In the premier issue of Nature spin-off journal, Nature Medicine, thelead article reports results from "the first placebo-controlled trial ofgene therapy, and the first trial of liposome-mediated CFTR cDNAtransfer to patients with CF."

Seven groups worldwide are currently conducting gene therapy trialsin some 50 cystic fibrosis patients. Six of them rely on viral ratherthan liposome vectors to deliver the cystic fibrosis transmembraneconductance regulator gene (CFTR) to the clogged and infection-prone airways of their life-threatened patients. (See BioWorldFinancial Watch, Oct. 17, 1994.)

The unprecedented liposome-vector Phase I trial took place at thecystic fibrosis department of London's Royal Brompton Hospital. Itsreport in Nature Medicine bears the title: "Liposome-mediated CFTRgene transfer to the nasal epithelium of patients with cystic fibrosis."

That paper's lead author is molecular geneticist Natasha Caplen, apost-doctoral resident fellow at Brompton. "Our Phase I nasal trialbears an obviously interesting relationship to assessing the basiccellular defect," she told BioWorld Today, "but is not going to be oftherapeutic use."

She and her colleagues are therefore tooling up to shift their genetarget from nasal passages to the CF-menaced lung itself. Instead ofaiming a spray at the nostrils, they will nebulize their plasmidpackage and diffuse its cloud-like respirable aerosols deep into thelungs via a mouthpiece. "For therapy," Caplen observed, "the lung'sthe main thing."

She explained: "The situation at the moment is that we have ethicalpermission to conduct a DNA-nebulization trial to the lungs of 12 CFpatients." This study is approved at the ethical level by the U.K.'sGene Therapy Advisory Committee (comparable to the U.S.Recombinant DNA Committee of the National Institutes of Health).It now awaits authorization by the U.K. Medicine Control Agency,the final licensing body for clinical trials (equivalent to the FDA).

"We're hoping we'll start this study next summer," Caplen said,"and suspect it will probably take about a year from start topublication." Meanwhile, we're doing a full safety study."

Their non-viral vector is a cationic liposome, a charged lipid dropletto the surface of which the transgene adheres by ionic interaction.Gene therapist Ronald G. Crystal, who initiated the first gene therapytrial for CF in April 1993, using an adenoviral vector, calls cationicliposomes "the only non-viral vector system that has been shown tobe capable of transferring genes in vivo to the airway epithelium ofexperimental animals with sufficient efficiency and safety toconsider initiating human trials."

Crystal made this observation in an editorial accompanying theCaplen paper. Of that trial, he wrote, "The paper by Caplen et al. inthis inaugural issue [dated January 1995] of Nature Medicine movesthe field toward the goal of `the gene as the drug' by demonstratingthat it is feasible to use cationic liposomes to transfer and express ahuman gene in the human nasal epithelium in vivo, with transient,functional expression."

Safe? Yes. Effective? 20 Percent. Therapeutic? Maybe

Fifteen male CF patients in their 20s and 30s enrolled in theBrompton nasal trial. All had inherited a double dose, paternal andmaternal, of a mutant CFTR gene. They were assigned at random toreceive varying doses of the transgene or of liposome-only placebos.

"The primary goal of any Phase I trial," Caplen observed, "is to lookat safety. We saw no adverse clinical effects consistent with thetreatment any of the patients received, up to the doses that weregiven."

She continued: "Then we came on to the assessment of gene transferefficacy. The majority of patients had both DNA and messengerRNA present in their nasal epithelia that was plasmid-specific.Overall, five of eight subjects who were available for assessment bynasal biopsy, had evidence of transgene expression."

In CF, the primary cellular defect is dysfunction of chloride iontransfer in airway epithelium, caused by a mutant CFTR. "In patientswho received the CFTR cDNA," Caplen said, "we saw a 20 percentimprovement in chloride secretion, but no change at all in those whoreceived the placebo."

Whether this electrophysiological effect reflects a therapeuticbenefit, she added, "is the only thing we don't know." She cited"obvious suggestions that because of this lack of chloride secretion,you get disruption in water movement, which leads to the buildup ofthick mucus in the lungs, which leads to infection and thenpathology."

Liposome Contender Made In U.S.

The cationic liposomes were synthesized for Brompton as part of anacademic collaboration with Leaf Huang, who heads the laboratoryof drug targeting at the University of Pittsburgh, Caplen said. He isalso a founding scientist of RGene Therapeutics, Inc., TheWoodlands, Texas, which has patented the liposomal vector for genetherapy of solid tumors. (See BioWorld Today, Dec. 15, p. 1.)

Caplen finds it difficult to compare the apple of liposome vectors tothe oranges of viral delivery systems. "We can't relate our work atall to retroviruses," she said; "they are not applicable to cysticfibrosis." As for the two adenovirus studies published to date, "theprotocols they've done for efficacy are very different from ours. Butbroadly speaking, I think we're very much in line with the resultsfrom the University of Iowa, published by Mike Welsh and hiscolleagues."

She added, "What is probably more important is the study by RonCrystal. In that case, they are having an inflammatory response inone of their patients. So there are safety issues in relation toadenovirus that we don't seem to see. Yet we feel we have definitelyseen some efficacy." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.