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Widespread and highly persistent gene transfer to the CNS by retrovirus vector in utero : implication for gene therapy to Krabbe disease
Author(s) -
Shen JinSong,
Meng XingLi,
Yokoo Takashi,
Sakurai Ken,
Watabe Kazuhiko,
Ohashi Toya,
Eto Yoshikatsu
Publication year - 2005
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.719
Subject(s) - genetic enhancement , biology , transduction (biophysics) , transgene , retrovirus , in utero , viral vector , gene expression , gene delivery , gene , krabbe disease , lysosomal storage disease , central nervous system , pathology , genetics , medicine , fetus , endocrinology , leukodystrophy , recombinant dna , disease , pregnancy , biochemistry , enzyme
Abstract Background Brain‐directed prenatal gene therapy may benefit some lysosomal storage diseases that affect the central nervous system (CNS) before birth. Our previous study showed that intrauterine introduction of recombinant adenoviruses into cerebral ventricles results in efficient gene transfer to the CNS in the mouse. However, transgene expression decreased with time due to the non‐integrative property of adenoviral vectors. In this study, in order to obtain permanent gene transduction, we investigated the feasibility of retrovirus‐mediated in utero gene transduction. Methods Concentrated retrovirus encoding the LacZ gene was injected into the cerebral ventricles of the embryos of normal and twitcher mice (a murine model of Krabbe disease) at embryonic day 12. The distribution and maintenance of the transgene expression in the recipient brain were analyzed histochemically, biochemically and by the quantitative polymerase chain reaction method pre‐ and postnatally. Results Efficient and highly persistent gene transduction to the brain was achieved both in normal and the twitcher mouse. Transduced neurons, astrocytes and oligodendrocytes were distributed throughout the brain. The transduced LacZ gene, its transcript and protein expression in the brain were maintained for 14 months without decrement. In addition, gene transduction to multiple tissues other than the brain was also detected at low levels. Conclusions This study suggests that brain‐directed in utero gene transfer using retrovirus vector may be beneficial to the treatment of lysosomal storage diseases with severe brain damage early in life, such as Krabbe disease. Copyright © 2005 John Wiley & Sons, Ltd.