Genteric Inc.

Genteric is harnessing the body's ductal system to get genes into the gastrointestinal organs and on into the circulation, without directly confronting the circulatory system. The firm believes this direct route will improve transfection rates and reduce immune reactions, regardless of the sort of vector--and has been pitching gene-therapy companies on the concept. So far, they've been hard to convince, but Genteric is confident they will come to appreciate the benefits of its delivery method.

Improving anyone's gene therapy, anatomically

• 2061 Challenger Drive

• Alameda, CA 94501

• Phone: [phone]

• Fax: [phone]

• Web Site: www.genteric.com

• Contact:Martin Cleary, President and CEO

• Industry Segment:Biotechnology

• Business:Delivery systems for gene therapy

• Founded:1997

• Founders:Stephen Rothman, PhD; Ira Goldfine, MD; Michael German, MD; Michael Nantz, PhD

• Employees:21

• Financing to date:$9.1 million

• Scientific Advisory Board:Stephen S. Rothman, DDS, PhD, Professor of Physiology, UCSF; Michael Nantz, PhD, Professor of Chemistry at UC Davis, Michael S. German, MD, Assistant Professor of Medicine, UCSF; Bruce Baum, PhD, DMD, Chief of the Gene Therapy & Therapeutics Branch, National Institute of Dental & Craniofacial Research (NIH); Richard Bergman, PhD, Chair and Professor of Physiology and Biophysics at the University of Southern California Medical School; Philip Felgner, PhD, internationally recognized researcher in gene therapy and cationic lipid technologies; Jerome Teitel, MD, FRCPC, Associate Professor, Department of Medicine, The University of Toronto and Director, Division of Hematology and Oncology, St. Michael's Hospital.

Martin Cleary has started and sold two gene therapy companies: first Theragen Inc., which merged with GenVec Inc. in 1994 [See Deal] and then CardioGene Therapeutics Inc. (founded by Cleary and others), acquired by Boston Scientific Corp. in 1998 [See Deal]. In the course of building up those firms, he says he became aware that viral vectors used to penetrate cells brought with them "a lot of baggage that interrupted the therapeutic effort."

Cleary was intrigued when the founders of Genteric Inc. approached him to say they had an anatomically-based technology that could overcome the limitations of viral vectors. The company is harnessing the body's ductal system to get genes into the gastrointestinal organs and on into circulation, without directly confronting the circulatory system. The scientists who founded the firm in 1997 believed this direct route would improve transfection rates, and reduce potentially dangerous immune reactions to foreign proteins. Now, nearly two years after becoming the company's president and CEO, Cleary says it's increasingly apparent to him that "Genteric's way of delivering genes gets results superior to anything other firms have achieved."

The organs Genteric is focusing on—the liver, pancreas and salivary glands—can all be accessed through a ductal system. "When we put a gene in retroductally, we get a better therapeutic effect than anybody would if they didn't do it that way," Cleary asserts. He figures there's a whole collection of companies working in the gene therapy field that ought to be interested in utilizing the firm's method of delivering gene therapy constructs, which is protected by "bullet-proof intellectual property."

At the moment, Cleary says "it's exceedingly difficult to convince a company that's done things in a dogmatic way, to consider another way." But he's betting firms in the area will eventually come around, and decide to deliver their constructs his way, when they see the results. Genteric is willing to do meaningful experiments to demonstrate its platform, he says, but isn't interested in getting involved in co-development without some kind of deal in place. Genteric is offering gene therapy companies the right to deliver their constructs to its anatomical sites, for a licensing fee, milestones and royalties when the therapy comes to market.

If it sounds like Genteric is asking for a lot in exchange for a little, Cleary says, "We see ourselves as offering a turnkey solution: every vector will work better this way." How could this be? David Olson, PhD, Genteric's head of molecular biology, explains that "Using the anatomy makes everything simple." Introducing material directly to a duct that leads to an organ means there's limited dilution of the vector, which helps improve transfection efficiency. It's easier on the patient if the vector doesn't have to go into the blood stream, given that immune cells are ever on the lookout for foreign substances. The direct route also helps ensure that material gets only to the cells of interest.

The cells of gastrointestinal organs like the liver, pancreas and salivary glands are good destinations for vectors, because they have a native ability to produce and secrete proteins. More importantly, they can secrete to the right place—into the blood, Olson emphasizes. The liver makes secreted proteins such as albumen and clotting factors; the pancreas creates a variety of hormones and enzymes. By contrast, protein made in muscle tissue is structural, and so doesn't go anywhere. "We're focused on local delivery of genes for systemic effect, so it's important that these cells secrete into the blood," Olson says.

Genteric is targeting delivery to the liver, in part because it's a relatively large organ and therefore reasonably approachable, but also because most of the gene therapy companies practicing today have developed their delivery methods to this organ. Cleary says, "People are desperate for liver data—it's the only way for us to do head-to-head tests." He acknowledges that the gene therapy community paid more attention to his firm's story after the tragic death of Jesse Gelsinger, the young gene therapy patient who'd been receiving infusion of adenoviral vector into the liver. It seems he had a toxic response to high levels of viral protein in the blood.

Before long, Genteric hopes to have honed its technology sufficiently to deliver genes through the salivary glands, which connect through the salivary ducts to the mouth. The firm views these as ready-made gene delivery routes lined with cells with secretory ability. It would be easier to access these ducts, which open into the mouth above the upper second molar—than to travel down to the liver with an endoscope. So far, though, the cells of this gland have been more difficult to transfect than cells of the liver or pancreas.

To date, the company has done its experiments only in rats and mice, but the executives are convinced the results will translate to humans. The first deals it will pursue will entail enhancing other companies' constructs. But Genteric also plans to attempt non-viral delivery of genes with its own system. Cleary says the firm is talking to gene owners, trying to get rights, and he notes that the novelty of the technology may help it considerably. In earlier days, hardly anyone thought of delivering genes without a viral vector of some sort. Consequently, the intellectual property tends not to claim that.

—DE