BETHESDA, Md. -- The NIH's Recombinant DNA AdvisoryCommittee (RAC) on Thursday unanimously approved twonearly identical protocols for Phase I trials of gene therapytechniques to treat cystic fibrosis.

Both techniques call for insertion of the cystic fibrosistransmembrane conductance regulator (CFTR) gene into thelung using an adenovirus, a novel vector. To prevent infectionby adenovirus, all or part of the E section of the genome, whichis crucial for viral replication, is removed.The major difference between protocols is that Ronald G.Crystal, chief of the pulmonary branch at the National Heart,Lung and Blood Institute drips the recombinant adenovirusesinto the proximal portion of the lung, while James M. Wilson,chief of molecular medicine and genetics at the University ofMichigan Medical Center, occludes the distal portion of the lungwith the recombinant virus for 10 minutes.

The approvals were granted only after the principalinvestigators agreed to several modifications proposed by theRAC. One major concern among RAC members was thepossibility of contamination by replication-componentadenoviruses. Accordingly, the RAC stipulated that therecombinant virus should be purified to where less than oneparticle of 10-11 particles should be able to reproduce.

Additionally, both protocols had excluded fertile people. Forreasons not understood, most males with cystic fibrosis areinfertile. The fraction of fertile female cystic fibrosis sufferersis unknown, but RAC member Doris T. Zallen, professor ofscience studies and humanities at Virginia PolytechnicInstitute, said that many of these women wished to havechildren.The researchers had excluded fertile people out of fear thatgerm line cells could be transduced. But RAC members weresatisfied that the data from animal studies did not support thisconjecture.

Still another objection, raised by Georgetown Universitybioethicist Leroy Walters was that as written, the protocols didnot make clear that clinical improvement was unlikely. Thetarget cells have a life span that is at most little more than amonth, and repeat infusions of the recombinant virus would benecessary to keep patients' airways clear. The protocols call forjust one infusion.

-- David C. Holzman Special to BioWorld

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

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