Persistence of transgene expression

Figure 21.5 Persistence of transgene expression. Animals were injected with 1,6ml saline containing 1 Opg ( ) or 50[ig (o) of either pCMV-Luc (A) or pCMVhAAT (B) plasmid DNA. For luciferase gene expression, animals were sacrificed at various time intervals and luciferase activity in the liver was determined by standard luciferase assay. For human a 1-antitrypsin gene expression, blood was collected at appropriate times and serum concentration of human q 1-antitrypsin was determined by a standard ELISA. Error bars represent s.e.m. from three mice in A and five mice in B.

Persistence of transgene expression. Animals were injected with 1.6ml saline containing 10 427... 

The relationship between the dose level of the gene therapy product administered and the level and persistence of transgene expression in specific tissues and any toxicities that are observed should be determined. These data are important to ascertain, as they will affect the clinical monitoring and planned dose escalation in the clinical trials. 

Michou AI, Santoro L, Christ M, Julhard V, Pavirani A, Mehtali M (1997) Adenovirus-mediated gene transfer Influence of transgene, mouse strain and type of immune response on persistence of transgene expression. Gene Ther 4 473 82. 

Bruder JT, Jie T, McVey DL, Kovesdi I (1997) Expression of gpl9K increases the persistence of transgene expression from an adenovirus vector in the mouse lung and liver. J Virol 71 7623-7628 Bruder JT, Kovesdi I (1997) Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression. J Virol 71 398-404 Burgert H-G (1996) Subversion of the MHC class I antigen presentation pathway by adenoviruses and herpes simplex viruses. Trends Microbiol 4 107-112... 

Bruder JT, Jie T, McVey DL, Kovesdi 1. Expression of gpl9K increases the persistence of transgene expression from an adenovirus vector in the mouse lung and liver. J Virol 1997 71 7623-7628. 

Li Z., Fehse B., Schiedlmeier B., Diillmann J., Frank O., Zander A.R., Ostertag W. and Baum G. (2002) Persisting multilineage transgene expression in the clonal progeny of a hematopoietic stem cell. Leukemia 16, 1655 1663. 

Gene delivery system Transgene size capacity (Kizana and Alexander, 2003) Duration of transgene expression Persistence Onset of transgene expression Limitations... 

However, a variety of issues have implications for the use of viral vectors in gene therapy. Obvious potential concerns are the immune and inflammatory responses to viral vectors. Patients who received VEGF-121 via an adenoviral vector had increased levels of serum antiadenoviral neutralizing antibodies, but there was no report on an inflammatory response in these patients (27). The use of adenovirus-mediated gene therapy in treating brain tumors has been reported to lead to active brain inflammation as well as persistent (up to three months after treatment) transgene expression (30). 

Riu E, Chen ZY, Xu H et al (2007) Histone modifications are associated with the persistence or silencing of vector-mediated transgene expression in vivo. Mol Ther 15 1348-1355... 

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