Hematopoietic cell transplantation ameliorates clinical phenotype and progression of the CNS pathology in the mouse model of late onset Krabbe disease.

Krabbe disease is a genetic demyelinating disease caused by a deficiency of galactosylceramidase. The majority of cases are of infantile onset with rapid clinical course. A rare late onset form with milder clinical symptoms also exists. The latter form has been reported to respond well to the bone marrow transplantation (BMT) therapy. We tested whether the BMT could be an effective therapy for the mouse model of the late onset form, saposin-A-/- (SAP-A-/-) mice. We used green fluorescent protein transgenic mice as the donors. Chimeric SAP-A-/- mice that received BMT showed very little evidence of neurologic symptoms. At postnatal day 190 when severe demyelination was evident in naive SAP-A-/- mice, demyelination was virtually absent in the brain of chimeric SAP-A-/- mice. Presence of residual enzyme activity, at the time of rapid myelination in SAP-A-/- mice, appears to limit initial inflammatory responses and macrophage infiltration, thereby preventing progression of demyelination in the CNS in SAP-A-/- mice. In contrast, the peripheral nerves showed features of hypertrophic neuropathy with hypomyelination and onion bulb formation, suggesting that there are different cellular responses to the BMT in the CNS and PNS.