Journal
MOLECULAR THERAPY
Volume 3, Issue 3, Pages 284-292Publisher
ACADEMIC PRESS INC
DOI: 10.1006/mthe.2001.0267
Keywords
in utero; gene therapy; adeno-associated virus; visible bioluminescence; intraperitoneal; luciferase; fetal
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Funding
- NHLBI NIH HHS [R01 HL62389-01, 1RO1 HL58013] Funding Source: Medline
- NICHD NIH HHS [5RO1 HD37543-02] Funding Source: Medline
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Recombinant adeno-associated viruses (rAAV) are promising gene transfer vectors that produce long-term expression without toxicity. To investigate future approaches for in utero gene delivery, the efficacy and safety of prenatal administration of rAAV were determined. Using luciferase as a reporter, expression was assessed by whole-body imaging and by analysis of luciferase activity in tissue extracts, at the time of birth and monthly thereafter. Transgene expression was detected in all injected animals. Highest levels of luciferase activity were detected at birth in the peritoneum and liver, while the heart, brain, and lung demonstrated low-level expression. In vivo luciferase imaging revealed persistent peritoneal expression for 18 months after in utero injection and provided a sensitive whore-body assay, useful in identifying tissues for subsequent analyses. There was no detectable hepatocellular injury. Antibodies that reacted with either luciferase or rAAV were not found. AAV sequences were not detected in germ-line tissues of injected animals or in tissues of their progeny. In utero AAV-mediated gene transfer in this animal model demonstrates that novel therapeutic vectors and strategies can be rapidly tested in vivo and that rAAV may be developed to ameliorate genetic diseases with perinatal morbidity and mortality.
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