Premium
Minimum requirement of donor cells to reduce the glycolipid storage following bone marrow transplantation in a murine model of Fabry disease
Author(s) -
Yokoi Takayuki,
Kobayashi Hiroshi,
Shimada Yohta,
Eto Yoshikatsu,
Ishige Nobuyuki,
Kitagawa Teruo,
Otsu Makoto,
Nakauchi Hiromitsu,
Ida Hiroyuki,
Ohashi Toya
Publication year - 2011
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.1566
Subject(s) - globotriaosylceramide , chimera (genetics) , bone marrow , transplantation , haematopoiesis , glycolipid , stem cell , immunology , biology , hematopoietic stem cell transplantation , fabry disease , genetic enhancement , andrology , medicine , pathology , disease , biochemistry , gene , microbiology and biotechnology
Abstract Background Fabry disease (FD) is a lysosomal storage disorders characterized by a deficiency of the lysosomal enzyme, α‐galactosidase A. This results in the accumulation of glycolipids, mainly globotriaosylceramide (GL‐3), in the lysosomes of various organs. Although bone marrow transplantation and hematopoietic stem cell‐based gene therapy can offer the potential of a curative therapeutic outcome for FD, the minimum requirement of donor cells or gene‐corrected cells to reduce GL‐3 levels is not known. Methods Lethally‐irradiated FD mice were transplanted intravenously with normal bone marrow cells (Ly5.1 positive) mixed with those of FD mice (Ly5.2 positive) at various ratios to investigate the level of engraftment and enzyme activity necessary to effect a reduction in GL‐3 storage. Results Chimerism of whole white blood cells of recipients' peripheral blood remained stable at 8 weeks after transplantation, and chimerism of granulocytes, monocytes, B cells and T cells was equal to that of white blood cells. GL‐3 levels were significantly reduced in the lung and heart of animals with a 30% and 50% chimera, respectively. The extent of reduction in these mice was almost identical to that with 100% chimera. Conclusions In FD mice, reconstitution with 100% donor cells is not required to obtain a therapeutic effect following bone marrow transplantation. These results suggest that a 30% gene correction might be sufficient to reverse disease manifestations in FD. Copyright © 2011 John Wiley & Sons, Ltd.