HAMBURG, Germany - Noxxon Pharma AG, a Berlin startup based on technology to design stable therapeutic and diagnostic RNA molecules, is growing faster than expected. By the end of this year, Noxxon expects to begin development of its own therapeutic products.

Noxxon was founded in 1996 with DM5.4 million. With a staff of 16, a powerful technology and a strong patent portfolio, the company just entered a DM2.8 million collaboration with Grünenthal GmbH, of Aachen, Germany, and is in the final stages of negotiation for another alliance with a big German pharmaceutical company.

A couple of years ago, Jens Peter Fürste, co-founder of the company, was exploring the therapeutic potential of small RNA molecules. That potential is hampered by the molecules' susceptibility to RNA-cleaving enzymes.

“One can try to enhance the stability by chemical modifications,“ Fürste told BioWorld International, “but these alterations have to be compatible with the polymerases used. In addition, breakdown of altered RNA molecules leads to compounds with a mutagenic or teratogenic potential.“ The solution to this problem came to Fürste's mind while he was watching a science fiction film featuring a mirror world. “I realized that molecules in such a mirror world would be inert to our enzymes, because of their different chirality. Nevertheless, they could be designed to bind to molecules of our kind.“

This was the birth of the spiegelmer concept, now the core of Noxxon's proprietary technology. To design a stable therapeutic or diagnostic RNA molecule, or aptamer, Noxxon's researchers first build a spiegelmer mirroring the original target molecule, usually a protein or peptide. This is done by synthesizing a peptide from D-aminoacids, mirror images of the L-aminoacids all organisms on earth use in their metabolism.

“Fortunately, chemical synthesis of peptides and strategies for their ligation are very advanced today,“ Fürste said. “One can chemically produce polypeptides consisting of 200 or 300 aminoacids. Usually the active centers of large enzymes do not exceed that size. But even whole enzymes have been synthesized as mirrors, for example, the HIV protease.“

In the next step, aptamers from a library are selected against the target. “We can build a library of a 25-mer oligonucleotide - that's four to the twenty-fifth molecules - within a week.“

Once a matching structure is identified, it can be optimized in eight to nine circles using combinatorial chemistry. In the end, these aptamers are not only smaller than conventional antibodies but more specific and they bind more strongly to the targets.

To get the final molecules, a further mirror step is necessary. The sequence of the small RNA molecules selected and optimized is read and used to synthesize a mirror RNA using nucleotides with opposite chirality. The result is a “spiegelmer“ that binds perfectly to the original, natural target.

“The beauty is that even though these spiegelmers are nucleic acids,“ Fürste explained, “they are non-physiological in their entirety. Nucleases cannot break them down because they are not recognized by the enzymes. Nevertheless, they bind to their targets and excess molecules are excreted unchanged.“

In 1996, Fürste filed for international patents on the core technology. Last year he founded Noxxon with two partners. Funds were raised mainly from the company founders and private investors.

Grünenthal Deal Focuses On Pain Drugs

Among the scientific advisors are Paul Schimmel, of Scripps Research Institute, in La Jolla, Calif., and Volker Erdmann, director of the University of Berlin's Institute for Biochemistry and initiator of the RiNA Netzwerk, a Berlin-based network of research institutions, clinics and companies. (See BioWorld International, Aug. 5, 1998, p. 4.)

Thomas Klein, co-founder and chief financial officer, told BioWorld International that Noxxon intends to concentrate on its own therapeutic projects and will work with the partners participating in the RiNA Netzwerk. “This network is a big advantage for us. It will aid clinical investigations and stimulate further cooperations,“ Klein said. “We hope Berlin will become an important international center of RNA research.“

For other applications, such as diagnostics, Noxxon will license technology and develop application patents with strategic partners.

Under terms of its first partnership, Noxxon will design spiegelmers against targets provided by Grünenthal, which is developing compounds that bind to pain receptors.

Noxxon will receive DM2.8 million and has an option for royalties on therapeutic applications developed from the research.

Klein added the company was in the process of negotiating with a big German pharmaceutical company as a second partner.

“If this is closed, we will start a new financing round and begin our own therapeutic projects,“ he added.

The company is expected to grow to a staff of 25 by the end of this year and to expand to 50 employees, mostly in research and development, by the end of next year. *