By Mark Ratner

Special To BioWorld Today

CAMBRIDGE, Mass. — In collaboration with Judah Folkman's laboratory at Harvard Medical School, Genetix Pharmaceutical Inc. is developing a retroviral gene transfer system to deliver angiogenesis inhibitors to tumor sites.

However, with current opinions about gene therapy — especially systems using retroviral vectors — ranging from cautiously optimistic to downright skeptical, privately held Genetix has not attracted the level of public attention given to others, such as EntreMed Inc., of Rockville, Md., which are trying to advance Folkman's approach of inhibiting angiogenesis to beat cancer. (See BioWorld Today, May 5, 1998, p. 1.)

Genetix is completing work in animal models and expects to file an investigational new drug (IND) application with the FDA by the end of the year, either with a gene construct for delivery of an angiostatin-endostatin fusion protein to ovarian tumors or with a vector containing an as-yet-undisclosed angiogenesis gene injected directly into ischemic myocardial tissue to provide proof of principle.

This time frame to the clinic, company President Steve Niemi said, puts Genetix ahead of Folkman's lab, which, he said, still needs 12 to 18 months to obtain sufficient amounts of purified protein.

"Angiostatin and endostatin are hard-to-make protein fragments," Niemi explained. "Protein approaches to angiogenesis inhibition continue to be thwarted by scale-up issues." He sees gene therapy as "a way to deliver therapeutic doses cost effectively."

In addition to its angiogenesis regulation program, Genetix has ongoing Phase I/II trials using a retroviral vector to deliver the MDR1 (multidrug resistance) gene as a chemoprotectant for patients undergoing high-dose chemotherapy.

The company also is developing a second-generation retroviral packaging cell line using lentivirus, which it expects will enable sustained transduction and chromosomal integration in vivo into non-dividing cells such as bone marrow stem cells and heart muscle.

Gene Therapy Vectors Remain Problematic

Will retroviral vectors prove to be safe? Richard Selden, president and CEO of Transkaryotic Therapies Inc., in Cambridge, Mass., pointed out, "A few years ago, close to 100 percent of the gene therapy field was working with retroviral vectors. Now, it's probably closer to one-third, and there's a reason for that."

One concern is the possible formation of replication-competent retroviruses (RCRs) during manufacture — a particularly acute issue when dealing with the lentivirus family, which includes HIV. To address this problem, Genetix and other companies remove or disable retroviral sequence signals and design their vectors so that different parts of the genome are segregated onto separate constructs, to virtually eliminate random recombination and viral contamination.

Both Genetix and fellow gene therapy delivery specialist Cell Genesys Inc., of Foster City, Calif., claim broad intellectual property protection for the use and manufacture of lentiviral vectors to deliver gene therapy.

Mitchell Finer, vice president of research at Cell Genesys, explained, "In any viral system, there's a chance of contamination. It's a stochastic phenomenon, whether it's adeno-associated virus, adenovirus or lentivirus. It's a question of scale. Like any drug development problem, you push manufacturing but keep below the threshold of one event per lot."

In addition, he noted, quality control assays can identify any bad lots during manufacture and cells transduced ex vivo can be screened directly for RCRs before reintroduction into patients.

Nonetheless, the potential for RCRs and other concerns about the safety of retroviral vectors, such as recombination with retroviruses in the patient, likely will remain until data from long-term follow-up of patients in clinical trials are gathered and analyzed.

The early stage of development and long wait for compelling data justify the low level of current enthusiasm for gene therapy as a public investment, said Kathy Kirk, managing director for Hambrecht & Quist LLC, of New York.

"Long term it's a viable strategy, but public investors must rely on clinical data: It's the regulating gate with a capital 'G.' Without it, even with a good technology, there's nothing to buy."

Added Selden, "In the gene therapy field there's far too much hype, and I believe current investor interest is appropriately low. It is irresponsible to be promising cures in the short term. Clinical data that demonstrate a dramatic benefit in the patient's condition, as opposed to a mild palliation should excite people."

Given these long time frames, he said it is difficult to support a company with gene therapy. "But if you have other near-term opportunities, I can't think of a better thing to be working on."

Niemi said Genetix, which has 10 employees, expects to close a $10 million second round of financing in the next few months and will use the added resources to double its scientific staff, file IND applications for the clinical trials in cancer and cardiovascular therapy and initiate trials with its lentiviral vector system. *

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