title: Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations.
abstract: Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies.
authors.affiliation: The Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Soldner
authors.forename: Josée
authors.initials: J
authors.lastname: Laganière
authors.forename: Albert W
authors.initials: AW
authors.lastname: Cheng
authors.forename: Dirk
authors.initials: D
authors.lastname: Hockemeyer
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.forename: Raaji
authors.initials: R
authors.lastname: Alagappan
authors.forename: Vikram
authors.initials: V
authors.lastname: Khurana
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Golbe
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Dmitry
authors.initials: D
authors.lastname: Guschin
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Fong
authors.forename: B Joseph
authors.initials: BJ
authors.lastname: Vu
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Meng
authors.forename: Fyodor D
authors.initials: FD
authors.lastname: Urnov
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Rebar
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: H Steve
authors.initials: HS
authors.lastname: Zhang
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D002460:Cell Line; D053595:Embryonic Stem Cells; D005818:Genetic Engineering; D055106:Genome-Wide Association Study; D006801:Humans; D016296:Mutagenesis; D009841:Oligonucleotides / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology*; D039904:Pluripotent Stem Cells; D017354:Point Mutation; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D009841:Oligonucleotides; D051844:alpha-Synuclein