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.
| Yeager, A M; Kanof, M E; Kramer, S S et al. (1987) Pneumatosis intestinalis in children after allogeneic bone marrow transplantation. Pediatr Radiol 17:18-22 |
| Toyoshima, E; Yeager, A M; Brennan, S et al. (1986) Nerve conduction studies in the Twitcher mouse (murine globoid cell leukodystrophy). J Neurol Sci 74:307-18 |
| Yeager, A M; Kaizer, H; Santos, G W et al. (1986) Autologous bone marrow transplantation in patients with acute nonlymphocytic leukemia, using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide. N Engl J Med 315:141-7 |
| Yeager, A M; Moser, H W; Tutschka, P J et al. (1986) Allogeneic bone marrow transplantation in adrenoleukodystrophy: clinical, pathologic, and biochemical studies. Birth Defects Orig Artic Ser 22:79-100 |
| Yeager, A M; Singer, H S; Buck, J R et al. (1985) A therapeutic trial of amniotic epithelial cell implantation in patients with lysosomal storage diseases. Am J Med Genet 22:347-55 |
