Globoid cell Leukodystrophy (GLD) or Krabbe disease is a rapidly progressing, neurodegenerative disease caused by the deficiency of the lysosomal enzyme Galactocerebrosidase (GALC). The pathological characteristics include presence of globoid cells and decreased myelin. In its severe infantile form, the symptoms appear within the first 6 months of life and complete loss of GALC function is fatal by 2-3 years old. The murine model of infantile GLD, the twitcher mouse, has been used to evaluate potential therapeutic approaches for GLD. Hematopoietic stem cell transplantation (HSCT) provides modest benefit in presymptomatic patients and mice indicating a slowdown in the progression of the disease, but no complete cure. Neonatal gene transfer experiments using viral vectors also has shown some limited success in extending the survival of the twitcher mice. The translatability of neonatal therapy in mice to human has met with difficulties as the stage of the disease in human and mice differ due to the difference in their gestation periods. So there is a need for testing out later stage interventions for GLD treatment. In the present study, we compare multiple vector designs along with a combination treatment of AAV plus bone marrow transplant (BMT) in juvenile twitcher mice. Initially, three single stranded (ss) AAV serotypes, two natural and one engineered (with oligodendrocyte tropism), were packaged with a codon-optimized murine GALC gene driven by the beta actin promoter. The vectors were delivered via a lumbar intrathecal route for global CNS distribution on post-natal day (PND) 10-11, at a dose of 2×1011 vg per mouse. The results show a significant extension of life span of the twitcher mice for all three serotypes (AAV9, AAVrh10, and AAV-Olig001) when compared to control cohorts. The treatment produced similar survival benefit regardless of which capsid was used. The rAAV gene transfer facilitates GALC biodistribution and detectable enzymatic activity throughout the CNS as well as in sciatic nerve and liver. When combined with BMT from syngeneic wild type mice, there was significant improvement in survival and enzymatic activity over either treatment alone. Immunohistochemical analysis of the brain and spinal cord showed reduced inflammation and pathology. Additionally, we have also tested a novel self-complementary (sc) AAV vector with a minimal synthetic promoter, which would mediate a weaker overall level of GALC expression but express in more cells. Preliminary results indicate that this vector design provides a survival advantage over the ssAAV vector designs. In summary, we demonstrate that lumbar intrathecal delivery of rAAV/mGALCopt can significantly enhance the life span of twitcher mice treated at juvenile stage (PND10-11) and BMT synergizes with this treatment to further improve the survival. This effect is mediated by increased GALC activity in various parts of the nervous system as well as by the reduction in neuro-inflammation. Together, these studies detail a therapeutic approach for GLD in mice which is feasible and relevant for human translation.