This is a revision of application 1 ROI NS 29099-01 which had been reviewed and approved by a Special Review Committee SRC-03. This revision proposes to test the hypothesis that bone marrow transplantation can prevent severe psychomotor retardation and neurologic disability in seven storage diseases (MPS:I,II,III) (Leukodystrophies: MLD, GCLD, Adrenoleukodystrophy) (Gaucher's disease III). Normalization of enzyme activity does inhibit the substrate accumulation which in itself causes the inexorable loss of central nervous system function. Biochemically, marrow transplantation has been shown to metabolically correct and prevent cerebrospinal fluid accumulation of glycosaminoglycan in mucopolysaccharidosis and sulfatide in metachromatic leukodystrophy. Neurological and intellectual outcomes in individual patients have been reported to be better than historical or sibling controls. However, most of the patients have been left with considerable central nervous system dysfunction. The concept of successfully providing a permanent and normal amount of active enzyme without need of medication for the individuals entire life in these incapacitating diseases has strong appeal since there is no alternative therapy. The transplant process has a mortality and a morbidity due to infection and graft versus host disease during the first 3-6 months. After engraftment has been present for a year,a new clinical spectrum is produced. Because of the increased medical care and attention given to the transplanted patient, the neurologic and intellectual status is difficult to compare to historical or sibling controls. Furthermore, the biologic diversity within each clinical syndrome provides a lack of assurance of comparability. Because of the gravity of entering patients into a costly and lengthy procedure, a data consortium of 20 institutions in the United States and Canada with over 75 investigators has been constructed to quantitatively and qualitatively measure value of such bone marrow transplants in a prospective manner. A non-transplanted and transplanted group will be simultaneously studied as selected by an unbiased method since only 50% of patients will have a compatible donor with an acceptable risk factor of mortality and morbidity. Annual neuro-psychologic, radiologic and neurophysiologic measurements are detailed in the application. Specific testing process, delineation of end-points, data accrual, and statistical analysis has been provided in depth. There has been an increase in number of institutions and investigators willing to participate. Detection of benefit or disadvantage in comparable groups of transplant and non-transplanted patients can only be documented in an acceptable scientific manner by fullest use of this revised grant proposal.
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