Rewriting The Future of Cystic Fibrosis

Oct 06, 2021 at 11:26 am by steve

Steven Rowe, MD

For the parents of a sick child, it was news they never wanted to hear. Learning that their child had cystic fibrosis not only swept away dreams of a long, happy future. It also brought the sadness of knowing their child would likely suffer through repeatedly struggling to breathe, having to endure pounding on the back to clear lungs, and dealing with pain and damage in other organs. When they heard those words come out of a pediatrician's mouth, there was little to feel hopeful about.

Now there is. After improvements in length of survival over the past couple of decades, a new three-drug combination researched and trialed at UAB is helping 90 percent of cystic fibrosis patients breathe easier. It is even returning the labs of some patients to levels typically seen in people who don't have the disease. There is also hopeful news for the other 10 percent of patients who have an additional mutation that are currently blocking the benefits of this breakthrough. Recently announced research being conducted in UAB's cystic fibrosis lab suggests that overcoming the second mutation is possible and help is likely to soon be on its way.

Much of the basic science and clinical research development of these medications were done under the leadership of Steven Rowe, MD, director of UAB's Gregory Fleming Cystic Fibrosis Research Center.

"The effects of Cystic Fibrosis are caused by an imbalance of salt and water within the cell, due to a lack of the protein that usually regulates it," Rowe said. "This is caused by a mutation in the CFRT gene, which leads to a misfolding that results in the protein production being reduced or completely lacking.

"The first of the three drugs we tested was Ivacaftor, released in 2012 by Vertex Pharmaceuticals. It was designed to help correct the misfolding, and we saw positive results in patients that encouraged us to push forward. In 2015, Tezacaftor was the second drug approved, and it was also aimed at further improving the correct folding. The third drug, Elexacaftor, has now been added to the combination and works as an activator that is giving us the results we had hoped to see."

Marketed as Trikafta®, the effects of the combination drug in alleviating symptoms and improving labs have been game-changing. Measured in expelled breath volume, sweat tests and other indicators, there are reasons to be optimistic. The drug isn't inexpensive, but has been covered under most insurance plans.

It will require time and data, following patients who are taking the medications for a few years to make a definitive evaluation, but researchers and physicians are hopeful that by reducing the symptoms and the tissue damage Cystic Fibrosis does, this three-drug combination will have a significant positive effect on the prognosis for longer survival and a better quality of life.

"The thick, sticky mucus that accumulates in lungs encourages infections that tend to cause scarring and other long-term damage that reduces function. By keeping lungs clearer and not giving infections a place to grow, we hope to prevent the damage, which should have a positive effect on outcomes," Rowe said.

Happy for the 90 percent of patients who are doing better, UAB's cystic fibrosis researchers haven't stopped working on new therapies to help the 10 percent of patients who have an additional mutation that interferes with their ability to share the same benefits of the triple combination medication.

"These patients have an additional mutation of 'nonsense' genes that act like a red light that stops read through of the protein-producing gene," Rowe said. "For over ten years, we have been working on an idea using a small molecule like a bridge to jump past the nonfunctioning part of the gene. This would allow the production of the protein to be completed.

"We worked with Southern Research Institute to identify promising candidates and tested one that met the profile. It was successful in getting past the nonsense section to allow the protein to be produced. While this first test substance hasn't met all our criteria for human testing, it does prove the principle that a new medication can work for patients with the additional mutation. We are working now to identify other small molecules that can have the same effect and meet our safety criteria with a low potential for side effects."

In addition to benefiting patients with an additional cystic fibrosis mutation, this type of advance could be a trail blazer for medications to get past the genetic roadblocks in other diseases like muscular dystrophy and inborn errors in metabolism such as Hunter's Syndrome.

It could be the news many parents whose children are suffering from genetics disorders are waiting to hear.

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