BERLIN - The liver disease company Hepavec AG last week signed an exclusive option agreement with the Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO) to evaluate sheep adenovirus as vectors for the gene therapy treatment of liver diseases.

Hepavec, of Berlin, was founded in 1996 to develop novel gene- and cell-based products for currently incurable malignant, inborn or acquired liver diseases with a poor prognosis, such as liver cancer, hepatocellular carcinoma and Wilson's disease.

The company has a strong proprietary position with 10 patents, including those covering different types of baculo- and adenovirus vectors for liver-specific gene therapy, a novel method to induce apoptotic cell death in malignant cells, a human immortalized liver cell line, and a set of ribozyme technologies such as an expression cassette for antisense expression of ribozymes and a ribozyme library.

To fight hepatocellular carcinoma, Hepavec is developing a gene therapy protocol using adenovirus vectors.

"Despite the current discussion caused by the death of a young man participating in a gene therapy trial using an adenovirus vector, these viruses can still be regarded as excellent tools for gene therapy," Herbert Stadler, CEO of Hepavec AG, told BioWorld International. "However, one has to take into account that infections with human adenoviruses are widespread in the human population so that neutralizing antibodies exist in most patients. And this can cause serious effects when a high dose of an adenovirus vector is injected. We are well prepared to the new situation because we have already looked for alternatives. One is a human adenovirus vector that shows only weak reactions with human serum and a second one is the sheep adenovirus we have now obtained via our CSIRO option agreement."

The ovine adenovirus originally had been studied at CSIRO as a tool to treat diseases of sheep, but soon it became clear that it could be engineered for human gene therapy as well. As published in the Journal of Virology in August, such vectors safely enter several cell types in vivo, including liver cells, and express their cargo genes. Experiments carried out at Hepavec have shown that the expression level is as efficient as that achieved with the human counterpart.

"Hence, the opportunity for product development arising from this novel vector is excellent," Stadler said. He added that Hepavec intends to initiate Phase I/II clinical trials using modified adenovirus vectors next year in patients suffering from hepatocellular carcinoma, a condition showing high and rapid mortality.

"We will deliver a proprietary combination of p53 and p16 genes," Stadler said. "We have already published that this combination is synergistic and able to drive cancer cells toward apoptosis very selectively, while an overexpression in healthy cells is without any detrimental effect. In mice, our experiments result in the complete disappearance of pre-established liver tumors."

The development of baculovirus as a vector would take some time, he added: "We have solved the problem to overcome the reaction of the human complement system, and are now addressing some technical details. Baculovirus is a very promising tool as it can deliver genes of up to 35 kb size."

To fight metastatic liver carcinomas, Hepavec follows a two-step approach: "We will use our vectors carrying the two cell-cycle control genes and combine this therapy with a DNA vaccination using special antigens displayed on the cell surface of these metastatic tumors," Stadler said.

Hepavec is looking for a partner for the development of DNA vaccines.

"Our strategy is to achieve a low burn rate and to diversify in order to become a big player in the therapy of liver disorders," he said. "We are developing new therapies to treat Wilson's disease, a hereditary liver disorder with an incidence of 1 in 30,000 and have obtained an exclusive license of the gene. And we are developing ways of using our proprietary immortalized human liver cell line in a reactor as an artificial liver. Besides, we acquired interests in other companies."

Hepavec holds a majority stake in Mondogen, of Martinsried, a company developing a liver-specific gene delivery system based on hepatitis B virus to complement its own liver vector development program. In addition, Hepavec holds shares of Centers for Medical Innovation GmbH (CMI), of Munich, Germany, a company developing plant-derived products to treat hepatitis B and C. Stadler added he was already negotiating with other companies for cooperation or acquisition. A second financing round will be closed in December this year. The main investor is Techno Venture Management, of Munich.