The Hopes and Fears of In Utero Gene Therapy for Genetic Disease—A Review

Coutelle, Charles; Themis, Michael; Waddington, Simon N.; Gregory, L; Nivsarkar, M; Buckley, Smk; Cook, Terry; Rodeck, Charles H.; Peebles, Donald; David, Anna L.

doi:10.1016/s0143-4004(03)00140-1

Cited by 25 publications

(14 citation statements)

References 28 publications

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“…4 These considerations have led to the development of gene therapy in fetal and neonatal animal models. [5][6][7] Several studies have established that fetal gene transfer can tolerize mice to foreign therapeutic proteins. Adenoviral and lentiviral clotting factor IX expression vectors were administered to fetal mice.…”

Section: Introductionmentioning

confidence: 99%

Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

Seppen¹,

Til²,

Rijt³

et al. 2005

Gene Ther

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Gene therapy for inherited disorders might cause an immune response to the therapeutic protein. A solution would be to introduce the gene in the fetal or neonatal period, which should lead to tolerization. Lentiviral vectors mediate long-term gene expression, and are well suited for gene therapy early in development. A model for fetal or neonatal gene therapy is the inherited disorder of bilirubin metabolism, Crigler-Najjar disease (CN). The absence of bilirubin UDP-glucoronyltransferase (UGT1A1) activity in CN patients causes high serum levels of unconjugated bilirubin and brain damage in infancy. CN is attractive for the development of gene therapy because the mutant Gunn rat closely mimics the human disease.Injection of UGT1A1 lentiviral vectors corrected the hyperbilirubinemia for more than a year in rats injected as fetuses and for up to 18 weeks in rats injected the day of birth. UGT1A1 gene transfer was confirmed by the presence of bilirubin glucuronides in bile. All animals injected with UGT1A1 lentiviral vectors developed antibodies to UGT1A1. Animals injected with green fluorescent protein (GFP) lentiviral vectors did not develop antibodies to GFP. Our results indicate that fetal and neonatal gene therapy with immunogenic proteins such as UGT1A1 does not necessarily lead to tolerization.

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Section: Introductionmentioning

confidence: 99%

Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

Seppen¹,

Til²,

Rijt³

et al. 2005

Gene Ther

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show abstract

“…Gene transfer research is a developing field, and we have much to learn before we can carry out such therapy safely and effectively. A number of requirements for successful gene therapy have been identified (Somia and Verma, 2000;Coutelle et al, 2003). For gene therapy to work, normal DNA must reach the appropriate target cells.…”

Section: Introductionmentioning

confidence: 99%

“…Fourth, there may be a greater uptake of DNA in the fetus compared with the infant, particularly when retroviral vectors are used, because retroviral vectors integrate into dividing cells, and cell division is high during gestation. Given these potential advantages, various diseases are being considered for prenatal gene therapy, including hemophilia, cystic fibrosis, muscular dystrophy, and sickle cell anemia, among others (Coutelle et al,, 2003;Waddington et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Regulatory and Ethical Issues for Phase IIn UteroGene Transfer Studies

Strong

2011

Human Gene Therapy

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“…A variety of animal models have been employed for prenatal, in utero gene transfer [6,9] . The rabbit is a middle-sized animal model allowing accurate organ-directed manipulation and delivery of gene transfer vectors.…”

Section: Introductionmentioning

confidence: 99%

Feasibility of Retroviral Vector-Mediated in utero Gene Transfer to the Fetal Rabbit

Moreno

Rosal²,

Cabero³

et al. 2005

Fetal Diagn Ther

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Objectives: Successful treatment or prevention of severe hereditary diseases could conceivably be achieved by genetic intervention early in development. Viral vector-mediated fetal gene transfer is proving a valuable tool to test the above concept in relevant animal models. Although the pregnant rabbit is a well-recognized model for fetal therapy, few preclinical assays have used it to validate fetal gene transfer approaches. In this preliminary study we assessed for the first time the feasibility of retroviral vector-mediated in utero gene transfer in the fetal rabbit. Methods: Different amounts of the vesicular stomatitis virus G pseudotyped MFG(nls)LacZ retroviral vector, expressing a nuclear-localized β-galactosidase reporter protein were injected intraperitoneally and -hepatically into 20- to 22-day-old fetuses. At 8–9 days post-treatment, the pups were sacrificed and the tissues harvested for analysis. Evidence of gene transfer was obtained by PCR amplification of proviral sequences within genomic DNA isolated from the treated samples. Transgenic β-galactosidase expression was assessed by X-gal histochemical staining. Results: By intraperitoneal injection 43% of the viable fetuses treated (3/7) showed evidence of successful LacZ gene transfer and low-level β-galactosidase expression into liver and heart, whereas by intrahepatic injection roughly 38% (3/8) of the livers were positive for LacZ gene transfer and expression. The success rate for the viable fetuses rose to 67% positive livers (4/6) when a near double amount of recombinant virus was injected using a 10-fold concentrated virus stock. In terms of short-term safety, fetal and maternal survival rates approached 80% of treated fetuses, and 100% of treated does. Conclusions: The pregnant rabbit is a useful and reliable model allowing the design of further studies to optimize the conditions for effective, safer, and persistent retroviral vector-mediated fetal gene transfer.

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The Hopes and Fears of In Utero Gene Therapy for Genetic Disease—A Review

Cited by 25 publications

References 28 publications

Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

Regulatory and Ethical Issues for Phase IIn UteroGene Transfer Studies

Feasibility of Retroviral Vector-Mediated in utero Gene Transfer to the Fetal Rabbit

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