Globoid Cell Leukodystrophy (GLD; also Krabbe’s disease) is a hereditary disorder resulting from a deficiency in the lysosomal enzyme, galactocerebrosidase (GALC). Myelin forming cells [oligodendrocytes and Schwann cells in the central nervous sytem (CNS) and peripheral nervous system (PNS), respectively] require this enzyme to breakdown a myelin component, galactosylceramide. The lack of GALC activity causes the accumulation of toxic lipid metabolite, psychosine in the nervous system, which appears to be responsible for the death of myelin forming cells resulting in demyelination in the CNS and PNS. The majority of GLD patients develop rapidly progressive neurological dysfunction as infants, and die by 2 years of age. To-date, transplantation of bone marrow stem cells (BMT) and umbilical cord blood stem cells (UCBT) have been found to be beneficial in infantile patients who are diagnosed prenatally or before the onset of disease and in late-onset cases. It appears that these stem cell therapies provide GALC via donor-derived macrophages. However, only supportive care is available for the remaining GLD patients.

A characteristic pathology of GLD is the massive infiltration of blood-derived macrophages (globoid cells) in the demyelinating lesions. The roles of these cells are not known yet. One of our goals is to answer the question: Are they friend or foe? In our ongoing research, we have modified the twitcher mouse, a model of GLD, to create a GALC-deficient environment free from macrophage infiltration, which will allow us to investigate the function of macrophages in GLD.

Replacing the missing enzyme may be a key therapeutic strategy in GLD. However, difficulties have been found with this approach. 1) Progression of GLD may be too rapid for BMT or UCBT to be effective. 2) The therapy must work in both the CNS and PNS. Hence, a prerequisite for therapeutic success is an efficient, systemic method of delivery of GALC to the entire nervous system. Using twitcher mice, we are now seeking effective cellular vehicles to deliver the therapeutic enzyme to the nervous system using a variety of cell types that have been transduced to over-express the GALC enzyme.