Genzyme General and Genovo form gene therapy collaboration.

Genzyme General (Cambridge, MA; 617-591-7140) and privately held Genovo, Inc. (Sharon Hills, PA; 610-522-8501) announced that they have entered into an agreement to develop gene therapy products for lysosomal storage disorders, a class of rare genetic diseases.

Under the terms of the collaboration, Genovo will conduct research and development activities employing its proprietary viral vectors to develop one gene therapy product through the successful completion of a phase I clinical trial. Genzyme subsequently will have the option to pursue further development of that product, and to develop additional gene therapy products, in collaboration with Genovo or on its own.

Genzyme will benefit from Genovo's significant gene therapy patent portfolio and vector manufacturing capabilities. Through its affiliation with Genovo, Genzyme will also gain the opportunity to work with James Wilson, MD, PhD, an international gene therapy expert, and 180 affiliated researchers at the Institute for Human Gene Therapy at the University of Pennsylvania (Philadelphia, PA).

In addition, Genzyme has been granted an exclusive, worldwide license to all of Genovo's vector patents and technology for use in developing and commercializing gene therapy products for lysosomal storage disorders.

Genovo will receive product development milestone payments and royalties on product sales. Genzyme will also make an equity investment in Genovo and has the option to make additional equity investments.

"This partnership is consistent with Genzyme's strategy to expand its development of therapies for lysosomal storage disorders, as well as its commitment to introduce next-generation products that benefit patients with rare genetic diseases," said Henri A. Termeer, president and chief executive officer of Genzyme Corporation (Cambridge, MA). "Our access to Genovo's vector expertise will strengthen our leading position in gene therapy development."

Eric I. Aguiar, MD, president and chief executive officer of Genovo, said: "We're pleased to be working with Genzyme, the leader in the field of lysosomal storage disorders and gene therapy. This partnership builds on our existing strategy of gene delivery for protein therapeutics by combining Genovo's vector technology and development capabilities with Genzyme's expertise with rare genetic diseases. Our goal is to create novel therapies for these disorders."

Viruses are commonly used as vectors in gene therapy because of their capacity to efficiently transport genes into cells. Genzyme's collaboration with Genovo will include research on a number of different types of viral vectors including adeno-associated virus vectors, in which viral genes are replaced with a therapeutic gene sequence. In preclinical studies, adeno-associated virus vectors have demonstrated efficient delivery of genes to a wide range of target tissues, long-term gene expression, and greater stability than other viral and non-viral gene delivery systems.

Genovo's adeno-associated virus vector manufacturing system produces high quality vectors at quantities sufficient to support clinical studies. The company is actively developing improved processes for large-scale adeno-associated virus vector production, purification, and formulation.

Genzyme has eight years of experience in gene therapy research and development, and has designed more than 200 different viral and lipid vectors for use in experiments. Genzyme has also established more than a dozen research collaborations with academic groups to focus on its gene therapy targets in cystic fibrosis, cardiovascular disease, cancer, and lysosomal storage disorders. As of August 1999, Genzyme had completed nine gene therapy clinical trials, with three more in progress and several more planned for this year.

Lysosomal storage disorders are a family of approximately 40 rare genetic diseases, each of which typically affects fewer than 10,000 people worldwide. These diseases are caused by a deficiency of one or more enzymes responsible for the breakdown of lipids or other molecules in the cells. Molecules that are normally broken down into smaller building blocks instead accumulate inside the part of the cell called the lysosome, affecting the cell's overall ability to function. Patients suffering from lysosomal storage disorders commonly experience developmental defects, defects in the neural and immune systems, skeletal abnormalities, and death at an early age.

Genzyme General has built a strong worldwide infrastructure to meet the special challenges of introducing treatments for these rare genetic diseases, through its work in developing and commercializing Cerezyme enzyme replacement therapy for Gaucher di sease. Genzyme is currently developing protein therapies for other lysosomal storage disorders, including MPS-I, Fabry disease, Pompe disease, and Niemann-Pick disorder.

