DUBLIN, Ireland — A gene therapy research program with a big international reputation is the basis for Italy's first major biotechnology spin-off from academia. The leaders of the gene therapy program at the Milan-based San Raffaele Institute have formed GenEra to develop gene therapy approaches to the treatment of cancer, AIDS and metabolic diseases.

The project was initiated late last year. However, the company, which sits adjacent to the San Raffaele Institute in the San Raffaele Biomedical Science Park, was only formally incorporated last month, scientific director Fulvio Mavilio told BioWorld International. His scientific co-founders include Claudio Bordignon, Catia Traversari and Giuliana Ferrari.

GenEra has already raised US$6 million through an unnamed Italian merchant bank, according to Mavilio. But the company aims to raise a further US$10 million to US$20 million from international venture capital funds very shortly. "Of course we are very open to the international markets, because essentially there is no national market," he said.

The company is not necessarily seeking to fund all of its projects from venture capital investment. Alliances with biotechnology and pharmaceutical companies are another option, although GenEra does not plan to offer any equity to outside firms, Mavilio said.

GenEra is concentrating on therapeutic areas with broad application and good investment potential. According to Mavilio, gene therapy has developed an image problem because too many high-risk projects are moving into clinical trials too early. "We're not working the same way," he said. "We're not rushing research into clinical trials in order to get more investors interested."

GenEra Finalizing Two Alliances

The company has inherited the San Raffaele Institute's patent portfolio and its most advanced projects. The institute, which holds an equity stake in the company, will continue its basic research programs on genetic diseases and on gene therapy approaches to more widespread conditions.

Some of this work may be spun off into GenEra at a future date, as its commercial potential develops. Recently published work on the potential use of genetically modified bone marrow cells as a treatment for muscular dystrophy falls into this category. However, the company is more interested in the broader clinical application of the technology than in the treatment of muscular dystrophy per se. (See BioWorld International, March 11, 1998, p. 1.)

GenEra currently is finalizing two alliances and is negotiating an extension to a third that is due to expire at the end of the year. This contract originally was signed by the San Raffaele Institute and Boehringer Mannheim, now part of F. Hoffmann-La Roche Ltd., of Basel, Switzerland. The alliance is based on GenEra's most advanced project, which aims to prevent the onset of graft-vs.-host disease in cancer patients who have received bone marrow transplants.

GenEra's approach involves the insertion of drug-inducible suicide genes into donor lymphocytes. The genes encode enzymes that convert the antiviral drug ganciclovir into a cytotoxic derivative. Thus, administration of the drug can eliminate donor lymphocytes if they mount an attack on host tissues. The treatment is undergoing a multicenter Phase II clinical trial in several European countries.

Cancer Program Outstrips AIDS Effort

GenEra currently is developing an improved, cell-cycle-independent suicide system, based on drug-induced apoptotic signals elicited by a modified form of the Fas molecule. The company also is working on an immunotherapeutic approach to cancer treatment. It is developing gene transfer systems, based on viral vectors and other "more original" approaches, for genetically manipulating cells for efficient presentation of tumor-specific antigens, Mavilio said.

The company's AIDS effort is, at the moment, smaller than its cancer program. "AIDS is a minor area, but it is an area," he said. Three years ago, the San Raffaele team reported on an "interfering mutant" of HIV. Cells infected with this strain were resistant to wild-type HIV infection. GenEra now is attempting to demonstrate this effect in CD4 lymphocytes transduced with a modified version of this mutant strain. The work is at the preclinical stage, but Phase I protocols are currently in preparation. The company hopes to gain approval for moving into clinical work next year, Mavilio said.

GenEra's third area of activity centers on the genetic engineering of tissues for systemic delivery of therapeutic proteins. The main focus is on diabetes and atherosclerosis. The company is developing a gene expression system to mimic pancreatic function in vivo. The goal is to develop a long-term, controlled release system for insulin to offset the chronic problems associated with current delivery methods. "It's at a very basic stage," Mavilio said. Clinical trials are three to five years away.

The company's atherosclerosis program is based on a protein molecule that binds and eliminates circulating cholesterol. This molecule could be administered as a drug, Mavilio said, but GenEra has opted to develop a constitutive delivery system. The company has filed a patent application for the protein and will publish its work shortly. *