Transgenics internal deletions

Major concerns in the use of retroviral vectors are the possibility of vector mobilization and recombination with defective (endogenous) retroviruses in the target cell. This led to the development of self-inactivating vectors (SIN) (38). In these vectors, the viral promotor and enhancer regions in the 3 U3 are deleted, thus preventing LTR-driven transcription in the transduced cells. Furthermore, transgene expression in these vectors is exclusively driven by an internal promotor, which improves the use of regulatory and tissue-specific promoters. 

Two intriguing activities of PrP emerged from studies with transgenic mice expressing mutants lacking the internal hydrophobic domain (HD). First, deleting residues 105-125 from the HD was sufficient to convert PrP from a stress-protective into a neurotoxic protein [52]. Second, co-expression of wild-type PrPc completely blocked the toxic activities of PrPAHD mutants [48, 51, 52] (Fig. 1). The toxic activity of PrPAHD mutants could be related to that of Doppel, a neurotoxic protein with a tertiary structure similar to that of the C-terminal domain of PrPc [140]. Notably, Doppel-induced neurodegeneration is also rescued by the co-expression of PrPc [141-144]. A comprehensive review of Doppel is provided by David West-away in this book. 

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