In some lysosomal storage diseases, considerable alterations of the central nervous system (CNS) occur prior to birth and neurodegeneration progresses rapidly soon after birth causing early death in patients. No effective treatment is available after birth. Treatment may need to be initiated before birth to prevent the onset or progression of neurological changes and thereby irreversible brain damage. The aim of this study is to investigate the feasibility and effectiveness of brain-directed prenatal gene therapy for lysosomal storage diseases.
Recombinant adenovirus encoding the lacZ gene was injected into the lateral ventricles of mouse embryos and the pattern of gene transduction to the CNS was investigated. In the therapeutic experiment, adenovirus expressing β-glucuronidase was injected into the cerebral ventricles of the embryos of mucopolysaccharidosis VII mice and the therapeutic effects on the brain were evaluated.
Injection of adenoviral vectors to the cerebral ventricles of mouse embryos led to widespread gene transduction throughout the brain and the spinal cord and transgene expression persisted over 10 months in those surviving the procedure. The prenatal transduction of the therapeutic gene to the brain of the mucopolysaccharidosis VII mouse efficiently prevented lysosomal storage in most brain cells before birth until 4 months after birth.
Brain-directed in utero gene therapy through an intra-ventricular route would be an effective strategy to treat some lysosomal storage diseases with early and severe CNS alterations. Copyright © 2004 John Wiley & Sons, Ltd.