beta-hexosaminidase lentiviral vectors: transfer into the CNS via systemic administration.

Abstract

Brain inflammation in GM2 gangliosidosis has been recently realized as a key factor in disease development. The aim of this study was to investigate the effects of a FIV beta-hexosaminidase vector in the brain of HexB-deficient (Sandhoff disease) mice following intraperitoneal administration to pups of neonatal age. Since brain inflammation, lysosomal storage and neuromuscular dysfunction are characteristics of HexB deficiency, these parameters were employed as experimental outcomes in our study. The ability of the lentiviral vector FIV(HEX) to infect murine cells was initially demonstrated with success in normal mouse fibroblasts and human Tay-Sachs cells in vitro. Furthermore, systemic transfer of FIV(HEX) to P2 HexB-/- knockout pups lead to transduction of peripheral and central nervous system tissues. Specifically, beta-hexosaminidase expressing cells were immunolocalized in periventricular areas of the cerebrum as well as in the cerebellar cortex. FIV(HEX) neonatal treatment resulted in reduction of GM2 storage along with attenuation of the brain inflammation and amelioration of the attendant neuromuscular deterioration. In conclusion, these results demonstrate the effective transfer of a beta-hexosaminidase lentiviral vector to the brain of Sandhoff mice and resolution of the GM2 gangliosidosis after neonatal intraperitoneal administration.

• Authors: Stephanos Kyrkanides, Jennie H Miller, Sabine M Brouxhon, John A Olschowka, Howard J Federoff
• Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res) Vol. 133 Issue 2 Pg. 286-98 (Feb 18 2005) ISSN: 0169-328X [Print] Netherlands
• PMID: 15710246 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Galactosides
• Glial Fibrillary Acidic Protein
• Histocompatibility Antigens Class II
• Indoles
• G(M2) Ganglioside
• Hymecromone
• 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-beta-glucopyranoside
• Hexosaminidase B
• beta-N-Acetylhexosaminidases
• 5-bromo-4-chloro-3-indolyl beta-galactoside

Topics

• Animals
• Animals, Newborn
• Behavior, Animal
• Cell Count (methods)
• Cell Line
• Central Nervous System (anatomy & histology, metabolism, virology)
• Cricetinae
• Fibroblasts (metabolism, virology)
• G(M2) Ganglioside (metabolism)
• Galactosides (metabolism)
• Gene Expression Regulation (drug effects)
• Genetic Vectors (administration & dosage)
• Glial Fibrillary Acidic Protein (metabolism)
• Hexosaminidase B
• Histocompatibility Antigens Class II (metabolism)
• Histocytochemistry (methods)
• Humans
• Hymecromone (analogs & derivatives, pharmacology)
• Immunodeficiency Virus, Feline (physiology)
• Indoles (metabolism)
• Lentivirus (genetics)
• Lentivirus Infections
• Mice
• Mice, Knockout
• Peripheral Nerves (metabolism, virology)
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Rotation
• Transduction, Genetic (methods)
• beta-N-Acetylhexosaminidases (biosynthesis, classification, deficiency, genetics)