COMPANY TO WATCH | Ingenium develops models with gene alterations

By John Blau 

Sept 16, 2004 | If mice helped put Ingenium Pharmaceuticals AG on the radar screen of competitors and investors, rats could turn the German company's still faint blip into a flashing beam.

Rats have become the model of choice for many therapeutic areas, including cardiovascular, behavioral, and neurological disease research. But the development of specific genetically modified rat models, unlike mouse knockout models, has posed a huge hurdle despite years of intense research worldwide.

Munich-based Ingenium is overcoming that hurdle by developing new genetic rat models based on methods it has proven in mouse models. The technology, called INGENOtyping, allows rodent models to be developed with gene-specific alterations. Essentially, it involves using ethylnitrosourea to create subtle alterations throughout the animal's genome.

When Ingenium first used INGENOtyping in the mouse, it produced gene knockouts several times faster than those achieved through the standard procedure of homologous recombination in embryonic stem (ES) cells, according to Ingenium CEO Michael Nehls.

Ingenium Pharmaceuticals AG Location: Martinsried/Munich, Germany CEO: Michael Nehls Founded: 1998 Funding to date: o74 million — lead funds include Polaris Venture Partners, Techno Venture Management, and HBM BioVentures. Employees: 79

"For more than 15 years, scientists have been trying to develop ES cells in rats that could be used, in turn, to create a whole organism from a cultured cell," Nehls says. "Because no one has been able to develop these, the pathway for manipulating cells in a targeted fashion and creating a genetic rat model out of it hasn't worked. So the question is: How do you knock out a gene in a rat if you don't have embryonic cells?"

In search of a solution, Ingenium found help in its mouse modeling work. The company, spun out of the German Human Genome Project in 1998, has generated a wealth of information from its Deductive Genomics drug discovery technology, which involves breeding mice in its "mouse clinic" with chemically induced random mutations and then analyzing these models for new information that could help cure disease.


Hitting the Jackpot 
Ingenium has compiled these data into its own bioinformatics software system, called the GENcyclopedia, which is used to capture, process, and analyze most of the information generated within the company.

"In the case of rats, when applying our INGENOtyping method, we don't manipulate embryonic cells but rather sperm cells in living organisms," Nehls says. "This means we treat a rat with a chemical that generates subtle genetic alterations with a defined frequency." This generates random point mutations in every cell, including the stem cells of sperm.

DESIGNER RODENTS: Ingenium CEO Michael Nehls says the company has developed a way to generate "subtle genetic alterations" in rats.

Ingenium creates a sufficiently large library to take "the randomness out of the approach," Nehls says. Every mutation is, essentially, pre-made in every gene.

Nehls compares the process to a lottery: "If, for instance, you have to generate six hits out of 49, you just buy a sufficient number of lottery tickets to cover every conceivable combination, and then you'll win. The only problem with this approach in a real lottery is that the aggregate of tickets is more expensive than the jackpot, so no one does it. With INGENOtyping, we can make this process quite cheap by generating an aggregate of hits for whatever jackpot we want to hit."

Ingenium has created a "rolling-circle" production pipeline that represents a living, inbred rat model archive. One year's production creates enough rat models so that every gene is mutated independently several times. This provides pharmaceutical partners with a probability of more than 90 percent of identifying a specific gene model of choice in less than 12 months. In April, Ingenium signed an agreement to provide Merck with novel rat models developed with its INGENOtyping technology.

In addition to its work on genetic rat models, Ingenium continues to provide mouse models to big pharmas, including Bayer, Elan, and F. Hoffmann-La Roche. And it is conducting its own research in areas such as diabetes and neurological disorders.

Nehls is particularly proud of the GENcyclopedia system, for which the company's team of bioinformaticians wrote every line of code. "German government officials have told us that they have never seen a more advanced system," he says.

It is recognition like this — and agreements to supply high-profile companies with its INGENOtyping technology — that are helping Ingenium brighten its radar blip in the fiercely competitive biotech sector.

John Blau is a reporter for IDG News Service based in Germany.