DESCRIPTION (provided by applicant): Krabbe disease (globoid cell leukodystrophy) is an inherited neurodegenerative disorder caused by mutations in the galactosylceramidase gene (GALC), leading to galactolipid accumulation, abnormal central and peripheral nervous system (CNS and PNS) myelination, oligodendrocyte and Schwann cell death, and the infiltration of multinucleated macrophages (globoid cells). Cognitive decline and motor deterioration develop in affected infants with death commonly occurring before the age of five. Newborn screening for Krabbe disease is currently performed in many states, thereby allowing for treatment of presymptomatic babies with hematopoietic stem-cell transplantation (HPCT), the current standard of care. However, while HPCT results in some cognitive improvement, motor deficits persist. There is no cure for Krabbe disease. Recent studies in the Twitcher mouse, a murine model of Krabbe disease, have shown that a combination of intracranial injection of an adeno-associated virus (AAV) vector carrying a wild type copy of murine GALC cDNA synergizes with HPCT to significantly improve motor deficits, survival time, and CNS pathology. Although clearly promising at a therapeutic level, the mechanisms responsible for the synergy of combination therapy observed in the Twitcher mouse are not understood. We hypothesize that the synergy observed with combination therapy results from HPCT-driven effects in the CNS effects and AAV-mediated gene therapy effects in the PNS. Differences in disease phenotype between murine and human Krabbe disease and the small size of the mouse limit the translational utility of this model. In contrast, naturally-occurring Krabbe disease in dogs recapitulates the clinical, pathological, and biochemical abnormalities of human disease. Additionally, the dog, similar in size to that of an infant, allows for the evaluation of HPCT and CNS gene transfer methods identical to those that can be used in infants, and for the identification and validation of clinicl, biochemical, and imaging markers of nervous system disease severity and therapeutic efficacy using methods that are used in pediatric clinics. The proposed studies will help determine the mechanism of the synergy seen with combination therapy, and will provide insight into disease pathogenesis, potentially identifying new pathways for future design of additional therapeutic strategies. Our lab is uniquely suited to evaluating the mechanistic effects of experimental therapies in large animal models of human nervous system disease.

PUBLIC HEALTH RELEVANCE: Krabbe disease, an inherited neurodegenerative disorder in which normal CNS and PNS myelin formation is compromised, results in cognitive decline and motor deterioration that ultimately results in early death. There is no cure. The proposed studies will help determine the mechanism of the synergistic positive effects seen when hematopoietic stem cell transplantation is combined with gene therapy in animal models of Krabbe disease, and will provide insight into disease pathogenesis, potentially identifying new pathways for future design of additional therapeutic strategies.