New avenue for improved treatment of cystic fibrosis

July 9, 2013, McGill University
New avenue for improved treatment of cystic fibrosis
Structure of the CFTR protein, based on PyMOL rendering of PDB 1xmi. Credit: Wikimedia Commons User Emw - CC:BY

(Medical Xpress)—Cystic fibrosis is caused by a mutation in the gene that encodes a particular protein, known as the cystic fibrosis transmembrane conductance regulator (or CFTR). Although this discovery was made 25 years ago and the lives of those with the disease have been extended, there is still no effective cure for the disease. Now new information about the nature of the most common form of mutation in the CFTR gene, gathered by a research team led by Dr. Gergely Lukacs of the Department of Physiology at McGill University, offers exciting new avenues for improving the treatment of the disease.

To better understand the difficulty of looking for a cure, or even effective treatment, one must understand the large and complex nature of the CFTR . It is made up of 1,480 strung together in five three-dimensional strands (called domains) that spin together and fold to act as building blocks for the CFTR protein.

"Looking for a treatment or cure for the disease is like trying to repair a tear in a braided rag rug," says Lukacs. "We need both to figure out where the tear originates in an individual coil of cloth, and then we need to discover how best to reattach this individual coil to the larger rug in order to make a solid whole. It's a monumental task."

Scientists already have part of the information needed to move ahead with this work. Although there are about 2,000 associated with the CFTR gene, the most common mutation, known as F508del, found in 90 per cent of patients with the disease, involves the deletion of a single amino acid at position 508 in the CFTR protein. Like a single missing stitch in the carpet, this single absence weakens the whole and renders it non-functional.

The best hope for treating symptoms of at the moment is a drug called Vertex VX-809, which is currently under clinical trial. However, this is ineffective for the vast majority of those who suffer from the disease. That is because VX-809 seems only to restore inter-domain communication within the protein (i.e. to continue with the rug analogy, it can help reattach the coils of rags to one another) but the domains within the protein remain weak (i.e. each individual braided strand in the rug still has tears in it).

In their previous research, Dr. Lukacs and his colleagues have been able to show in cell cultures that the F508del structural effect is not restricted to the domain where it is found. The mutation has negative effects on the other four domains of the protein as well, which compromises the appearance of CFTR at the cell surface. It's as though the weakness or break in a single strand of braided rug affected not just the strength of the strand next to it but that of the rug as a whole.

Lukacs and his team then tried combining Vertex VX-809 with other chemical compounds that target two major structural defects in the protein at the same time. The results were startling. By combining Vertex VX-809 with chemical compounds that act as correctors on the domain containing the F508del mutation, the efficiency of the combination of drugs went up from 15 per cent to 60-80 per cent in cell culture models.

"These findings offer a rational way of choosing drug candidates with distinct mechanisms of action," says Lukacs. "What is even more crucial is that they also suggest the importance of combining drugs which target complementary structural defects in order to overcome the limited success of individual corrector molecules that are currently under clinical trial.

To read the full paper in Nature Chemical Biology: www.nature.com/nchembio/journa … l/nchembio.1253.html

Explore further: New research could provide roadmap for more effective drug discovery for cystic fibrosis

Related Stories

New research could provide roadmap for more effective drug discovery for cystic fibrosis

March 12, 2012
A recent study led by Gergely Lukacs, a professor at McGill University's Faculty of Medicine, Department of Physiology, and published in the January issue of Cell, has shown that restoring normal function to the mutant gene ...

Insights into a new therapy for a rare form of cystic fibrosis

October 29, 2012
Scientists at the Hospital for Sick Children in Toronto have established that a drug recently approved by the U.S. Food and Drug Administration to treat a rare form of cystic fibrosis works in an unconventional way. Their ...

Discovery could increase efficacy of promising cystic fibrosis drug

March 21, 2013
(Medical Xpress)—A little more than a year after the FDA approved Kalydeco (Vx-770), the first drug of its kind to treat the underlying cause of cystic fibrosis, University of Missouri researchers believe they have found ...

Cystic fibrosis drug reverses genetic abnormality in the CF mutation

November 28, 2011
The Lung Institute of WA (LIWA) has recently made a breakthrough in the search for a drug to improve the quality of life of patients with Cystic Fibrosis (CF).

An 'unconventional' path to correcting cystic fibrosis

September 1, 2011
Researchers have identified an unconventional path that may correct the defect underlying cystic fibrosis, according to a report in the September 2nd issue of the journal Cell. This new treatment dramatically extends the ...

New insights into functionality of cystic fibrosis protein

September 26, 2012
CFTR is an important protein that, when mutated, causes the life-threatening genetic disease cystic fibrosis. A study in The Journal of General Physiology (JGP) details how an accidental discovery has provided new understanding ...

Recommended for you

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.