Genovo focuses on the design, manufacture and early stage clinical development of gene-based therapeutic products for the treatment of human disease using adeno-associated virus and adenovirus vectors. Genovo's technology includes intellectual property covering gene therapy vectors, manufacturing and methods of use. In addition to the partnership with Genzyme, Genovo formed a partnership in 1995 with Biogen, Inc. (Cambridge, MA; 617-252-9200)(1998 revenue - $558 million) and a joint venture in 1997 with ARIAD Pharmaceuticals, Inc. (Cambridge, MA; 617-694-8144).

Genzyme General develops and markets therapeutic products and diagnostic products and services. A division of the biotechnology company Genzyme Corporation, Genzyme General has its own common stock intended to reflect its value and track its economic performance.

Genzyme has one of the largest and most diverse gene therapy programs in the world. The company began its gene therapy program in 1991 to develop treatments for cystic fibrosis. Since then, Genzyme's gene therapy efforts have expanded to target cardiovascular disease, cancer, and lysosomal storage disorders.

Genzyme has established more than a dozen gene therapy research collaborations with academic groups to focus on these targets. The company's gene therapy researchers have achieved a number of important scientific and regulatory "firsts" in gene therapy studies and vector development, and have designed more than 200 viral and lipid vectors for use in experiments.

Genzyme also has a strong track record with the United States Food and Drug Administration in gaining approval to conduct gene therapy clinical studies. As of August 1999, Genzyme had completed nine gene therapy clinical trials, with three more in progress and several more planned for this year.

Genzyme's molecular genetics expertise, understanding of cystic fibrosis, and commitment to develop therapies based on that understanding has made cystic fibrosis one of the primary programs in the company's gene therapy research.

Cystic fibrosis is the most common fatal hereditary disease in the United States, affecting approximately 30,000 people. A gene called cystic fibrosis transmembrane conductor normally regulates the transfer of chloride ions in and out of cells in the lungs, pancreas, colon, and urogenital tracts. Mutation of this gene causes faulty delivery of ions and water in and out of the body's cells, and results in recurrent respiratory infections, breathing difficulties, and physical damage to the lungs. Virtually every person with cystic fibrosis will develop chronic lung disease, and 85 percent will also experience digestive problems. The average life-expectancy of a person with the disease is 31 years.

Genzyme's approach to treating this disease is to use gene therapy to deliver normal genes to the cells of cystic fibrosis patients. This way, the cells may be able to produce the normal cystic fibrosis transmembrane conductor gene, which would restore proper chloride ion regulation in the patients' cells.

The company uses naturally-occurring viruses and synthetic lipids as vectors, or delivery systems, to transfer the genes to the affected cells. Proprietary vector technologies used by Genzyme in preclinical and clinical trials include adenovirus, adeno-associated virus and lipid/DNA complexes.

Adenovirus, a common cold virus, is adept at inserting genes into human lung cells. Adeno-associated virus is non-pathogenic, and can deliver genes to both dividing and non-dividing cells. An alternative, synthetic vector is made from fatty substances called lipids, which are joined with DNA in a complex carrying the therapeutic gene.

Genzyme has conducted seven different cystic fibrosis clinical trials with adenovirus or lipid/DNA vectors. A total of 108 patients or normal volunteers have been treated. Genzyme has shown through these studies that cystic fibrosis transmembrane conductor gene therapy is deemed to be safe via multiple delivery modes and that low-levels of gene expression can be detected.

Genzyme's gene therapy program for lysosomal storage disorders initially targets Gaucher disease and Fabry disease.

