Dr. Dutta and colleagues recruited known mammalian replication initiation factors (either ORC or CDC6) to a defined GAL4 DNA-binding site on a plasmid, demonstrating that replication initiation factor recruitment is sufficient to specify a DNA replication origin.

The researchers have extended the classic transcription factor reporter assay to work for any eukaryotic replication initiation factor. The artificial mammalian replication origin will enable scientists to explore the mechanism of replication initiation, as well as "provide a new direction for creating vectors for gene therapy that are less mutagenic than current integrating vectors and that do not require viral proteins," explains Dr. Dutta.

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Testing their idea, Small and his Hopkins colleague Katherine Whartenby used an experimental compound called CEP-701, already known to block actions of the growth-promoting FLT3 gene, on human dendritic cells and in mice engineered to mimic multiple sclerosis, a disease that causes T-cells to destroy the myelin protein sheath around nerves in the central nervous system. The drug had a similar effect on dendritic cells, causing most of them to die. In the mouse model, investigators found that more of the myelin sheath was preserved in mice treated with CEP-701 than those not treated.

Small cautions that massive die-off of dendritic cells poses a possible risk of immune system suppression, a condition that could leave patients vulnerable to infections or other diseases. "But our studies show that though many dendritic cells were destroyed, some still remained," he said.

Their tests also revealed that mice infected with a potent bacterium survived after treatment with CEP-701.

Additional authors include Peter A. Calabresi, Erin McCadden, Bao Nguyen, David Kardian, Tianhong Wang, Claudio Mosse and Drew M. Pardoll from Johns Hopkins.

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