title: Intravenous injection of AAVrh10-GALC after the neonatal period in twitcher mice results in significant expression in the central and peripheral nervous systems and improvement of clinical features.
abstract: Globoid cell leukodystrophy (GLD) or Krabbe disease is an autosomal recessive disorder resulting from the defective lysosomal enzyme galactocerebrosidase (GALC). The lack of GALC enzyme leads to severe neurological symptoms. While most human patients are infants who do not survive beyond 2 years of age, older patients are also diagnosed. In addition to human patients, several naturally occurring animal models, including dog, mouse, and monkey, have also been identified. The mouse model of Krabbe disease, twitcher (twi) mouse has been used for many treatment trials including gene therapy. Using the combination of intracerebroventricular, intracerebellar, and intravenous (iv) injection of the adeno-associated virus serotype rh10 (AAVrh10) expressing mouse GALC in neonate twi mice we previously have demonstrated a significantly extended normal life and exhibition of normal behavior in treated mice. In spite of the prolonged healthy life of these treated mice and improved myelination, it is unlikely that using multiple injection sites for viral administration will be approved for treatment of human patients. In this study, we have explored the outcome of the single iv injection of viral vector at post-natal day 10 (PND10). This has resulted in increased GALC activity in the central nervous system (CNS) and high GALC activity in the peripheral nervous system (PNS). As we have shown previously, an iv injection of AAVrh10 at PND2 results in a small extension of life beyond the typical lifespan of the untreated twi mice (~40 days). In this study, we report that mice receiving a single iv injection at PND10 had no tremor and continued to gain weight until a few weeks before they died. On average, they lived 20-25 days longer than untreated mice. We anticipate that this strategy in combination with other therapeutic options may be beneficial and applicable to treatment of human patients.
authors.affiliation: Department of Neurology, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: Mohammad.Rafi@jefferson.edu.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Rafi
authors.affiliation: Department of Neurology, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Han Zhi
authors.initials: HZ
authors.lastname: Rao
authors.affiliation: Department of Neurology, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Luzi
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Luddi
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Curtis
authors.affiliation: Department of Neurology, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wenger
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000201:enzymology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005698:Galactosylceramidase / Q000235:genetics* / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007275:Injections, Intravenous; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology / Q000628:therapy*; D051379:Mice; D008817:Mice, Mutant Strains; D017933:Peripheral Nervous System / Q000201:enzymology
chemical_list: D005698:Galactosylceramidase
keywords: AAVrh10; GALC; Galactocerebrosidase; Gene therapy; Globoid cell leukodystrophy; Krabbe disease