Long-term and significant correction of brain lesions in adult mucopolysaccharidosis type VII mice using recombinant AAV vectors

Mol Ther. 2000 Jan;1(1):63-70. doi: 10.1006/mthe.1999.0005.


Most lysosomal storage diseases, including mucopolysaccharidosis, affect the central nervous system (CNS). They often induce severe and progressive mental retardation. Replacement therapy by purified enzyme infusions is a promising approach for the treatment of peripheral organs but without effect on CNS pathology because the enzyme cannot cross the blood-brain barrier. Intracranial injection of recombinant adeno-associated virus (AAV) vectors offers an alternative for sustained local enzyme delivery from genetically engineered cells. We stereotactically injected an AAV vector containing the human beta-glucuronidase cDNA into the striatum of adult mice severely affected by mucopolysaccharidosis type VII at the time of treatment. Six weeks later, beta-glucuronidase activity in the injected hemisphere was comparable to that of heterozygous mice, which have a normal phenotype. Areas staining positive for enzyme activity enlarged with time, representing more than 10% of the hemisphere volume by 16 weeks. A complete reversion of lysosomal storage lesions was evident in these areas, as well as in most neurons located in surrounding negative areas and in the noninjected hemisphere. Thus, a single intracerebral injection of AAV vectors could achieve a broad and sustained lysosomal enzyme delivery, allowing for stable reversion of storage lesions in a significant fraction of the adult brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / enzymology*
  • Brain / pathology
  • DNA, Complementary / administration & dosage
  • DNA, Complementary / genetics
  • Dependovirus / genetics*
  • Gene Expression
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Glucuronidase / genetics*
  • Glucuronidase / metabolism
  • Histocytochemistry
  • Humans
  • In Situ Hybridization
  • Injections
  • Mice
  • Mice, Mutant Strains
  • Mucopolysaccharidosis VII / enzymology*
  • Mucopolysaccharidosis VII / pathology
  • Mucopolysaccharidosis VII / therapy*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • DNA, Complementary
  • RNA, Messenger
  • Glucuronidase