Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements

Twitcher mouse is a murine model of human globoid cell leukodystrophy (Krab be disease), which is characterized by a genetic deficiency in galactocereb rosidase (GALC) activity. The nervous system is affected early and severely by demyelination in the white matter. So far, there is no effective treatm ent for Krabbe disease except bone marrow transplantation (BMT), However, B MT has inherent limitations such as unavailability of donors and graft-vers us-host disease. In this study, we injected recombinant adenovirus encoding GALC into the lateral ventricle of twitcher mice at postnatal day 0 (PND 0 ) and the therapeutic effects were evaluated. Our results showed slight, bu t significant improvements in motor functions, body weight and twitching an d a prolonged life span. In brain, GALC activity was increased to 15% that of normal littermates and psychosine concentration was decreased to 55% tha t of untreated twitcher mice at PND 15. The number of PAS-positive globoid cells in brain stem was also reduced significantly at PND 35. In contrast, when adenoviruses were injected to the twitcher mice at PND 15, almost no i mprovements were observed. These results demonstrate that the timing of tre atment may be of great importance in Krabbe disease.