By Randall Osborne


Say "gene therapy" to the casual biotech investor these days, and eyebrows are likely to rise.

Say "adenoviral vector" after that, and the palm will go to the forehead. A deep sigh may be heard.

But you can say the phrase "gene therapy using adenoviral vectors" to industry watchers with a longer, shrewder view, and prompt scarcely a flinch.

Some may even smile. A few may reach for the phone to call their brokers.

"We're at the end of the beginning of gene therapy," said Sam Wadsworth, senior director of gene therapy at Genzyme Corp.

Although not always considered first as a gene therapy firm, Genzyme devotes 15 percent to 20 percent of its effort to such research. The company, with 125 scientists working specifically on gene therapy, began its program in 1991.

Belief in the much-touted "promise of gene therapy" seemed to weaken a year or so ago, when experiments failed to yield unambiguously favorable data as fast as some had hoped. The science later enjoyed a brief resurgence of faith, which was seen by some analysts to reflect simply a more circumspect view of this relatively new field.

Then, last September, confidence in gene therapy seemed to dissolve altogether in the general public, anyway with the death of an 18-year-old gene-therapy patient involved in a clinical trial that used adenoviral vectors at the University of Pennsylvania's Institute for Gene Therapy.

The event made plenty of headlines. The university quit research on human subjects, and the Clinton administration recently said it would ask Congress to fine scientists up to $250,000 for violating federal rules, and fine universities as much as $1 million.

The FDA is taking a harder line, too, said Richard Gregory, vice president of gene therapy for Genzyme Corp.

"I don't know that they've changed the letter of the rules, but things have evolved over the past year," he said. "Clearly, the environment we're operating in is somewhat stricter."

Science marches on. At the American Society of Gene Therapy's third annual meeting in Denver last week, companies trotted out findings in preclinical and clinical gene-therapy trials. Among those on hand was Gregory who offered attendees a lively defense of the much-maligned adenoviral vectors, involved the Pennsylvania clinical-trial death.

"It doesn't matter to us what the vector is," he told BioWorld Financial Watch. "Many of the comments made about vector systems are made by people who have a vested interest in one vector or another. In the cancer program, [adenoviral vectors] are very effective in dendritic cells."

Genzyme uses adenoviral vectors to transfect dendritic cells with tumor antigens. Bruce Roberts, senior director of cancer gene therapy for Genzyme Molecular Oncology (GMO), called adenoviral vectors "extremely efficient" as a delivery system.

Gregory said the company also has found what scientists call "ad vectors" useful in cardiovascular indications.

"Where short term exposure, local exposure, or even ex vivo administration are all possible, the downsides [of ad vectors, which are immunogenicity and a complex genome] don't necessarily come into play," he said.

Genzyme started its gene-therapy program in 1991, directing its efforts at cystic fibrosis, and has since designed more than 200 viral and lipid vectors.

In March, GMO began a Phase I/II cancer vaccine clinical trial using the melanoma antigens MelanA/MART-1 and gp100, combined in a single vaccine, targeted at dendritic cells. Two months later, immune response was evident in two of nine patients enrolled so far.

GMO also has an antigen discovery program, aimed at finding antigens for major solid tumors for use with delivery vectors as immunotherapies for breast, colon, prostate and ovarian cancer.

Genzyme Surgical Products, another Genzyme Corp. division, is conducting a Phase I trial evaluating its gene-therapy product, hypoxia-inducible factor-1 (HIF-1), to promote angiogenesis and fight ischemia, specifically in peripheral vascular disease. HIF-1 is expressed by cells exposed to subnormal levels of oxygen. The FDA has approved an investigational drug application for a trial of the same product in patients undergoing coronary artery bypass grafts, whose hearts are not suitable for surgical revascularization.

A third Genzyme division, Genzyme General, is working on gene therapies for lysosomal storage disorders, with initial focus on Gaucher disease and Fabry disease.

Genzyme already makes Cerezyme, an enzyme replacement for Gaucher disease, which is caused by genetic deficiency of the enzyme beta-glucocerebrosidase.

