Trial Information

Use of SV40 siRNA Vectors to Treat CML

A novel methodology that facilitates specific silencing of genes has recently been
developed. The method is based on the property of small molecules of nucleic acids (RNA) to
specifically repress expression of targeted genes. These small interfering RNA (siRNA)
molecules were recently demonstrated to repress, in tissue culture cells, one of the two
types of the common fusion genes present in CML patients. Those studies showed that
treatment with synthetic siRNA inhibited cell growth and increased the sensitivity to
imatinib. These findings offer hope that a novel form of gene therapy based on this strategy
may improve the treatment outcome of CML patients, particularly when used in combination
with other approaches such as the tyrosine kinase inhibitor imatinib that was mentioned
above.

Our group has developed an innovative vector that is most suitable to deliver siRNA
molecules into human hematopoietic cells with sufficient efficacy. The vector is based on a
monkey virus called simian virus 40 (SV40). The viral coat, or capsid, is produced
biosynthetically. It was engineered to self-assemble in the test tube around the nucleic
acids of choice, and to deliver this DNA or RNA into target cells. This vector is safer than
other available viral vectors since all the viral genetic material is excluded from the
final product. The vector does not elicit immune response, thus allowing repeated
administration.We will start the project by testing the recently published siRNA molecules
against one of the fusion genes, and several alternative siRNA molecules that we will design
against the other fusion genes. The molecules will be tested for efficacy in tissue culture
cell-lines, by measuring repression of the respective fusion gene, reduction in the level of
the tyrosine kinase and inhibition of cell growth. The most effective siRNA molecules will
be selected for further studies. The vectors will be tested on cell-lines for gene silencing
and cell death as before. At the final stage we will test the best vectors for their
efficacy in white blood cells obtained from CML patients.