AVI BioPharma’s NeuBiotics touted for microbial drug resistance

Randall C Willis
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PORTLAND, Ore.—August 8, 2007—Following on its earlier success with its Neugene antisense platform, AVI BioPharma announced it will refocus its clinical pipeline and research programs to advancing candidates for cardiovascular, infectious, and genetic diseases, as well as developing new discovery platforms that build off of the Neugene technology.
PORTLAND, Ore.—Leveraging its expertise in nucleic acid technologies, AVI BioPharma and colleagues at Oregon State University (OSU) recently developed new antisense-based antibiotics that are showing preclinical efficacy against vari­ous microbes. They reported the results of their studies in a recent issue of Antimicrobial Agents and Chemotherapy.
Antisense technology, which has almost become the forgotten sibling of RNAi in the $210-bil­lion nucleic acid-based thera­peutics market, works by bind­ing to specific gene transcripts, setting them up for degrada­tion. AVI's NeuGene technol­ogy works in a slightly different manner, according to OSU pro­fessor and AVI BioPharma sci­entist Dr. Bruce Geller, by inter­fering with the translation of these transcripts into proteins.
Dr. Patrick Iversen, AVI BioPharma vice president of R&D, also notes that unlike antisense molecules, NeuGenes (phosphorodiamidate morpho­lino oligomers or PMOs) are charge-neutral, making them particularly resistant to degra­dation and good for peptide con­jugation.
In the case of NeuBiotics, Geller explains, the scientists took their cue from research performed a decade ago that showed bacteria would take up traditional antibiotics when the drugs were attached to a syn­thetic peptide carrying a combi­nation of ionic and hydrophobic (oily) residues.
"Their mechanisms of action are controversial, but it is thought that the positive charges interact with the negative-charged compo­nents of the bacteria cell surface," he says. "Following this ionic inter­action, the hydrophobic residues of the peptide interact with the membrane lipids. Ultimately, the peptides penetrate the membrane, dragging their attached cargo with them."
The researchers found that the NeuBiotics inhibited growth of a variety of bacteria, including the human pathogens E. coli and S. typhimurium. And when tested on human tissues infected with microbes, NeuBiotics only inhibit­ed bacterial growth with no impact on the human tissues.
Because antisense targets spe­cific genes of known sequence, AVI sees NeuBiotics as an opportunity to slow or reverse the growing problem of antibiotic resistance in many human infections.
"If resistance to antisense oligo­mers arises by mutations in the region of the gene targeted by the antisense oligomer, it would be a simple matter to sequence the target region and change the base sequence of the antisense oligomer to complement the mutations," Geller explains. "We have also found that Neubiotics can inhibit known mechanisms of antibiotic resistance and restore effective­ness of small molecule antibiotics such as tetracycline."
According to Iversen, there are a large number of clinical set­tings where AVI might develop a NeuBiotic agent and the company will continue to fine-tune the tech­nology to the best indication for success.
"We continue to compare the peptide-PMO with 'naked' PMO so that we evaluate a full spectrum of advantages and disadvantages," he says. "The priority for this proj­ect is safety and to anticipate the potential for toxicity in the setting of an infected patient."
"The next important step is showing efficacy in animal mod­els of infection," Geller says. "We already published results that show Neubiotics are effective in reducing infection in mice."

Randall C Willis

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