Novel Therapies for Globoid-Cell Leukodystrophy

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DESCRIPTION (provided by applicant): Globoid-cell leukodystrophy (GLD, Krabbe disease) is a demyelinating neurodegenerative disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC). GLD affects both the central (CNS) and peripheral (PNS) nervous systems, and is characterized histologically by the influx of periodic-acid Schiff (PAS)-positive macrophages (globoid-cells) and profound demyelination. The infantile form of GLD is characterized clinically by an early onset (three to six months of age) with irritability, dysphagia, spasticity, cognitive and sensory deterioration, seizures, and death usually by two to three years of age. A murine model of infantile GLD (Twitcher mouse) has been described which is completely deficient in GALC activity and exhibits many of the biochemical, histological, and clinical features of human GLD. Currently, the only therapeutic approach that has shown any efficacy and has been used in affected children is allogeneic bone marrow transplantation (BMT). It has been shown that BMT performed in both presymptomatic children and the Twitcher mouse can provide dramatically increased efficacy compared to BMT performed after symptoms have developed. However, BMT only provides a partial response and children with GLD and Twitcher mice still have significant clinical disease. Taken together these data suggest that: 1) early diagnosis and intervention are critical for successful treatment of this disease, and 2) new and innovative approaches are required to more effectively treat this disease. The investigators recently showed that a combination of CNS-directed AAV2/5-mediated gene therapy and BMT following myeloreductive conditioning was more effective than either therapy alone. In fact, there was dramatic synergy between these two disparate approaches. Twitcher mice treated with BMT alone, AAV2/5 alone or a combination of AAV2/5 and BMT lived an average of 43, 53, and 105 days, respectively. The goals of this research are to better understand the progression of disease and develop effective therapeutic approaches for GLD. These goals will be accomplished with Specific Aim 1, to quantify the temporal and spatial pattern of cellular infiltration, inflammatory mediator expression, apoptosis, and other histological changes in the CNS and PNS of Twitcher mice, and Specific Aim 2, to determine the efficacy of various combinations of CNS- and hematopoietic-directed gene therapy approaches.