title: Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs.
abstract: Combination of stem cell-based approaches with gene-editing technologies represents an attractive strategy for studying human disease and developing therapies. However, gene-editing methodologies described to date for human cells suffer from technical limitations including limited target gene size, low targeting efficiency at transcriptionally inactive loci, and off-target genetic effects that could hamper broad clinical application. To address these limitations, and as a proof of principle, we focused on homologous recombination-based gene correction of multiple mutations on lamin A (LMNA), which are associated with various degenerative diseases. We show that helper-dependent adenoviral vectors (HDAdVs) provide a highly efficient and safe method for correcting mutations in large genomic regions in human induced pluripotent stem cells and can also be effective in adult human mesenchymal stem cells. This type of approach could be used to generate genotype-matched cell lines for disease modeling and drug discovery and potentially also in therapeutics.
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Guang-Hui
authors: GH
authors: Liu
authors: Keiichiro
authors: K
authors: Suzuki
authors: Jing
authors: J
authors: Qu
authors: Ignacio
authors: I
authors: Sancho-Martinez
authors: Fei
authors: F
authors: Yi
authors: Mo
authors: M
authors: Li
authors: Sachin
authors: S
authors: Kumar
authors: Emmanuel
authors: E
authors: Nivet
authors: Jessica
authors: J
authors: Kim
authors: Rupa Devi
authors: RD
authors: Soligalla
authors: Ilir
authors: I
authors: Dubova
authors: April
authors: A
authors: Goebl
authors: Nongluk
authors: N
authors: Plongthongkum
authors: Ho-Lim
authors: HL
authors: Fung
authors: Kun
authors: K
authors: Zhang
authors: Jeanne F
authors: JF
authors: Loring
authors: Louise C
authors: LC
authors: Laurent
authors: Juan Carlos
authors: JC
authors: Izpisua Belmonte
references: Stem Cells. 2009 Aug;27(8):1836-46
references: 19544414
references: Nat Rev Mol Cell Biol. 2010 Aug;11(8):567-78
references: 20651707
references: Mol Ther. 2010 Jun;18(6):1192-9
references: 20407427
references: Cell Stem Cell. 2011 Jan 7;8(1):31-45
references: 21185252
references: Biochem Biophys Res Commun. 2009 Oct 30;388(4):711-7
references: 19695233
references: Nat Biotechnol. 2007 Nov;25(11):1298-306
references: 17965707
references: Stem Cells. 2009 Jul;27(7):1496-506
references: 19544466
references: Protein Eng Des Sel. 2011 Jan;24(1-2):27-31
references: 21047873
references: Nature. 1988 Nov 24;336(6197):348-52
references: 3194019
references: Exp Cell Res. 2010 Oct 1;316(16):2578-86
references: 20542027
references: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6537-42
references: 21464322
references: Cell Stem Cell. 2010 Jan 8;6(1):80-9
references: 20074536
references: Nature. 2011 Mar 3;471(7336):58-62
references: 21368824
references: Nat Biotechnol. 2003 Mar;21(3):319-21
references: 12577066
references: Cell Mol Biol Lett. 2011 Mar;16(1):114-48
references: 21225470
references: Genes Dev. 2008 Apr 1;22(7):832-53
references: 18381888
references: Nat Biotechnol. 2011 Feb;29(2):143-8
references: 21179091
references: J Virol. 2004 Sep;78(18):10009-22
references: 15331734
references: Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a000760
references: 20182615
references: Stem Cells Dev. 2010 Jun;19(6):853-66
references: 19905894
references: Cell Stem Cell. 2009 Jul 2;5(1):97-110
references: 19540188
references: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13781-6
references: 18768795
references: Clin Pharmacol Ther. 2011 May;89(5):746-9
references: 21389982
references: Nat Biotechnol. 2009 Sep;27(9):851-7
references: 19680244
references: Cell Stem Cell. 2011 Mar 4;8(3):335-46
references: 21362573
references: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6640-5
references: 10829079
references: Nature. 2011 Mar 3;471(7336):68-73
references: 21289626
references: Nat Biotechnol. 2007 Dec;25(12):1477-82
references: 18037879
references: Nat Med. 2005 Apr;11(4):440-5
references: 15750600
references: J Cell Physiol. 2010 Feb;222(2):278-81
references: 19877154
references: Stem Cells. 2010 Mar 31;28(3):585-96
references: 19967788
references: Cell Stem Cell. 2011 Jan 7;8(1):106-18
references: 21211785
references: Mol Ther. 2004 Oct;10(4):792-8
references: 15451463
references: Traffic. 2001 Oct;2(10):675-83
references: 11576443
references: Nature. 2011 Apr 14;472(7342):221-5
references: 21346760
references: Stem Cells. 2011 Mar;29(3):462-73
references: 21425409
references: Curr Gene Ther. 2011 Feb;11(1):28-37
references: 21182467
references: J Med Genet. 2004 Apr;41(4):304-8
references: 15060110
references: Cell Stem Cell. 2010 Jun 4;6(6):535-46
references: 20569691