TRANSPLANT THERAPY IN MURINE GLOBOID CELL LEUKODYSTROPHY

Genetic storage diseases such as the mucopolysaccharidoses and
sphingolipidoses are associated with significant morbidity and mortality in
pediatric patients and are not adequately treated with present therapeutic
modalities. Theoretically, transplantation of proliferating, normal
allogeneic cells could provide long-term enzyme replacement therapy in
these disorders and thus reverse or attenuate the neurological
deterioration atributable to accumulated storage material in the CNS. The
"twitcher" mouse is an authentic animal model of globoid cell
leukodystrophy (Krabbe disease; galactosylceramidase deficiency), a
sphingolipidosis which causes progressive psychomotor degeneration in
infants. The proposed studies examine the effect of transplantation of
allogeneic hematopoietic or amniotic epithelial cells from normal mice into
affected twitcher mice. The clinical course and survival of transplanted
and untransplanted twitcher mice will be compared. At selected time points
after transplantation, levels of galactosylceramidase will be assayed in
various tissues of transplanted mice and appropriate controls, using
tritiated galactysylceramide as the substrate. Histologic examinations of
neural tissue will be conducted to detect characteristic neuropathologic
features of globoid cell leukodystrophy and histopathologic alterations of
these features following transplantation. In addition, studies will be
performed to examine the clinical and biochemical effects of perturbation
of the blood-brain barrier on transplanted and untreated twitcher mice.
The proposed project should provide basic information on the biochemical,
neuropathologic, and overall clinical effects of allogeneic cellular
transplantation in a prototypic animal model of genetic storage disease.
The information thus obtained is relevant to the applicability of
transplantation therapy in human lysosomal diseases and provides the basis
for subsequent studies of the biology of cellular transplantation in inborn
errors of metabolism.