Here's a group to watch. The abstract is clearly worded, and may provide some light re. allele-specific cancer therapeutics or "Variagenic Targeting"? Would it be wise for some VCs to fund a joint venture with a company like Isis?............
Nucleic Acids Res 2000 Mar 1;28(5):1133-8
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Polymorphisms in the large subunit of human RNA polymerase II as target
for allele-specific inhibition.
ten Asbroek AL, Fluiter K, van Groenigen M, Nooij M, Baas F.
Neurozintuigen Laboratory, Academic Medical Center, PO Box 22700, 1000 DE Amsterdam,
The Netherlands.
The lack of specificity of cancer treatment causes damage to normal cells as well, which limits the
therapeutic range. To circumvent this problem one would need to use an absolute difference
between normal cells and cancer cells as therapeutic target. Such a difference exists in the
genome of all individuals suffering from a tumor that is characterized by loss of genetic material
[loss of heterozygosity (LOH)]. Due to LOH, the tumor is hemizygous for a number of genes,
whereas the normal cells of the individual are heterozygous for these genes. Theoretically,
polymorphic sites in these genes can be utilized to selectively target the cancer cells with an
antisense oligonucleotide, provided that it can discriminate the alleles and inhibit gene expression.
Furthermore, the targeted gene should be essential for cell survival, and 50% gene expression
sufficient for the cell to survive. This will allow selective killing of cancer cells without concomitant
toxicity to normal cells. As an initial step in the experimental test of this putative selective cancer
cell therapy, we have developed a set of antisense phosphorothioate oligonucleotides which can
discriminate the two alleles of a polymorphic site in the gene encoding the large subunit of RNA
polymerase II. Our data show that the exact position of the antisense oligonucleotide on the
mRNA is of essential importance for the oligo-nucleotide to be an effective inhibitor of gene
expression. Shifting the oligonucleotide position only a few bases along the mRNA sequence will
completely abolish the inhibitory activity of the antisense oligonucleotide. Reducing the length of
the oligonucleotides to 16 bases increases the allele specificity. This study shows that it is possible
to design oligonucleotides that selectively target the matched allele, whereas the expression level
of the mismatched allele, that differs by one nucleotide, is only slightly affected. |