Gaucher disease is a genetically determined deficiency of the enzyme beta-glucocerebrosidase. Genzyme manufactures Cerezyme, an enzyme-replacement therapy for the treatment of Gaucher disease. Researchers are investigating an alternative treatment, a method of delivering genes that encode for this enzyme so that patients can produce the deficient enzyme themselves. This Gaucher disease research involving gene therapy techniques is being conducted through a research agreement between Genzyme and John Barranger, MD, PhD, at the University of Pittsburgh (Pittsburgh, PA).

Treatment of patients in a pilot clinical trial conducted by Genzyme and the University of Pittsburgh is expected to be completed by the end of 2000. In June 1999, a United States patent was issued to the University of Pittsburgh related to gene therapy for Gaucher disease using progenitor cells that include retroviral vectors expressing the glucocerebrosidase gene. Genzyme holds an exclusive license to this patent.

Fabry disease arises from a deficiency in the enzyme alpha-galactosidase. Genzyme is testing ways to deliver genes that encode for this enzyme to the liver and muscles of mice, and has had favorable preliminary results.

In August 1999, Genzyme General and Genovo entered into an agreement to develop gene therapy products for lysosomal storage disorders using Genovo's proprietary adeno-associated virus vectors. Genovo is a leader in the field of gene therapy vector development, and has a significant gene therapy patent portfolio and strong vector manufacturing capabilities. Through its affiliation with Genovo, Genzyme will also gain the opportunity to work with James Wilson, MD, PhD, an international gene therapy expert, and 180 affiliated researchers at the Institute for Human Gene Therapy.

Genzyme Molecular Oncology, one of Genzyme four divisions, is researching gene immunotherapy approaches to cancer treatment.

In collaboration with Stephen Rosenberg, MD, of the National Cancer Institute, Genzyme Molecular Oncology used its adenovirus vectors to deliver known melanoma antigens, MelinA/MART1 and gp100, in two phase I trials to patients to assist their immune systems' response to cancer cells. The trials demonstrated that this antigen-delivery approach is safe and well-tolerated. In addition, a small but notable number of patients showed clinically significant tumor regression.

Genzyme Molecular Oncology is conducting a phase I/II cancer vaccine trial combining these two antigens. The first patients began receiving treatment in April 1999, and it is anticipated that the study will be completed in 2000. This leading-edge trial evaluates the combination of the two tumor antigens to increase the potency of the vaccine. The vaccine will also capitalize on the immune stimulating abilities of dendritic cells by specifically targeting the vaccine to those cells. Also, because this vaccine is gene-based, as opposed to protein or peptide vaccines used in many previous tumor vaccine trials, there will be a more prolonged presentation of the antigens to T-cells. This allows the T-cells to make a more powerful attack on the tumor cells.

Genzyme Molecular Oncology is working with the Dana Farber Cancer Institute (Boston, MA) to initiate two trials of patient-specific cancer vaccines, one in breast cancer, anticipated to begin in the second half of 1999, followed by one in ovarian cancer. The technology, dendritic/cancer cell fusion, combines a patient's dendritic cells with their inactivated tumor cells in a laboratory procedure. The fused cells are injected back into the patient to stimulate an immune response against the patient's cancer. By automatically incorporating the entire menu of antigens found on the original tumor, fusion cell technology eliminates the need to identify specific antigens for the vaccine and allows the dendritic cells to elicit a powerful immune response. Genzyme has the option to obtain an exclusive license to the dendritic/cancer cell fusion technology from Dana Farber.

In addition to conducting clinical trials with its gene immunotherapy candidates, Genzyme Molecular Oncology has an intensive antigen discovery program from which it plans to identify antigens for the major solid tumors. Genzyme Molecular Oncology plans to use these newly identified antigens in combination with its delivery vectors to develop gene immunotherapies for breast, colon, prostate and ovarian cancer.

Genzyme Surgical Products, another of Genzyme's four divisions, is researching gene therapy approaches to the treatment of cardiovascular diseases. Its lead gene therapy product, GeneGraft, is designed to promote angiogenesis -- the growth of blood vessels in tissue that has been deprived of oxygen.

