GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 191Because adenoviruses provide highly efficient genetransfer yet transient expression, novel hybrid vectors havebeen developed to take advantage of adenovirus infectivityand the permanent nature of integrative vectors such asretroviruses and lentiviruses (Murphy et al, 2002; Kuboand Mitani, 2003). Hybrid vectors may offer efficient geneexpression to fetal organs such as the lung in which it hasso far proved difficult to achieve high level gene transferwith integrating vectors.5. Sendai virusRecently, the negative strand RNA cytoplasmicallyreplicating Sendai virus, a member of the paramyxovirusfamily was developed as a gene transfer vector. Earlyvectors still capable of self-propagation, were found toprovide very high levels of marker gene expression in awide range of tissues including bronchial epithelium(Yonemitsu et al, 2000), skeletal muscle (Shiotani et al,2001) and vascular endothelium (Masaki et al, 2001).Second generation vectors, although still capable of intracytoplasmicreplication of the RNA genome, are incapableof intercellular propagation. In these vectors, genesencoding surface glycoproteins including thehaemaglutinin-neuraminidase (HN) protein or the fusion(F) protein, which are responsible for cell binding andinfection, have been deleted from the viral genome (Inoueet al, 2003). Injection of F-deficient Sendai virus vectorinto the fetal mouse via various routes including intravascular,intra-amniotic, intra-muscular, intra-peritonealand intra-spinal resulted in expression of marker gene ingut wall, lung, muscle, peritoneal mesothelia and dorsalroute ganglia respectively. Further optimisation will beneeded to develop these first generation constructs intoclinically applicable vectors (Waddington et al,submitted).IV. Fetal gene therapy studiesSince the initial attempts in the early 1990s, in uterogene therapy has been investigated in a range of differentanimals using a variety of techniques. The possible routesof administration are illustrated in Figure 2.Figure 2. Routes of administration of gene therapy to the fetus. Routes in italics have not yet been applied in a fetal animal model usingultrasound guided injection.191