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Fetal gene therapy of α-thalassemia in a mouse model

Cardiovascular Research Institute, Institute of Human Genetics and Department of Medicine, University of California, San Francisco, CA 94143, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2007; 104(21):9007-11. DOI: 10.1073/pnas.0702457104
Source: PubMed

ABSTRACT Fetuses with homozygous alpha-thalassemia usually die at the third trimester of pregnancy or soon after birth. Hence, the disease could potentially be a target for fetal gene therapy. We have previously established a mouse model of alpha-thalassemia. These mice mimic the human alpha-thalassemic conditions and can be used as preclinical models for fetal gene therapy. We tested a lentiviral vector containing the HS 2, 3, and 4 of the beta-LCR, a central polypurine tract element, and the beta-globin gene promoter directing either the EGFP or the human alpha-globin gene. We showed that the GFP expression was erythroid-specific and detected in BFU-E colonies and the erythroid progenies of CFU-GEMM. For in utero gene delivery, we did yolk sac vessel injection at midgestation of mouse embryos. The recipient mice were analyzed after birth for human alpha-globin gene expression. In the newborn, human alpha-globin gene expression was detected in the liver, spleen, and peripheral blood. The human alpha-globin gene expression was at the peak at 3-4 months, when it reached 20% in some recipients. However, the expression declined at 7 months. Colony-forming assays in these mice showed low abundance of the transduced human alpha-globin gene in their BFU-E and CFU-GEMM and the lack of its transcript. Thus, lentiviral vectors can be an effective vehicle for delivering the human alpha-globin gene into erythroid cells in utero, but, in the mouse model, delivery at late midgestation could not transduce hematopoietic stem cells adequately to sustain gene expression.

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    • "R esearch on in utero gene transfer with animal models currently is under way, in an attempt to lay groundwork for clinical studies (Han et al., 2007; Gubbels et al., 2008; Niiya et al., 2009; Tarantal et al., 2010). If progress in this area continues, one can expect clinical research that initially will involve phase I studies. "
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    ABSTRACT: Clinical gene transfer research has involved adult and child subjects, and it is expected that gene transfer in fetal subjects will occur in the future. Some genetic diseases have serious adverse effects on the fetus before birth, and there is hope that prenatal gene therapy could prevent such disease progression. Research in animal models of prenatal gene transfer is actively being pursued. The prospect of human phase I in utero gene transfer studies raises important regulatory and ethical issues. One issue not previously addressed arises in applying U.S. research regulations to such studies. Specifically, current regulations state that research involving greater than minimal risk to the fetus and no prospect of direct benefit to the fetus or pregnant woman is not permitted. Phase I studies will involve interventions such as needle insertions through the uterus, which carry risks to the fetus including spontaneous abortion and preterm birth. It is possible that these risks will be regarded as exceeding minimal. Also, some regard the probability of therapeutic benefit in phase I studies to be so low that these studies do not satisfy the regulatory requirement that they "hold out the prospect of direct benefit" to subjects. On the basis of these considerations, investigators and institutional review boards might reasonably conclude that some phase I in utero studies are not to be permitted. This paper identifies considerations that are relevant to such judgments and explores ethically acceptable ways in which phase I studies can be designed so that they are permitted by the regulations.
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    • "), UDPglucuronyltransferase deficiency (Seppen et al. 2003), congenital blindness (Dejneka et al. 2004), a-thalassemia (Han et al. 2007), a-1-antitrypsin deficiency (Rosenfeld et al. 1991), and DMD (Reay et al. 2008). "
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    ABSTRACT: Efficient, widespread transgene expression in the muscle is one of the major challenges of gene transfer for the treatment of genetic muscle disorders. A good example of this disease is the Duchenne muscular dystrophy (DMD), a progressive, degenerative disease whose clinical symptoms manifest after birth, but whose genetic defect causing the disease is present at conception. The availability of prenatal testing for genetic muscle diseases provides the basis for treatments in utero. In utero gene transfer has the potential to achieve widespread transgene expression in the muscle by accomplishing gene delivery when the tissue mass is small and the immune system is still immature. In this chapter, we present preclinical experience with gene delivery strategies to treat muscle disorders in utero. Important issues include experience with different gene delivery vectors in preclinical models, gene expression in muscle tissue, and effects on immunity.
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