Therapeutic plasma concentrations of human factor IX in mice after gene delivery into the amniotic cavity: a model for the prenatal treatment of haemophilia B
✍ Scribed by Holm Schneider; Sheri Adebakin; Michael Themis; Terry Cook; Anne Marie Douar; Andrea Pavirani; Charles Coutelle
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 228 KB
- Volume
- 1
- Category
- Article
- ISSN
- 1099-498X
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✦ Synopsis
Background Several groups including our own have reported gene delivery to fetal organs by vector administration into the amniotic cavity. Based on these studies we hypothesised that the large surface of the fetal skin may be exploitable for high level production of systemically required gene products to be released into the fetal circulation.
Methods We administered E1/E3-deleted adenoviral vectors carrying a bacterial b-galactosidase gene or the human coagulation factor IX gene into the amniotic cavities of mid-to late-gestation mouse fetuses. The concentrations of human factor IX in the plasma of fetal or new-born mice were determined by ELISA. Reverse transcription PCR was used to identify sites of transgene expression.
Results Application of 5r10 8 infectious units of the factor IX gene vector in utero resulted in plasma concentrations of human factor IX of up to 1.2 mg/ml without signi®cant decrease in fetal survival. Transgenic protein was found to be produced in the fetal skin, mucosae and amniotic membranes and was shown to be present for several days after birth of healthy pups.
Conclusion
As ultrasound-guided amniocentesis in humans is a wellestablished diagnostic procedure, delivery of the factor IX gene into the amniotic cavity appears to be a safe route for prenatal treatment of haemophilia B and may prevent haemorrhagic complications such as intracranial bleeding during delivery. Our study allowed for the ®rst time a quanti®cation of the expression of a potentially therapeutic transgene in rodents after prenatal gene delivery. It thus provides a model for the prenatal treatment of haemophilia B, but may also serve as a path®nder to gene therapy of inheritable skin disorders such as epidermolysis bullosa. Copyright