A clue? (Rich)

[Guest guest]

Perhaps the following is a clue to how antibiotics do/don't work in our case as

well. The article indicates the the type of mutation is common in " other "

diseases.

Adrienne

October 17, 2003

Gentamicin Can Restore Function of Some Gene Aberrations in Cystic

Fibrosis Genes

By Karla Gale

NEW YORK (Reuters Health) Oct 08 - In patients with stop mutations

in the cystic fibrosis transmembrane conductance regulator (CFTR)

gene, nasal application of gentamicin restores CFTR function and

corrects electrophysiological abnormalities, investigators report in

the October 9th issue of The New England Journal of Medicine.

" Some patients show an impressive response to inhalation treatment

with gentamycin, even when bacterial resistance had developed to the

antibiotic, " senior author Dr. Eitan Kerem told Reuters Health.

Aminoglycosides such as gentamicin " skip over " nonsense mutations,

permitting translation of the full genetic transcript, he explained.

There is in vitro and in vivo evidence that gentamicin can restore

function of CFTR with stop-codon mutations.

Therefore, Dr. Kerem, of Shaare Zedek Medical Center in Mount

Scopus, Israel, and colleagues conducted a placebo-controlled,

crossover trial in 19 patients with stop mutations in CFTR. Five

patients with a deletion mutation not expected to be affected by

gentamicin served as control subjects. For 14 days, 900 g of

gentamicin or placebo was administered nasally each day.

Among subjects with stop mutations, but not those with genetic

deletions, transepithelial nasal potential difference was

significantly reduced by gentamicin (p = 0.005). Individuals

homozygous for stop mutations seemed to respond better than did

heterozygotes. In five subjects (26%), electrophysiological measures

reached normal levels.

In nasal epithelial cells of two patients responsive to gentamicin

treatment, immunofluorescent microscopy revealed primarily

perinuclear staining of the cells at baseline. After treatment,

however, the pattern of staining extended toward the periphery and

the surface, they note, similar to that seen in healthy control

subjects' cells.

" These results indicate gentamicin-induced suppression of the

nonsense mutation, resulting in the production of full-length CFTR,

and they are consistent with the measurements of potential

difference showing improvement in chloride transport in these

patients, " the authors write.

CF is associated with many different CTFR mutations, and only a

small percentage have stop mutations that would respond to

aminoglycoside treatment, Dr. Kerem pointed out.

However, " this type of mutation is very common in other diseases, "

such as muscular dystrophy and Hurler's syndrome, he noted. In

addition to further exploring the use of inhalational gentamicin in

CF patients with stop mutations, his team also plans to examine the

utility of gentamycin in these diseases.

Because aminoglycosides are can be quite toxic, the search is on for

other molecules able to reverse the cellular phenotype in CF and

other diseases, Dr. Gergely L. Lukacs and Dr. R. Durie say in

an accompanying editorial. " High-throughput screening of large

libraries of compounds with the use of a cell-based functional

assay " may be a valuable approach for identifying safer agents.

Dr. Durie is based at the Hospital for Sick Children in Toronto, and

Dr. Lukacs at the University of Toronto.

N Engl J Med 2003;349:1401-1404,1433-1441.