The company has developed an enzyme replacement therapy for Fabry disease, resulting from a shortage of the enzyme alpha-galactosidase. The product is called Fabrazyme, and Genzyme is in the process of filing a biologics license application for it with the FDA.

Now, the company is looking into alternative treatments, in which genes that encode for the missing enzymes are administered to patients so they can make the enzymes themselves. That's the definition of gene therapy, said Woodward.

"You can come up with a phrase like 'use of a gene-based molecule to treat human disease, wherein the molecule is administered to the patient,' but that sounds pretty clumsy," Woodward said. "Cerezyme is a simple example. We used recombinant plasmids in a cell, in a bioreactor, to make a protein and give it to the patient. If you take that same plasmid, and give it as the therapy, and the patient expresses the protein in his own cell, then you could call it gene therapy."

Nor has Genzyme forsaken its cystic-fibrosis roots. The company geared its research toward enabling cells to produce the normal CFTR gene, which would restore proper chloride ion regulation. Seven trials were conducted, and 108 patients treated. The company is integrating the data.

Gregory said Genzyme "hasn't made a tremendous effort to try to publicize ourselves, but within the gene therapy field we're very well known. We've never been the kind of company that puts out a press release for every patent," he added.

In the wake of the Pennsylvania death, Gregory noted, some firms quickly let the public know that they use vectors other than the adenovirus. Genzyme kept quiet, although its arsenal includes four others, he said.

Spin control or not, which companies stand at the scientific forefront of gene therapy? Transgene SA, GenVec Inc., Targeted Genetics Inc., Avigen Inc., and Cell Genesys Inc., Woodward said.

"I don't mind saying those are leaders, but I would say Genzyme, Transgene and GenVec probably occupy about the same level of expertise," he said.

Others working in the area, and reporting at the Denver gene therapy meeting, include AVI Biopharma, GenStar Therapeutics, Phogen Ltd., and Vical Inc.

Gregory, Woodward and Roberts agreed the most encouraging news has been related to gene therapy against hemophilia and severe combined immune deficiency (SCID).

Avigen reported positive data from a Phase I/II trial of Coagulin-B, which uses an adeno-associated virus vector to deliver the gene for Factor IX. A new trial will test safety and effectiveness of infusing Coagulin-B into the liver, which is the normal site of clotting factor production. GenStar and Cell Genesys also are taking aim at hemophilia, and French physicians are exploring gene therapy treatments for SCID in infants.

"The clinical trials in hemophilia are getting attention right now, but part of the reason for that is that the animal data for hemophilia looked good in mice, and then in dogs, and the very preliminary data available now looks quite good in humans. The typical pattern is a promising result in a mouse, but when it's taken to a larger animal, it doesn't do well. We need to see [more] clinical data."

Gregory called the SCID results, though early and scant, "very impressive. We were all enthused about it, and it's pretty solid. The question is, can we extend that to be more relevant in everyday life? I think there's a good chance we can."

How soon that might happen remains unclear. Small companies that have placed all their eggs in the figurative gene therapy basket may face trouble, but larger "companies can make mistakes, too," Gregory said, pointing to Novartis AG which had "a very large gene therapy effort, but it wasn't clear what their product was." The push faltered.

Gene therapy won't go away, he said; just as surely, it would be "a gross over-exaggeration" to predict it will take over medicine.

"Physicians are still going to use chemotherapy, protein therapeutics and small molecules," he said. "But even small molecules are designed with information from genetics. They may be right that all medicine will be founded in genetics, but that doesn't mean it will be gene therapy."

Investors sifting gene-therapy companies are smart to find those that can last the long haul, because they have big cash reserves or focus on multiple areas (or both), and keep their eyes always on products as the ultimate goal.

Roberts said history provides a lesson.

"Back in the 1980s, people got on the antibody wagon and had hard times," he said. "But if you stick with it and think of the application, you can find an opportunity."

Even with the Pennsylvania death and federal scrutiny, Roberts said, gene therapy is going stronger than before and the "promise" again seems realistic.

"We're on the upswing," he said. *