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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1625-1634
GENE THERAPY
In utero transplantation of fetal liver cells in the
mucopolysaccharidosis type VII mouse results in low-level
chimerism, but overexpression of  -glucuronidase can delay
onset of clinical signs
Margret L. Casal and
John
H. Wolfe
From the Department of Pathobiology and Center for
Comparative Medical Genetics, School of Veterinary Medicine, University
of Pennsylvania, and Children's Hospital of Philadelphia,
Philadelphia, PA.
Mice with the lysosomal storage disease mucopolysaccharidosis (MPS)
VII, caused by a deficiency of  -glucuronidase (GUSB), have signs of
disease present at birth. Bone marrow transplantation (BMT) or
retroviral vector-mediated gene transfer into hematopoietic stem cells
can partially correct the disease in adult mice, and BMT performed at
birth results in a better clinical outcome. Thus, treatment in utero
may result in further improvement. However, this must be done without
cyto-ablation, and the donor cells do not have a competitive
repopulating advantage over host cells. Transplantation in utero of
either syngeneic fetal liver hematopoietic stem cells marked with a
retroviral vector, or allogeneic donor cells that constitutively
express high levels of human GUSB from a transgene, resulted in only
about 0.1% engraftment in the adult. Immuno-affinity enrichment of
stem and progenitor cells of 5- to 10-fold resulted in significantly
higher GUSB activities at 2 months of age, but by 6 months engraftment
was about 0.1%. Attempts to further increase the number of stem and
progenitor cells were deleterious to the recipients. Nevertheless, GUSB
expressed during the first 2 months of life in MPS VII fetuses could
delay the onset of overt signs of disease. This suggests that the
expression of some normal enzyme activity beginning in fetal life may
offer the possibility of slowing the progression of the disease until more definitive postnatal transplantation or gene transfer to stem
cells could be accomplished.
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