KRABBE DISEASE--MOLECULAR ANALYSIS AND TREATMENT

Thomas Jefferson University, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION: Krabbe disease or globoid cell leukodystrophy (GLD) is a severe, autosomal recessive disorder caused by a deficiency of galactocerebrosidase (GALC) activity. This results in the inadequate catabolism of galactolipids important for the production of healthy, stable myelin. Although most patients present with symptoms before 6 months of age and die by 15 months, older patients are also diagnosed. The only treatment available at this time is heterologous bone marryow transplantation (BMT). This disease has three well characterizd naturally occurring animal models, the twitcher mouse, rhesus monkey, and the Cairn and West Highland White terriers. With the cloning of the human, mouse, monkey and dog GALC genes, disease-causing, as well as polymorphic, mutations have been identified. Recent findings, including a very high incidence of multiple polymorphisms in the GALC gene in individuals with low (10-25% of normal) GALC activity and undiagnosed white matter disease, and advances in constructing retroviral vectors expressing high levels of GALC activity, lead Dr. Wenger to propose the following aims: 1. Continue the molecular characterization of mutations in the GALC gene in a large number of patients available to him. All regions of the gene will be amplified and sequenced. 2. In order to investigate the effects of inheriting low, but not totally deficient, GALC activity, they plan to generate a transgenic mouse with similar changes and examine them biochemically, pathologically and clinically. He will examine the myelin, and its ability to remyelinate after experimental demyelination (by treating with cuprizone and lysolecithin). 3. Explore the use of retroviral vectors to transfer GALC cDNA to various cell types to provide enzyme to neighboring cells. 4. Produce affected Cairn terriers to explore treatment options including in utero and heterologous BMT, and the use of retrovirally transduced hematopoietic stem cells for autologous BMT. These studies will greatly improve the understanding of GLD, and provide the foundation for future attempts to successfully treat human patients.