VICTORIA, British Columbia - The cellular stress response is an essential survival process found in virtually all life, from bacteria to humans. When the cells of any organism are damaged, a subset of genes - stress genes - produce stress proteins which work to repair damage and to protect against further injury.

Stress proteins are also powerful, natural stimulants of the immune system, and studies have shown the body's immune system is primed to respond to stress proteins produced by foreign microbes.

StressGen Biotechnologies Corp., of Victoria, British Columbia, was one of the first companies to recognize the commercial significance of stress proteins and the potential of the cellular stress response.

Since the stress response is so ubiquitous, the company is building a variety of drug discovery platforms based on its core technology, Richard M. Glickman, StressGen's president and CEO, told BioWorld International.

One of these platforms will involve development of therapeutic products aimed at treating stroke, vascular surgery and cardiopulmonary bypass surgery. Stress proteins have been shown to protect cells from damage caused by ischemia and reperfusion as well as inflammatory reactions.

Alliance Involves Two U.S. Universities

Although this platform is an early-stage project, Glickman said, StressGen has entered into a drug discovery collaboration with the University of Miami, the University of Connecticut, in Storrs, and Hartford Hospital aimed at discovering small molecules that modulate the cellular production of stress proteins.

This multi-institutional research collaboration is based upon a novel discovery platform which StressGen licensed from the University of Miami earlier this year. It provides for access to a family of international patent applications broadly covering heat shock transcription factors (HSF), which regulate the production of stress proteins.

The University of Miami patent applications cover mutated forms of HSF's which regulate the expression of genes that encode stress proteins.

Mutated HSF's can be utilized to either up-regulate or down-regulate the production of endogenous stress proteins to alter a cell's sensitivity to stress. The protective effects of stress proteins have been observed in neural cells and in organs such as the heart, liver and skin.

As a result, researchers and physicians believe HSF therapy may be useful in conditions such as stroke, in which it is estimated that ischemic damage to the brain develops relatively slowly, and that cytoprotective intervention at the time stroke symptoms are first detected may provide some benefit.

HSF therapy also may be effective in those types of surgery, such as aortic surgery, where there is the risk of ischemic damage.

Glickman said the collaboration will draw on the expertise of each of the participating organizations to develop assays and screen chemical libraries to identify small molecules of interest. These then will be tested in animal models at the Hartford Hospital, a facility that has capability in the area of trauma and ischemic injury modeling.

The company expects to enter into similar agreements in the near future to further explore gene, protein and small molecule applications in this rapidly emerging field of cellular protection.

Using collaborative partners in cytoprotective research will allow StressGen to maintain its primary internal focus on developing immunotherapeutic products for cancer and infectious disease, Glickman added.

This strategy involves two main areas. First, StressGen is incorporating stress proteins into proprietary fusion protein products for specific cancer immunotherapy and prophylactic vaccines for prevention of infectious disease.

Second, through a joint venture with Genzyme Molecular Oncology, a division of Genzyme Corp., of Cambridge, Massachusetts, StressGen is using the genes encoding stress proteins to design gene therapy products for treatment of cancer.

The company's fusion protein products, such as its lead product, HspE7, combine a tumor-associated antigen and a stress protein in order to both prime the immune system and direct an immune attack on cancer cells.

HspE7 is composed of heat shock protein 65 (Hsp65) and the protein E7, derived from the human papillomavirus (HPV), which is known to be responsible for the malignant transformation of cervical epithelial cells.

In studies to date, HspE7 has been shown to completely regress large existing tumors and to provide complete protection against subsequent challenges with tumor cells in models of cancer recurrence.

StressGen expects to initiate its first clinical trial for HspE7, in the first part of 1999. *