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 β-glucuronidase cDNA into the striatum of adult mice severely affected by mucopolysaccharidosis type VII at the time of treatment. Six weeks later, β-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. © 2000 American Society for Gene Therapy.
Bosch, A., Perret, E., Desmaris, N., & Heard, J. M. (2000). Long-Term and Significant Correction of Brain Lesions in Adult Mucopolysaccharidosis Type VII Mice Using Recombinant AAV Vectors. Molecular Therapy, 1(1), 63–70. https://doi.org/10.1006/mthe.1999.0005