Long-term Improvements in Lifespan and Pathology in CNS and PNS After BMT Plus One Intravenous Injection of AAVrh10-GALC in Twitcher Mice

• Published in: Molecular therapy Vol. 23; no. 11; pp. 1681 - 1690
• Main Authors: Rafi, Mohammad A, Rao, Han Zhi, Luzi, Paola, Wenger, David A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2015; Elsevier Limited; Nature Publishing Group
• Subjects: Animals; Bone marrow; Bone Marrow Transplantation; Central Nervous System - metabolism; Central Nervous System - pathology; Dependovirus; Disease Models, Animal; Enzymes; Female; Fertility; Galactosylceramidase - genetics; Galactosylceramidase - metabolism; Genetic Therapy - methods; Genetic Vectors; Hematopoietic Stem Cell Transplantation - methods; Injections, Intravenous; Leukodystrophy, Globoid Cell - genetics; Leukodystrophy, Globoid Cell - therapy; Longevity; Male; Mice; Mice, Inbred C57BL; Nervous system; Original; Paralysis; Pathology; Peripheral Nervous System - metabolism; Peripheral Nervous System - pathology; Point Mutation; Spinal cord; Stem cell transplantation; Treatment Outcome; Vectors (Biology); United States > US; Pennsylvania
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2015.145

Krabbe disease is an autosomal recessive disorder resulting from defects in the lysosomal enzyme galactocerebrosidase (GALC). GALC deficiency leads to severe neurological features. The only treatment for presymptomatic infantile patients and later-onset patients is hematopoietic stem cell transplantation (HSCT). This treatment is less than ideal with most patients eventually developing problems with gait and expressive language. Several naturally occurring animal models are available, including twitcher (twi) mice, which have been used for many treatment trials. Previous studies demonstrated that multiple injections of AAVrh10-GALC into the central nervous system (CNS) of neonatal twi mice resulted in significant improvements. Recently we showed that one i.v. injection of AAVrh10-GALC on PND10 resulted in normal GALC activity in the CNS and high activity in the peripheral nervous system (PNS). In the present study, a single i.v. injection of AAVrh10-GALC was given 1 day after bone marrow transplantation (BMT) on PND10. The mice show greatly extended lifespan and normal behavior with improved CNS and PNS findings. Since HSCT is the standard of care in human patients, adding this single i.v. injection of viral vector may greatly improve the treatment outcome.