcomeric organisation, signal localisation


Pompe Disease Hypertrophy Patient iPS cells Exogenous factors


lack of acid alpha glucosidase activity, glycogen filled lysosomes


Enlarged cells size, sarcomeric organisation and ANNP mRNA expression


Hepatic Disease Alpha1-antitrypsin deficiency Familial hypercholesterolemia Glycogen storage disease type 1a Neuronal Disease Spinal muscular atrophy (SMA) Familial Dysautonomia (FD) Parkinson Disease (PD) Huntington’s Disease (HD) Misc Disease Dyskeratosis congenita Patient iPS Origin Cell phenotype Telemere shortening Citation Agarwal et al51 Source Patient iPS cells Patient iPS cells Genetic engineering Transgenic monkey iPS Expressed phenotype


Reduced levels of SMN1; response to compounds


Decreased neurogenic differentiation


Decreased number of dopaminergic neurons


Intracellular aggregates and intranuclear inclusions


Reference Ebert et al32 Lee et al33 Schneider et al50 Chan et al34 Source Patient iPS cells Patient iPS cells Patient iPS cells Expressed phenotype Aggregation of misfolded protein


Deficient LDL receptor-mediated cholesterol uptake


Elevated lipid and glycogen accumulation


Reference Rashid et al38 Rashid et al38 Rashid et al38 Reference Moretti et al35


Carvajal-Vergara et al36


Raval et al37


Foldes et al39; Kattman et al, unpublished


neural crest progenitor cells from an FD patient displayed the expected abnormal splicing of IKBKAP, exon skipping and a general reduction of


36


protein. These neurons displayed a reduced ability to migrate, a reduction in the number of focal adhesion points, and the expected and appropriate


Drug Discovery World Winter 2010/11


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80