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Publication Detail
Sustained delivery of therapeutic concentrations of human clotting factor IX - a comparison of adenoviral and AAV vectors administered in utero
  • Publication Type:
    Journal article
  • Publication Sub Type:
    JOUR
  • Authors:
    Schneider H, Mühle C, Douar AM, Waddington S, Jiang Q, Mark KVD, Coutelle C, Rascher W
  • Publication date:
    2002
  • Pagination:
    46, 53
  • Volume:
    4
  • Notes:
    Background Prenatal somatic gene therapy has been considered for genetic disorders presenting with morbidity already at birth. Haemophilia is associated with an increased risk of catastrophic perinatal bleeding complications such as intracranial haemorrhage. For both haemophilia A and B gene therapy attempts have been successful in animal models. Prenatal gene therapy may be more promising than postnatal treatment as the fetus may be more amenable to uptake and integration of therapeutic DNA and the immaturity of its immune system may permit life-long immune tolerance of the transgenic protein, thus avoiding the dominating problem in haemophilia treatment, the formation of inhibitory antibodies. Methods Adenoviral or AAV vectors carrying human factor IX cDNA or a reporter gene were administered intramuscularly, intraperitoneally or intravascularly to late-gestation mouse fetuses. Both vector types were evaluated with respect to the kinetics of human factor IX delivery to the systemic circulation and possible immune responses against vector or transgene product. Results Mice treated in utero by intramuscular injection of an adenoviral vector carrying human factor IX cDNA exhibited high-level gene expression at birth and therapeutic - albeit continuously decreasing - plasma concentrations of human factor IX over the entire 6-months time course of the study. Adenoviral vector spread to multiple organs was detectable by nested PCR. Intramuscular, intraperitoneal or intravascular application of AAV vectors carrying human factor IX cDNA led to comparatively lower plasma concentrations of human factor IX shortly after birth, which declined during the first month of life - probably due to the rapidly increasing blood volume of the growing animals - but stabilised at low levels in some of the mice over the remaining five months of this study. No signs of humoral or cellular immune responses were found, neither against the adenoviral vector nor against AAV. Conclusion This study demonstrates for the first time that sustained systemic delivery of a therapeutic protein can be achieved by application of both adenoviral and AAV vectors in utero. It thus proves the feasibility of gene therapy in utero and provides a basis for considering this concept as a preventive therapeutic strategy for haemophilia and perhaps also for other plasma protein deficiencies.
Abstract
Background Prenatal somatic gene therapy has been considered for genetic disorders presenting with morbidity already at birth. Haemophilia is associated with an increased risk of catastrophic perinatal bleeding complications such as intracranial haemorrhage. For both haemophilia A and B gene therapy attempts have been successful in animal models. Prenatal gene therapy may be more promising than postnatal treatment as the fetus may be more amenable to uptake and integration of therapeutic DNA and the immaturity of its immune system may permit life-long immune tolerance of the transgenic protein, thus avoiding the dominating problem in haemophilia treatment, the formation of inhibitory antibodies. Methods Adenoviral or AAV vectors carrying human factor IX cDNA or a reporter gene were administered intramuscularly, intraperitoneally or intravascularly to late-gestation mouse fetuses. Both vector types were evaluated with respect to the kinetics of human factor IX delivery to the systemic circulation and possible immune responses against vector or transgene product. Results Mice treated in utero by intramuscular injection of an adenoviral vector carrying human factor IX cDNA exhibited high-level gene expression at birth and therapeutic - albeit continuously decreasing - plasma concentrations of human factor IX over the entire 6-months time course of the study. Adenoviral vector spread to multiple organs was detectable by nested PCR. Intramuscular, intraperitoneal or intravascular application of AAV vectors carrying human factor IX cDNA led to comparatively lower plasma concentrations of human factor IX shortly after birth, which declined during the first month of life - probably due to the rapidly increasing blood volume of the growing animals - but stabilised at low levels in some of the mice over the remaining five months of this study. No signs of humoral or cellular immune responses were found, neither against the adenoviral vector nor against AAV. Conclusion This study demonstrates for the first time that sustained systemic delivery of a therapeutic protein can be achieved by application of both adenoviral and AAV vectors in utero. It thus proves the feasibility of gene therapy in utero and provides a basis for considering this concept as a preventive therapeutic strategy for haemophilia and perhaps also for other plasma protein deficiencies.
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