The news that Genzyme Corp.'s gene therapy for treating cysticfibrosis (CF) is both safe and effective -- as evidenced bypreliminary results from a pilot clinical trial -- caused theCambridge, Mass., company's stock to jump 10 percent onThursday.
The common stock (NASDAQ:GENZ) gained $3.88 a share, closingat $38 in heavy trading of 2.4 million shares. And the units ofits spin-off, Neozyme II Corp. (NASDAQ:NIIUF), which Genzymeformed in 1992 specifically to fund the development ofproducts for treating CF, also picked up $3.50 a share to close at$30.50.
Researchers Michael Welsh, a Howard Hughes Medical Instituteinvestigator at the University of Iowa College of Medicine, andAlan Smith, senior vice president of research at Genzyme,announced the preliminary results of the gene therapy trialThursday at a press briefing in Dallas, the site of the SeventhAnnual North American Cystic Fibrosis Conference.
Welsh is presenting the results today in a plenary session atthat meeting, and the paper is coming out in the Oct. 22 issue ofCell.
The gene therapy protocol, which involves delivering a normalcopy of the gene that is defective in CF patients to the epithelialcells lining the nasal passages, is based on an understanding ofthe way in which the normal CF gene operates. That gene, firstidentified in 1989, was determined to code for a protein thatacts as an ion channel. The cystic fibrosis transmembraneregulator (CFTR) protein specifically regulates the transport ofchloride ions out of the cell.
When chloride ions, which carry a negative charge, can't betransported, the voltage across the membrane is altered. Thisin turn affects the voltage-sensitive transport of other commonions such as sodium (which has a positive charge) andultimately alters the distribution of water molecules.
In CF patients, who have inherited defective CFTR genes, thisabnormality is manifested in the lungs, pancreas, colon andgenitourinary tracts. But it's the accumulation of thick,dehydrated mucus in the lungs -- and the recurrentrespiratory infections that follow -- that are the main cause ofdeath among people with this disease.
In the pilot study, conducted at the University of Iowa, theresearchers introduced a normal CFTR gene into small portionsof the epithelium lining the nasal passages of three patients(aged 22, 36 and 50) with the disease, then measured thevoltage across the surface of the epithelial cells in vivo todetermine whether chloride ion transport had been restored.The CFTR gene was delivered to the cells by insertion into adisabled recombinant adenovirus.
In CF patients, the transmembrane voltage is usually moreelectrically negative than in normal subjects. But aftertreatment with the CFTR gene-containing viral vector, the basalvoltage became less negative in all three CF patients, indicatingto the researchers that the gene therapy had indeed correctedthe ion transport difficulty.
"Even at very low doses (at multiplicities of infection of one to25 infectious units per cell) we could see correction of thedefect in a small part of the lining of the nose," said Welsh.
This effect lasted for at least three weeks, and the researchersdid not observe any adverse effects resulting fromadministration of the virus per se.
The researchers have recently determined that the change involtage was indeed due to the introduction of the normal CFTRgene. "We now find messenger RNA for the CFTR gene in thesecells (of two of the three patients)," said Welsh.
"This research is another small but significant step in devisinga successful gene therapy treatment for cystic fibrosis," Welshsaid. He added that these results should be viewed in context,as preliminary evidence that the biochemical defect in CF canbe corrected. "It's impossible for us to determine (from theresults of these experiments) if we have an effective, safetreatment," Welsh cautioned.
A number of issues remain to be addressed, he continued.These include whether the therapy is safe at higher doses, theeffects of repeat administration and the effects of treating lungtissue rather than nasal epithelium.
In fact, it's still not clear whether this particular type of genetherapy protocol -- in which the delivery vehicle for the geneis a viral vector -- will turn out to be the one chosen in the end.Genzyme is also investigating the possibility of using non-viralvectors for gene delivery.
Just last week Genzyme signed an agreement with Vical Inc.(NASDAQ:VICL) to determine whether the San Diego company'scationic lipids (cytofectins) will work as a delivery vehicle forthe CFTR gene.
"At this point we don't know the best method of introducinggenes into cells," explained Smith. "Viruses are obvious becausethat's what they do for a living. But are they safe? We don'tknow the answer to that."
Still, Genzyme researchers and their colleagues are in the midstof readying a "second-generation" adenovirus vector for trials."We will be going back to the Recombinant DNA AdvisoryCommittee (RAC) of the National Institutes of Health (NIH) andto the FDA with (a gene therapy protocol employing) our nextgeneration virus and a larger number of patients," Welshremarked.
Whichever protocol eventually pans out, one thing is certain:The treatment is not a cure. "We do feel sure that the duration(of the treatment) will not be infinite," explained Smith. "We'recertain that we'll have to treat patients on a fairly regularbasis. This is not a one-shot treatment."
-- Jennifer Van Brunt Senior Editor
(c) 1997 American Health Consultants. All rights reserved.