A new drug for cystic fibrosis, PTC124, can bypass the genetic defect in the protein-making machinery of patients and improve the functioning of cell membranes that is normally hampered by the condition. These are the conclusions of an Article published early Online and in an upcoming edition of The Lancet, authored by Dr Eitan Kerem and Dr Michael Wilschanski Hadassah Hebrew University Hospital, Jerusalem, Israel, and colleagues.
In around 10% of patients worldwide, and over 50% in Israel*, cystic fibrosis results from premature 'stop' signals (nonsense mutations) in the genes responsible for the cystic fibrosis transmembrane conductance regulator (CFTR), which forms the protein channels which cross the cell membrane to allow chloride ion transport. This defect leads to dehydration of the mucus surrounding the body's epithelial cells, and in turn to chronic inflammation, respiratory problems, repeated infections and eventually death at an early age. PTC124 was developed to allow the protein-making machinery to bypass the premature stop signals and allow the CFTR pathway to function normally. This phase II trial included 23 patients receiving PTC124 in two cycles. In each cycle the patients received three doses of PTC124 per day for 14 days, followed by 14 days without treatment. In the first cycle the patients received a lower dose than the second. The efficacy of the drug was measured by calculating improvements in chloride ion transport through the cell membranes, by measuring tiny voltage changes across the nasal epithelial cells.
Voltage changes were measured in 23 patients in the first cycle and 21 patients in the second. Mean total chloride ion transport increased in the first cycle, with a change of -7.1mV, and also in the second cycle but by a lesser amount, -3.7mV. A response in total chloride transport, defined as a change of -5.0mV or more, was recorded in 16 of 23 patients in the first cycle and eight of 21 in the second cycle. Chloride ion transport entered the normal range for 13 of 23 patients in the first cycle and nine of 21 in the second cycle. As well as these voltage changes, use of PTC124 was associated with small increases in lung respiratory function and bodyweight in most patients, as well as a reduction in numbers of neutrophils – cells of the immune system that respond to inflammation. Some patients also reported decreases in lung-related symptoms such as cough. Two patients given PTC124 had constipation without intestinal obstruction, while four had mild dysuria (painful urination).
They conclude: "This trial exemplifies the concept of personalised medicine: integrating selection of patients with a specific genetic defect, use of a treatment designed to overcome that defect in gene expression, and direct assessment of protein function within disease-affected tissues…The further 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."
In an accompanying Comment, Dr Stephen Hyde and Dr Deborah Gill, UK Cystic Fibrosis Gene Therapy Consortium and Nuffield Department of Clinical Laboratory Sciences, University of Oxford, UK say it is encouraging to note how specific PTC124's mode of action is, as it prevents nonsense stop signals in the CFTR gene without interrupting the body's genuine stop signals. They add that given the positive findings of the study, future placebo-controlled trials of PTC124 are warranted.
Notes to editors: *The incidence of cystic fibrosis of this type in a population is dependent on its genetic background, hence this higher incidence in Israel
Dr Eitan Kerem, Hadassah Hebrew University Hospital, Jerusalem, Israel T) +972-50-7874491 / +972-54-8820678 E) ek@cc.huji.ac.il
Alternative contact: Dr Michael Wilschanski, Hadassah Hebrew University Hospital, Jerusalem, Israel (Note: will be traveling all day Wed 20 Aug) T) +972-508-573572 E) michaelwil@hadassah.org.il
Dr Stephen Hyde, UK Cystic Fibrosis Gene Therapy Consortium and Nuffield Department of Clinical Laboratory Sciences, University of Oxford, UK T) +44 (0) 7986 877951 E) steve.hyde@ndcls.ox.ac.uk
full Article and Comment:
http://press.thelancet.com/cysticfibrosisfinal.pdf
Journal
The Lancet