Widespread gene transduction to the central nervous system by adenovirus in utero: implication for prenatal gene therapy to brain involvement of lysosomal storage disease.
BACKGROUND
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.


METHODS
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 beta-glucuronidase was injected into the cerebral ventricles of the embryos of mucopolysaccharidosis VII mice and the therapeutic effects on the brain were evaluated.


RESULTS
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.


CONCLUSIONS
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.
Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Minato-Ku, Tokyo 105-8461, Japan.
Jin-Song
JS
Shen
Xing-Li
XL
Meng
Hiroshi
H
Maeda
Toya
T
Ohashi
Yoshikatsu
Y
Eto
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D005260:Female; D046128:Fetal Therapies / Q000379:methods*; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007276:Injections, Intraventricular; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D016538:Mucopolysaccharidosis VII / Q000196:embryology* / Q000235:genetics / Q000628:therapy*; D011247:Pregnancy; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D001616:beta-Galactosidase