Gene therapy by allele selection in a mouse model of beta-thalassemia

被引:7
作者
Eckardt, Sigrid [1 ]
Leu, N. Adrian [2 ]
Yanchik, Ashley [2 ]
Hatada, Seigo [3 ]
Kyba, Michael [4 ,5 ]
McLaughlin, K. John [1 ,6 ]
机构
[1] Nationwide Childrens Hosp, Res Inst, Ctr Mol & Human Genet, Columbus, OH 43205 USA
[2] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA
[3] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA
[4] Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN USA
[5] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA
[6] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA
关键词
EMBRYONIC STEM-CELLS; HUMAN PARTHENOGENETIC BLASTOCYSTS; AUTOSOMAL-DOMINANT; PLATELET DISORDER; LINES; TRANSPLANTATION; MUTATION; PLURIPOTENT; EXPRESSION; DERIVATION;
D O I
10.1172/JCI45377
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
To be of therapeutic use, autologous stem cells derived from patients with inherited genetic disorders require genetic modification via gene repair or insertion. Here, we present proof of principle that, for diseases associated with dominant alleles (gain-of-function or haploinsufficient loss-of-function), disease allele-free ES cells can be derived from afflicted individuals without genome manipulation. This approach capitalizes on the derivation of uniparental cells, such as parthenogenetic (PG) ES cell lines from disease allele-free gametes. Diploid mammalian uniparental embryos with only maternally (oocyte-) or paternally (sperm-)derived genomes fail early in development due to the nonequivalence of parental genomes caused by genomic imprinting. However, these uniparental embryos develop to the blastocyst stage, allowing the derivation of ES cell lines. Using a mouse model for dominant beta-thalassemia, we developed disease allele-free PG ES cell lines from the oocytes of affected animals. Phenotype correction was obtained in donor-genotype recipients after transplantation of in vitro hematopoietic ES cell derivatives. This genetic correction strategy without gene targeting is potentially applicable to any dominant disease. It could also be the sole approach for larger or more complex mutations that cannot be corrected by homologous recombination.
引用
收藏
页码:623 / 627
页数:5
相关论文
共 32 条
[1]   ROLE OF PATERNAL AND MATERNAL GENOMES IN MOUSE DEVELOPMENT [J].
BARTON, SC ;
SURANI, MAH ;
NORRIS, ML .
NATURE, 1984, 311 (5984) :374-376
[2]   SELECTIVE ERYTHROID REPLACEMENT IN MURINE BETA-THALASSEMIA USING FETAL HEMATOPOIETIC STEM-CELLS [J].
BETHEL, CA ;
MURUGESH, D ;
HARRISON, MR ;
MOHANDAS, N ;
RUBIN, EM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (21) :10120-10124
[3]   THE COSTS OF HUMAN INBREEDING AND THEIR IMPLICATIONS FOR VARIATIONS AT THE DNA LEVEL [J].
BITTLES, AH ;
NEEL, JV .
NATURE GENETICS, 1994, 8 (02) :117-121
[4]   DIFFERENTIAL ACTIVITY OF MATERNALLY AND PATERNALLY DERIVED CHROMOSOME REGIONS IN MICE [J].
CATTANACH, BM ;
KIRK, M .
NATURE, 1985, 315 (6019) :496-498
[5]   Quebec platelet disorder is linked to the urokinase plasminogen activator gene (PLAU) and increases expression of the linked allele in megakaryocytes [J].
Diamandis, Maria ;
Paterson, Andrew D. ;
Rommens, Johanna M. ;
Veljkovic, D. Kika ;
Blavignac, Jessica ;
Bulman, Dennis E. ;
Waye, John S. ;
Derome, Francine ;
Rivard, Georges E. ;
Hayward, Catherine P. M. .
BLOOD, 2009, 113 (07) :1543-1546
[6]   Hematopoietic reconstitution with androgenetic and gynogenetic stem cells [J].
Eckardt, Sigrid ;
Leu, N. Adrian ;
Bradley, Heath L. ;
Kato, Hiromi ;
Bunting, Kevin D. ;
McLaughlin, K. John .
GENES & DEVELOPMENT, 2007, 21 (04) :409-419
[7]  
Eckardt S, 2009, TRENDS IN STEM CELL BIOLOGY AND TECHNOLOGY, P19, DOI 10.1007/978-1-60327-905-5_2
[8]   Gene therapy of inherited diseases [J].
Fischer, Alain ;
Cavazzana-Calvo, Marina .
LANCET, 2008, 371 (9629) :2044-2047
[9]   G-CSF receptor mutations in patients with congenital neutropenia [J].
Germeshausen, Manuela ;
Skokowa, Julia ;
Ballmaier, Matthias ;
Zeidler, Cornelia ;
Welte, Karl .
CURRENT OPINION IN HEMATOLOGY, 2008, 15 (04) :332-337
[10]   Genetic modification of human embryonic stem cells for derivation of target cells [J].
Giudice, Antonietta ;
Trounson, Alan .
CELL STEM CELL, 2008, 2 (05) :422-433