Insertional mutagenesis induced by viral vectors is an ongoing problem in gene therapy. Vector-induced mutagenesis has been a concern ever since 4 of 9 human patients treated for Xlinked severe combined immunodeficiency developed leukemia following treatment with a retroviral vector. As a result of this, lentiviral vectors with increased safety properties were developed. Nevertheless, proliferative hematopoietic disorders have recently been described in mice and human patients treated with modern lentiviral vectors. This has resulted in the design of ever more sophisticated lentiviral vector safety features including the incorporation of suicide genes, cell or tissue specific promoters, local/regional delivery of viral vectors, locus-targeted transgene integration and the use of “insulators” to prevent oncogene activation. To provide an additional measure of control, the replicationdefective lentiviral vector system creates the potential for influencing PF-4217903 cell-specific tropism via vector pseudotyping. Selection of certain viral envelope glycoproteins or other proteins facilitates cell targeting to enhance directed gene transfer. For example, cell-specific targeting has been achieved through the use of lentiviral vectors pseudotyped with the Rabies virus glycoprotein or the CD4 receptor. A variety of envelope-like genes are currently available to provide vector-target cell specificity. Optimally, vector targeting of long-lived cells could potentially abrogate the need to continuously readminister the viral vector. An optimal lentiviral vector may include hypoxia response element-regulated expression of rfEPO cDNA and the incorporation of a suicide gene into the vector design. A combination of these various strategies may provide a clinically relevant in vivo method for the treatment of non-regenerative anemia associated with CRF in cats. DNA methylation is a stable epigenetic feature that is involved in gene silencing and the maintenance of long-lasting cell memories. Dynamic regulation of the DNA methylation pattern is crucial for mammalian development, as well as differentiation and reprogramming. In particular, the active loss of 5-methylcytosine independent of cell division is considered to be a major initial event in the epigenetic reprogramming of early mammalian embryos. It has been demonstrated that the loss of 5mC at the paternal pronucleus of a zygote is linked to the accumulation of 5-hydroxymethylcytosine. The 5hmC is converted from 5mC by the teneleven translocation family of proteins, and therefore 5hmC is considered to be an intermediate formed during the active DNA demethylation process in early embryos. A recent study proposed a novel model for the removal of 5hmC, wherein activation-induced cytidine deaminase induces the deamination of 5hmC, which is followed by base excision repair, resulting in the conversion of 5hmC into unmethylated cytosine. Based on this model for active DNA demethylation, coordinated actions of both the production and removal of 5hmC may regulate the conversion of 5mC into unmethylated cytosine. However, little is known how these proteins involved in the production and removal of 5hmC affect each other. Aid is a well-known enzyme that converts cytosine into uracil in single-stranded DNA, causing somatic hypermutation and class switch recombination. Aid is mainly localized in the cytoplasm under steady state conditions, but has the ability to shuttle between the nucleus and the cytoplasm.