Globoid cell leukodystrophy is a rare autosomal recessive genetic disease caused by low levels of B-galactosidase activity, an enzyme important in myelin metabolism. An infant rhesus monkey had lesions morphologically identical to those of globoid cell leukodystrophy in humans. We examined relatives of the affected infant for levels of B-galactosidase activity and identified several possibly heterozygous individuals. These animals were placed in corncribs for breeding. All offspring are clinically normal to date. Due to the difficulty of definitively identifying heterozygous individuals based on biochemical evaluation alone, in 1992 we instituted a program of artificial insemination to test breed different males in hopes of increasing the likelihood of producing another homozygous infant and of positively identifying heterozygous parents. The human gene for Krabbe's disease was cloned in 1994. Last year we initiated a collaboration with Dr. David Wenger to identify heterozygous individuals by molecular biological techniques, thus eliminating the difficulties in unambiguously identifying heterozygous monkeys by enzyme biochemistry. We grew fibroblasts from a known heterozygote and a normal animal upon which to perform preliminary studies. Dr. Wenger's laboratory sequenced the rhesus B-galactosidase gene, but unfortunately found no meaningful mutations. This sometimes occurs in obligate heterozygotes from affected human families also. A homozygous affected infant will be needed to go any farther with this project. We have reduced the number of animals being held on this project and will focus our efforts to produce a homozygous infant on the most promising breeders based on repeated biochemical findings. We hope to be able to superovulate and in vitro fertilize ova from the obligate heterozygous female this year. This represents the only available nonhuman primate model of a lysosomal storage disease and, once developed, may be a useful model for testing gene therapy and for studying the pathogenesis of Krabbe's disease, the least understood lysosomal storage disease.
NIH ExPorter
NIH ExPorter