GeneGraft is based on the naturally occurring transcription factor hypoxia-inducible factor, which has been shown to trigger the body's natural response to ischemia, or oxygen starvation. Genzyme Surgical Products plans to initiate clinical trials of GeneGraft in patients with peripheral vascular disease and ischemic heart disease by the end of 1999.

Genzyme Surgical Products is also conducting a variety of cardiovascular gene therapy studies with researchers at leading academic institutions. In particular, Genzyme Surgical Products is working to develop gene-based therapies to inhibit vascular smooth muscle cell proliferation, which often occurs following angioplasty and stenting procedures. Smooth muscle cell proliferation leads to blockage of newly opened blood vessels, a process called restenosis. Genzyme is also evaluating several different gene-based approaches to improve cardiac function in patients with congestive heart failure.

Unlike many current treatments that address symptoms, the aim of gene therapy is to introduce therapeutic genes into target cells via a variety of biological, chemical or physical procedures. One of the goals of gene therapy is to treat the cause of a particular disease by replacing an unhealthy gene with a healthy one. Gene therapy alters specific cells to target disease processes at their genetic roots.

Scientists use gene therapy to correct defects in the genes themselves so that the body can be stimulated to produce healthy cells instead of those programmed by defective or destructive genes. Alternatively, a gene can be introduced into a cell to keep another gene from being expressed.

The first step in gene therapy is identifying, or mapping, the gene responsible for an illness. Gene-mapping technology allows scientists to isolate genes and discover their purposes in protein production.

The next step involves using vectors to send corrected genes to the cells of the body that need them. If the therapeutic gene is delivered to an area of the body where it is not needed, it may cause unwanted side-effects or do serious harm.

Viruses are commonly used as vectors because they have evolved efficient ways of inserting their own genes into the cells of their host. A virus is essentially deoxyribonucleic acid or ribonucleic acid surrounded by a protein coat. Viruses take over the reproductive capabilities of living cells, and they force the cells to copy viral DNA or RNA, often killing the cells in the process.

To use a virus as a vector, scientists remove a virus' DNA, and substitute it with DNA carrying therapeutic genes. Then the virus is administered to the patient's body, where it inserts its new "gene package" into the patient's cells. A major focus of gene therapy research is the delivery of therapeutic genes to specific regions of the body. Aerosols can deliver viruses to the lung, and intravenous solutions can be also used to administer viruses to specific organs, such as the liver. A preferential uptake method can also be used to target the lung, the heart, or certain tumors after intravenous administration.

In using virus vectors, such as adenovirus, researchers must be careful to strip the virus of disease-causing traits and ensure that the patient's immune system doesn't destroy the virus before the desired gene has been transferred.

Once inside the patient's targeted cells, the altered genes can produce the proper protein to make the tissue or organ function properly. Some genes can be delivered to the body that will bind with other genes to stop the production of an unwanted protein. This is called antisense therapy.

Alternative vector systems are made from fatty substances called cationic lipids. In the cationic lipid vector system, the therapeutic gene is integrated into a stable loop of DNA called a plasmid and covered with positively charged fatty molecules, or lipids. The lipid/plasmid complex penetrates the patient's cell and the therapeutic gene causes the cell to produce the desired protein. These vectors are synthetic, whereas viral vectors are naturally-occurring.

Advantages to using lipids is that they are less likely to cause disease, and are easier to make than viral vectors. Unfortunately, lipid vectors that are highly effective in getting genes into cells are hard to design. And once the gene is transferred by the lipid vector, genes may not produce some proteins, such as the cystic fibrosis transmembrane conductor protein, as long as they do when inserted by a virus.

As more genes are linked to specific illnesses, the possible applications of gene therapy will increase. The advance of gene therapy will depend upon the discovery of new ways to safely target the desired cells with therapeutic genes, and the proper control of the expression of these genes.