In a step toward making gene therapy a reality, researchers have succeeded in partially repairing a cystic fibrosis - associated gene using an approach that targets the RNA copy of the gene. The gene in question encodes a protein (known as the cystic fibrosis transmembrane conductance regulator, or CFTR) that controls the flow of chloride ions across cell membranes; this gene can be defective in people with cystic fibrosis. Working on cystic fibrosis tissue that had been transplanted into mice, the researchers have restored chloride ion conductance to 22% of that seen in normal cells -- a level that should alleviate disease symptoms if it can be achieved in individuals with cystic fibrosis.
The goal of gene therapy is to substitute “normal” genes for defective genes associated with disease. Such genes give rise to faulty proteins through a series of steps, and gene therapy researchers can try to correct the genetic defect at any of these steps. In this issue of Nature Biotechnology (Vol. 20, No. 1, 01 Jan 02), John Engelhardt and his team focused on the point at which an RNA copy of the gene is processed by a cellular machine that splices out long stretches of the molecule to create a mature RNA, which then goes on to direct the production of a protein. The researchers used a harmless adenovirus to carry the correct genetic sequence into cells, where it was spliced into the mature RNA. This “corrected” RNA was then used by the cells to synthesize a normal version of the CFTR protein.
Unlike many more traditional forms of gene therapy, in which a “normal” gene sequence is introduced into cells to counteract the deleterious effects of a defective gene, Engelhardt’s approach has the advantages of both correcting the genetic defect and ensuring that the “corrected” RNA is expressed at levels appropriate to ensure attaining airway function closer to that seen in healthy individuals. Although the results are very encouraging, modifications will be required before this RNA-targeted approach can be tested on people with cystic fibrosis. For example, an alternative virus carrier will be needed, because adenovirus does not readily enter human lung cells.
John F. Engelhardt
Department of Anatomy and Cell Biology
College of Medicine
The University of Iowa
Iowa City, IA 51141
News and Views:
Ronald G. Crystal
Weill Medical College of Cornell University
New York, NY 10021
(C) Nature Biotechnology press release.
Message posted by: Trevor M. D'Souza
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