Pantheco A/S, a Copenhagen-based start-up developing antisense nucleic acid analogues for infectious diseases, reported positive results in animal studies at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Toronto last week.

The company is developing antisense molecules based on peptide nucleic acids (PNAs), which differ from naturally occurring nucleic acids by having a peptide rather than a sugar-phosphate backbone. The technology was invented in 1991 by researchers Ole Buchardt, Peter Nielsen and Michael Egholm at the University of Copenhagen and by Rolf Berg from the Riso National Laboratory. Isis Pharmaceuticals Inc., of Carlsbad, Calif., holds the rights to the PNA technology, but has exclusively licensed applications in the infectious diseases area to Pantheco and is its second-largest shareholder.

The Danish company demonstrated that PNA-based molecules cured an Escherichia coli ATTC 25922 infection causing peritonitis sepsis in mice. The candidate molecules, which the company tested with the Statens Serum Institut of Copenhagen, were effective at 4 mg per kg of body weight, Pantheco CEO Anker Lundemose told BioWorld International.

The firm is focusing initially on developing PNA molecules to target antibiotic-resistant bacteria that cause nosocomial, or hospital, infections. It is working on both Gram-negative and Gram-positive bacteria, although the former program is more advanced, said Lundemose. The company will initiate antifungal and antiviral programs in the next six to 12 months, he said.

During the 1990-1996 period, according to CDC data, the four most common Gram-negative pathogens, E. coli, Pseudomonas aeruginosa, Enterobacter and Klebsiella pneumoniae, accounted for 32 percent of nosocomial infections. The three most prevalent Gram-positive pathogens, Staphylococcus aureus, coagulase-negative Staphylococci and Enterococci, accounted for 34 percent during the same period.

Pantheco has not disclosed the targets against which it is developing PNA candidates, but it is concentrating on highly conserved sequences that span several species, said Lundemose, as these are most likely to be linked with essential metabolic functions. Unlike traditional antibiotic development strategies, which rely on trial and error methods, the antisense approach enables it to preprogram the spectrum of activity.

Moreover, it rolls screening and target validation into one step. "If you have a positive result, you know the target works," said Lundemose.

The focus on highly conserved target sequences is also motivated by the goal of minimizing or eliminating the threat of bacterial resistance emerging. "All developed antibiotics have generated resistance at some point in time," said Lundemose. "But several established resistance mechanisms, such as enzymatic cleavage or modification, do not effect PNAs," he said. So far, the company has not detected any toxicity effects in animals.

The company plans to spend the next year on more extensive preclinical studies. The company raised US$15 million from a consortium of Danish investors, led by BankInvest of Copenhagen, in late 1998. It plans to raise about half of that figure before the end of the year, to fund its preclinical program, before seeking a larger sum for clinical trials. "I think we will be able to give the first human dose sometime during 2002," Lundemose said.

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