Genetic Correction of Huntington's Disease Phenotypes in Induced Pluripotent Stem Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Jul 4

PMID 22748967

Citations 187

Authors

Mahru C An

Ningzhe Zhang

Gary Scott

Daniel Montoro

Tobias Wittkop

Sean Mooney

Simon Melov

Lisa M Ellerby

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by the replacement of the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32-positive neurons in vitro and in vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-β, BDNF, and caspase activation) and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy.

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References

Sakurai K, Shimoji M, Tahimic C, Aiba K, Kawase E, Hasegawa K . Efficient integration of transgenes into a defined locus in human embryonic stem cells. Nucleic Acids Res. 2010; 38(7):e96. PMC: 2853137. DOI: 10.1093/nar/gkp1234. View

Dunnett S, Rosser A . Cell therapy in Huntington's disease. NeuroRx. 2005; 1(4):394-405. PMC: 534948. DOI: 10.1602/neurorx.1.4.394. View

Zuccato C, Ciammola A, Rigamonti D, Leavitt B, Goffredo D, Conti L . Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science. 2001; 293(5529):493-8. DOI: 10.1126/science.1059581. View

Davis R, Grandela C, Sourris K, Hatzistavrou T, Dottori M, Elefanty A . Generation of human embryonic stem cell reporter knock-in lines by homologous recombination. Curr Protoc Stem Cell Biol. 2009; Chapter 5:Unit 5B.1 1.1-34. DOI: 10.1002/9780470151808.sc05b01s11. View

Frendewey D, Chernomorsky R, Esau L, Om J, Xue Y, Murphy A . The loss-of-allele assay for ES cell screening and mouse genotyping. Methods Enzymol. 2010; 476:295-307. DOI: 10.1016/S0076-6879(10)76017-1. View

Battaglia G, Cannella M, Riozzi B, Orobello S, Maat-Schieman M, Aronica E . Early defect of transforming growth factor β1 formation in Huntington's disease. J Cell Mol Med. 2010; 15(3):555-71. PMC: 3922377. DOI: 10.1111/j.1582-4934.2010.01011.x. View

Ye L, Chang J, Lin C, Sun X, Yu J, Kan Y . 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 U S A. 2009; 106(24):9826-30. PMC: 2701047. DOI: 10.1073/pnas.0904689106. View

Zwaka T, Thomson J . Homologous recombination in human embryonic stem cells. Nat Biotechnol. 2003; 21(3):319-21. DOI: 10.1038/nbt788. View

Park I, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A . Disease-specific induced pluripotent stem cells. Cell. 2008; 134(5):877-86. PMC: 2633781. DOI: 10.1016/j.cell.2008.07.041. View

10.

Wu S, Hochedlinger K . Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol. 2011; 13(5):497-505. PMC: 3617981. DOI: 10.1038/ncb0511-497. View

11.

Tong Y, Ha T, Liu L, Nishimoto A, Reiner A, Goldowitz D . Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. J Neurosci. 2011; 31(41):14794-9. PMC: 3407803. DOI: 10.1523/JNEUROSCI.2774-11.2011. View

12.

Ku S, Soragni E, Campau E, Thomas E, Altun G, Laurent L . Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability. Cell Stem Cell. 2010; 7(5):631-7. PMC: 2987635. DOI: 10.1016/j.stem.2010.09.014. View

13.

Okita K, Ichisaka T, Yamanaka S . Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448(7151):313-7. DOI: 10.1038/nature05934. View

14.

Kiechle T, Dedeoglu A, Kubilus J, Kowall N, Beal M, Friedlander R . Cytochrome C and caspase-9 expression in Huntington's disease. Neuromolecular Med. 2002; 1(3):183-95. DOI: 10.1385/NMM:1:3:183. View

15.

Kelly C, Dunnett S, Rosser A . Medium spiny neurons for transplantation in Huntington's disease. Biochem Soc Trans. 2009; 37(Pt 1):323-8. DOI: 10.1042/BST0370323. View

16.

Zou J, Maeder M, Mali P, Pruett-Miller S, Thibodeau-Beganny S, Chou B . Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell. 2009; 5(1):97-110. PMC: 2720132. DOI: 10.1016/j.stem.2009.05.023. View

17.

Kandasamy M, Couillard-Despres S, Raber K, Stephan M, Lehner B, Winner B . Stem cell quiescence in the hippocampal neurogenic niche is associated with elevated transforming growth factor-beta signaling in an animal model of Huntington disease. J Neuropathol Exp Neurol. 2010; 69(7):717-28. DOI: 10.1097/NEN.0b013e3181e4f733. View

18.

Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, DeKelver R . Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol. 2009; 27(9):851-7. PMC: 4142824. DOI: 10.1038/nbt.1562. View

19.

Schwarz S, Schwarz J . Translation of stem cell therapy for neurological diseases. Transl Res. 2010; 156(3):155-60. DOI: 10.1016/j.trsl.2010.07.002. View

20.

Dey N, Bombard M, Roland B, Davidson S, Lu M, Rossignol J . Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington's disease. Behav Brain Res. 2010; 214(2):193-200. DOI: 10.1016/j.bbr.2010.05.023. View