title: Extended normal life after AAVrh10-mediated gene therapy in the mouse model of Krabbe disease.
abstract: Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). This deficiency results in accumulation of certain galactolipids including psychosine which is cytotoxic for myelin-producing cells. Treatment of human patients at this time is limited to hematopoietic stem cell transplantation (HSCT) that appears to slow the progression of the disease when performed in presymptomatic patients. In this study, adeno-associated virus (AAV) serotype rh10-(AAVrh10) expressing mouse GALC was used in treating twitcher (twi) mice, the mouse model of GLD. The combination of intracerebroventricular, intracerebellar, and intravenous (iv) injection of viral particles in neonate twi mice resulted in high GALC activity in brain and cerebellum and moderate to high GALC activity in spinal cord, sciatic nerve, and some peripheral organs. Successfully treated mice maintained their weight with no or very little twitching, living up to 8 months. The physical activities of the long-lived treated mice were comparable to wild type for most of their lives. Treated mice showed normal abilities to mate, to deliver pups, to nurse and to care for the newborns. This strategy alone or in combination with other therapeutic options may be applicable to treatment of human patients.
authors: Department of Neurology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. mohammad.rafi@jefferson.edu
authors: Mohammad A
authors: MA
authors: Rafi
authors: Han Zhi
authors: HZ
authors: Rao
authors: Paola
authors: P
authors: Luzi
authors: Mark T
authors: MT
authors: Curtis
authors: David A
authors: DA
authors: Wenger
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002531:Cerebellum / Q000201:enzymology / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005684:Gait; D005698:Galactosylceramidase / Q000096:biosynthesis / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007276:Injections, Intraventricular; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008017:Life Expectancy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength; D009186:Myelin Sheath / Q000473:pathology; D011597:Psychomotor Performance; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D005698:Galactosylceramidase