title: Cure of ADPKD by selection for spontaneous genetic repair events in Pkd1-mutated iPS cells.
abstract: Induced pluripotent stem cells (iPSCs) generated by epigenetic reprogramming of personal somatic cells have limited therapeutic capacity for patients suffering from genetic disorders. Here we demonstrate restoration of a genomic mutation heterozygous for Pkd1 (polycystic kidney disease 1) deletion (Pkd1(+/-) to Pkd1(+/R+)) by spontaneous mitotic recombination. Notably, recombination between homologous chromosomes occurred at a frequency of 1~2 per 10,000 iPSCs. Southern blot hybridization and genomic PCR analyses demonstrated that the genotype of the mutation-restored iPSCs was indistinguishable from that of the wild-type cells. Importantly, the frequency of cyst generation in kidneys of adult chimeric mice containing Pkd1(+/R+) iPSCs was significantly lower than that of adult chimeric mice with parental Pkd1(+/-) iPSCs, and indistinguishable from that of wild-type mice. This repair step could be directly incorporated into iPSC development programmes prior to cell transplantation, offering an invaluable step forward for patients carrying a wide range of genetic disorders.
authors.affiliation: Stem Cell Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto Japan.
authors.forename: Li-Tao
authors.initials: LT
authors.lastname: Cheng
authors.forename: Shogo
authors.initials: S
authors.lastname: Nagata
authors.forename: Kunio
authors.initials: K
authors.lastname: Hirano
authors.forename: Shinpei
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horie
authors.forename: Justin
authors.initials: J
authors.lastname: Ainscough
authors.forename: Takashi
authors.initials: T
authors.lastname: Tada
mesh_terms: D000818:Animals; D017690:Cell Transplantation; D002678:Chimera; D004260:DNA Repair; D057026:Induced Pluripotent Stem Cells; D051379:Mice; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000628:therapy*; D011995:Recombination, Genetic; D050396:TRPP Cation Channels / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D050396:TRPP Cation Channels