In a new twist on antisense technology, researchers at GentaInc. reported Thursday that they have developed a triple-strand approach to inhibiting protein synthesis.

Unlike methods that involve the formation of triple helicesconsisting of an antisense oligonucleotide bound to double-stranded DNA, Genta's method involves binding two identicalsingle-strand oligonucleotide sequences to a specific region ofmessenger RNA (mRNA).

"This creates a bulky molecular knot which is very effective atcontrolling protein expression at the translational level,"Thomas Adams, Genta's chief executive officer, told BioWorld.

In fact, "triple-stranding" can almost completely inhibit RNAtranslation in vitro at concentrations of less than onemicromolar, Adams explained. Lyle Arnold, Jr., Genta's vicepresident of exploratory research presented the data at theHuman Genetic Therapy Conference in London.

The particular sequences that Genta used in these experimentsare 15- or 16mers with high stability constants. And "becausethe sequence is basically read twice, the specificity is high,"said Adams. "Compared to other antisense compounds, ourconstructs showed better activity."

Genta's oligonucleotides are active at very low concentrations,below one micromolar. According to Adams, that activity"becomes important when you think about systemic therapy.One micromole of a 15mer is 250 milligrams for an average 70kilogram man." In contrast, he said, methylphosphonatesgenerally work in the 3-100 micromolar range, andphosphorothioates are active roughly in the one micromolarrange.

Genta, based in San Diego, has filed a series of U.S. patents onthis approach, and believes that its patent applications are thefirst to claim targeting mRNA using a triple-strand approach.Genta (NASDAQ:GNTA) closed Thursday at $8.75, up $1 a share.

-- Jennifer Van Brunt Senior Editor

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