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Researchers in Israel have found that a
new drug for cystic fibrosis, PTC124, is able to bypass the genetic
defect in
the protein-making machinery of patients and improve the performance of
weakened
cell membranes. The results in published in an upcoming edition of The
Lancet.
Dr Eitan Kerem (Hadassah Hebrew
University Hospital, Jerusalem, Israel) and colleagues banker's bill that 10% of
patients worldwide and over 50% in Israel have cystic fibrosis that is
referable to premature "stop" signals (nonsense mutations) in genes
responsible for the cystic fibrosis transmembrane conductance regulator
(CFTR). It is the CFTR that creates the protein channels crossway the
mobile phone membrane that permit chloride ion transportation. The untimely signals
are defects that result in
dehydration of the mucus encompassing the body's epithelial cells
(cells that line the cavities and surfaces of structures throughout the body), and
the resultant is chronic inflammation, respiratory problems, recurrent
infections, and usually death at an early age.
The new drug, PTC124, was created to earmark the CFTR pathway to function
commonly by allowing the protein-making machinery to avoid or bypass
the premature stop
signals. In the phase II tribulation described here, researchers studied 23
patients who received PTC124 in two cycles. Each cycle consisted of
three PTC124 doses per day for two weeks followed by two weeks without
handling. The lucy in the sky with diamonds in the first cycle was lower than the dose in the
irregular. The researchers measured drug efficacy by measuring bantam
voltage changes across the nasal
epithelial cells, making known improvements in chloride ion transport
through
the cell membranes.
Twenty-three patients received voltage-change measurements in the first-class honours degree
cycle and 21 were available in the second cycle. In the start cycle,
the average sum chloride
ion transport increased (noted by a -7.1mV change),
and in the second rhythm there was a lesser increase (illustrious by a -3.7mV
change). In 16 of 23 patients after the first round, there was a
response
in total chloride rapture (a change of -5.0mV or more); 8 of 21
responded to the second cycle. Thirteen of 23 patients in the first
cycle achieved the normal range of chloride ion raptus, and 9 of 21
in the second cycle did as well. Accompanying the electromotive force
changes, PTC124 use was linked to small
increases in lung respiratory function and bodyweight in most patients.
In plus, the do drugs was associated with a reduction in immune organization
cells that respond to inflammation called neutrophils. Other
side-effects included decreases in lung-related symptoms (such as
cough), constipation without intestinal obstruction (2 patients), and
mild dysuria or painful micturition (4 patients).
"This trial
exemplifies the conception of personalized medicine: integrating selection
of patients with a specific genetic defect, use of a intervention designed
to overcome that defect in gene reflection, and direct assessment of
protein map within disease-affected tissues...The farther
development of PTC124 could offer a practical means to address the
underlying cause of disease in patients with nonsense mutations as the
basis for cystic fibrosis," conclude the authors.
An consequent comment written by Dr
Stephen Hyde and Dr Deborah Gill (UK Cystic Fibrosis Gene Therapy
Consortium and Nuffield Department of Clinical Laboratory Sciences,
University of Oxford, UK) note that the way in which PTC124
specifically prevents nonsense halt signals in the CFTR gene without
interrupting the body's unfeigned stop signals is noteworthy. The
researchers hold that these positive findings should warrant future
placebo-controlled trials of PTC124 in the future.
Effectiveness of PTC124 treatment of cystic fibrosis caused by
nonsense mutations: a prospective phase II trial
Eitan Kerem, Samit Hirawat, Shoshana Armoni, Yasmin Yaakov,
David
Shoseyov, Michael Cohen, Malka Nissim-Rafinia, Hannah Blau, Joseph
Rivlin, Micha Aviram, Gary L Elfring, Valerie J Northcutt, Langdon L
Miller, Batsheva Kerem, Michael Wilschanski
The Lancet(2008).
DOI:10.1016/S0140-6736(08)61168-X
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Written by: Peter M Crosta
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