Treating an animal model of cystic fibrosis (CF) with Kalydeco (ivacaftor) during embryonic development and after birth revealed that early treatment improved pancreatic function, delayed lung disease, and reduced infections, a study suggests.
The study, titled “In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis,” was published in the journal Science Translational Medicine.
CF is caused by a genetic defect on the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for a “gate” protein — called CFTR — that controls the movement of charged salts, such as chloride, in and out of cells. Mutations in the CFTR gene result in the production of a faulty CFTR protein, causing the “gate” to be stuck closed.
Evidence suggests that CF begins during embryonic development in the uterus, and has a negative effect on the health of the newborn after birth.
“Growth of newborns with CF lags behind healthy controls within the first year of life,” with impaired growth correlating with earlier lung infections, the researchers said. Moreover, loss of CFTR during embryonic development impairs the function of the gut, testes — males with CF are usually infertile — and pancreas.
According to the team, this evidence highlights the need to better understand the long-term impact of CF manifestations during embryonic development, and whether CFTR modulators may halt disease progression when administered early in life.
Kalydeco, an approved CF therapy developed and marketed by Vertex Pharmaceuticals, rescues the CFTR protein function by keeping the CFTR gate open longer. In 2018, Kalydeco was approved as the first-ever therapy to treat the underlying cause of CF in 1-year-olds.
The study’s researchers hypothesized that Kalydeco administration during pregnancy could improve survival of the newborn, and help the scientists further understand the CF disease process.
To test their hypothesis, the researchers generated a ferret animal model of CF by introducing a Kalydeco–responsive mutation (called G551D) in the CFTR gene. This mutation is found in 2% to 5% of patients with CF, and similar to that of young human CF patients, these ferrets were prone to gut obstruction and were especially fragile newborns.
The researchers administered Kalydeco orally once a day to pregnant jills. The treatment began at day 28 of embryonic development due to the high CFTR levels in the intestine and pancreas at this stage. This time period is equivalent to the third semester of human pregnancy.
Kalydeco was administered until seven, 14, or 25 days post-birth.
Results showed that treatment with Kalydeco for 14 days (from day 28 until day 42 of embryonic development) enhanced CFTR function, and protected the animals from developing bowel obstruction after birth.
More than 99% of male CF patients develop an abnormal reproductive tract, leading to infertility. Male mutant ferrets also showed similar defects, but Kalydeco treatment rescued testis structure, indicating that male fertility could be protected by this therapy.
Treatment with Kalydeco during the embryonic development and maintained up to 25 days after birth rescued the animal’s growth rate, similar to that seen in wild-type (control) animals. The treatment also helped partially preserve the function of the pancreas, and helped stabilize sugar levels in animals that otherwise would have higher sugar levels (a condition called hyperglycemia).
The researchers then evaluated how Kalydeco impacted the development of lung infections, which are a major complication for CF patients.
Results showed that treatment maintained postnatally slowed lung disease progression. However, treatment and antibiotics termination after eight months allowed lung infections to be detected within 51 to 134 days after the last treatment. Additionally, without treatment, these ferrets showed mucus accumulation and inflammation in the lungs.
The animals also showed signs of acute pancreatitis once treatment stopped, and diabetes developed in a small proportion of animals.
Overall, “the findings from this study emphasize the importance of early interventions in the treatment of CF,” the researchers wrote.
“Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease, and offers opportunities for understanding CF pathogenesis and improving treatment,” the team concluded.