By David N. Leff

Phase I trials of a newly patented nonviral vector for gene therapy are well under way at two clinical centers in the U.S. and one in Europe.

They anticipated the issuance this week, on Oct. 14, 1997, of U.S. patent No. 5,676,954, covering "Method of in vivo delivery of functioning foreign genes," and an identical issuance from the European Patent Office, dated Aug.20, 1997, of No. 0 452 457 B1.

Its inventor, clinical and molecular pulmonologist Kenneth Brigham, of Vanderbilt University, in Nashville, has assigned the patent to the university. Vanderbilt, in turn, has licensed the invention in exclusivity to GeneMedicine Inc., of The Woodlands, Texas.

"The patent," explained GeneMedicine's director of intellectual property, Michael Fons, "embodies a method-of-use claim. It covers any cationic lipid complexed to DNA that's injected or inhaled, to deliver genes to cells in the body."

Fons observed that the patent's "quite broad coverage and very early priority date [Nov. 3, 1989] gives us a clear path toward commercialization, using cationic liposomes by the route claimed in the patent."

To which the firm's vice president and chief business officer, Josef Bosart, added: "Our business is to develop products, in a partnership-type manner, with major pharmaceutical companies. So I think this patent gives us the opportunity to show our current and potentially future partners that we really have a strong position in the area of nonviral gene therapy."

One such GeneMedicine alliance, with the German multinational BoehringerMannheim G.m.b.H. (acquired in May by Roche Holding Ltd., of Basel, Switzerland), "is enrolling patients right now in Germany," Bosart observed, for a Phase I gene therapy trial of the company's cationic liposome-DNA complex to treat head-and-neck cancer. Sixteen patients in all will receive injections directly into their tumors of the cationic vector complexed to genes that express the anticancer cytokine, interleukin-2.

A similar Phase I study began last month at The Johns Hopkins University School of Public Health, in Baltimore. It is enrolling 12 head-and-neck patients and expects to complete that trial during the first quarter of 1998.

Head-and-neck cancers represent a significant market for gene therapy, Bosart pointed out. "We estimate that, between Europe and North America, 120,000 patients are diagnosed annually with the disease."

Besides these cancer studies, GeneMedicine and Vanderbilt University are collaborating in a Phase I trial of the nonviral vector to treat patients with alpha-1-antitrypsin deficiency. This hereditary disease, in its severe form, involves emphysema, a clinical area of specific concern to Brigham, who is conducting this protocol.

"We've completed the first part of this Phase I trial," Brigham told BioWorld Today, "with a nasal instillation, using the gene. Results are currently being analyzed. We've recently completed in vivo studies in which we transfected animals with the alpha-1-antitrypsin gene, and showed that you can accomplish that therapy with cationic liposomes, either by airway aerosol or intravenously."

Brigham continued: "And in a piglet endotoxin model, it also protects the lungs against endotoxin injury. Gram-negative endotoxins," he pointed out, "are generally felt to be the bad actors in human sepsis."

He explained that "part of our reason for connecting with GeneMedicine is that nonviral strategies for delivering genes in vivo — particularly to the lungs, which is my primary interest — are likely to be more quickly clinically applicable than the viral-vector strategies. And of the nonviral strategies available, the cationic liposome technologies appear to be the most promising."

"Cationic liposomes," Fons pointed out, "are not really liposomes. A traditional liposome," he explained, "may be thought of as a soap bubble with an aqueous interior that entraps materials. Cationic means that the lipid is positively charged, so it and the negatively charged DNA plasmid attract each other.

"We start with a liposome," he continued, "but when we mix and mesh it with the DNA of interest, that tends to condense the DNA into a smaller, more tightly packed particle, which gets through the membrane into the cell more effectively."

Nonviral Vectors Vs. Virals

Fons ticked off the pluses of cationic lipids over viral vectors: (See BioWorld Today, Sept. 22, 1997, p. 1.)

"Among its advantages," he said, "is the ability to repeat the gene therapy dose without fear of immunogenicity or of viral regeneration. Also, the ability to characterize the product in a form that can be produced and distributed in a pharmaceutically acceptable way."

He also made the point that "in terms of transfection efficiency and efficacy, these nonvirals have the additional capability of delivering and expressing the genes of interest in the cells of interest." On this score, the patent text noted: "The present invention . . . can provide a possibility for targeting specific organs, unlike those methods disclosed in the prior art."

GeneMedicine's is not the only nonviral cationic lipid vector on the block. "Actually," Fons said, "they are the most common nonviral delivery systems in gene therapy clinical trials today."

He cited as most advanced, inhalation of the cystic fibrosis gene, CFTR, in Phase I trials by Genzyme Corp., of Cambridge, Mass., and by MegaBios Corp., of Burlingame, Calif. He also mentioned cationic gene therapy involving the E1A tumor suppressor gene, by Seattle-based Targeted Genetics Corp.

Asked whether GeneMedicine's new patents might preempt these and other rival users from bringing their cationic liposome applications to market, Fons replied, "'Preempt' is not the word I would use. According to the rules, they will need licenses to commercialize their product, under this patent."

In its summary, the patent text observes that ". . . the present invention could be used not only as a tool for correcting genetic abnormalities, but also as a new category of therapy which could broadly be applicable to human disease states." *

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