Growth factor makes a comeback in cystic fibrosis

Work in pigs points to culprit 

and potential treatment for growth retardation.

The stunted development common to cystic fibrosis begins at birth -- and could be a direct consequence of a growth-hormone deficiency caused by the disease.

In both people and pigs, newborns with cystic fibrosis tend to have abnormally low levels of a hormone called insulin-like growth factor 1 (IGF1), according to a study published this week in theProceedings of the National Academy of Sciences1. Unlike in healthy controls, in mutant pigs IGF1 levels do not increase over time. The blood concentration of IGF1 could one day be used as a marker to predict whether a patient with cystic fibrosis will have growth problems later in life, says David Stoltz, a physician in the Department of Internal Medicine at the University of Iowa, Iowa City, who led the study.

"We know there's variability -- some people progress quickly, some progress slowly. Some have a growth defect, some don't," says Stoltz. "There might be a sub-population of patients where IGF1 is really important."

Cystic fibrosis is a deadly genetic disease: many patients don't live past the age of 30. Scientists identified the culprit gene some two decades ago (see 'Human genetics: One gene, twenty years'). But the field is still struggling to understand how this glitch causes the disease's range of symptoms, which include scarring and mucus in the lungs and pancreas, diabetes, infertility, weak bones and impeded growth.

Revisiting the past

In the 1990s, researchers found that individuals with cystic fibrosis have low levels of IGF1 in their blood, driving speculation that this was at least partly responsible for their stunted growth. In 2001, researchers reported on a small trial that tested whether giving affected children aged 9-13 a synthetic version of the hormone would boost growth. It didn't, and most researchers lost interest in the connection.

"We were all discouraged by the results and moved on," says Robert Wilmott, a paediatrics expert at Saint Louis University in Missouri, who led that trial. But considering the new data, he says, "it's possible that we missed the boat by starting treatment at that age".

The prevailing wisdom is that the IGF1 deficiency and growth problems are not caused directly by the cystic fibrosis gene, but rather are by-products of malnutrition and lung inflammation. The new study challenges that idea by showing signatures of underdevelopment even at birth.

Stoltz and his collaborators took advantage of a pig model of cystic fibrosis that they debuted in 2008. The model has been the subject of much excitement among researchers because, unlike the mouse version, it develops symptoms similar to those seen in humans with the disease, such as infection and inflammation in the lungs.

Compared with controls, the team found that newborn mutant pigs had significantly less IGF1 in their blood at birth. Furthermore, in mutant newborns the humerus (shoulder to elbow) bones were 9% shorter.

The researchers then screened for IGF1 in samples of dried blood from 23 human newborns with cystic fibrosis. Like the pigs, the babies carried significantly less hormone than controls. "The data seem very robust," says David Dunger, a paediatric specialist at the University of Cambridge, UK. "They've done a lot of effort to repeat things in human subjects."

Brain drain

The cystic fibrosis gene -- CFTR -- codes for a protein called the cystic fibrosis transmembrane regulator, which helps to move chloride ions across cell membranes. Scientists don't know why damage to the gene leads to reduced IGF1 levels, but Stoltz and colleagues' study suggests that it is because of CFTR's action in the brain.

Normally, the brain's pituitary gland releases growth hormone, which travels to the liver and spurs the production and release of IGF1. The researchers found abnormally low levels of growth hormone in pituitary slices from the mutant pigs, which could explain the dearth of IGF1.

However, Dunger says that this hypothesis isn't very plausible because of human studies suggesting that IGF1 in fetuses is not affected by growth hormone. It's more likely, he says, that problems with insulin secretion associated with cystic fibrosis are responsible for the stalled IGF1 production in newborns -- insulin regulates the production of IGF1 in the liver in uteroand throughout life.

In any case, the findings point to IGF1 as a potential therapy for cystic fibrosis -- particularly because regulators in the United States and Europe have already approved synthetic IGF1 for the treatment of severely short stature.

Researchers at Stony Brook University Medical Center in New York are conducting a Phase I trial in which IGF1 is being administered to adults with cystic fibrosis. But before rushing to treat infants with the hormone, Stoltz says, it would be smart to try it in piglets.