A cystic fibrosis cure for all? Gene editing shows promise

Could next-generation gene editing mean a cure for cystic fibrosis (CF)? There's been a lot of advancement on the disease in the last decade, but there are still those living with the disease who get no relief from current treatments - especially those for whom health disparities already exist.

Paul McCray, M.D., professor of pediatrics, and microbiology and immunology at the University of Iowa and his collaborator, David Liu, Ph.D., at the Broad Institute, have been working on newer version of gene editing technologies. One known as prime editing allows any letter in the genetic code to be replaced, even sections of the code as long as a couple hundred letters.

CF is caused by mutations in one of the nearly 20,000 genes in the human genome - the cystic fibrosis transmembrane regulator (CFTR) gene. In a recent NHLBI-funded study, McCray and colleagues employed six different enhancements to the gene editing technology developed by Liu's team to make it more effective. These modifications corrected about 60 percent of the deletions in human lung cells and about 25 percent in airway cells taken directly from patient lungs and grown in a dish.

McCray is an expert using genomic approaches to better understand CF, an inherited disease that affects more than 160,000 people worldwide. CF is most well-known as a lung disease often marked by cough, breathing problems, and frequent lung infections. But it also impacts multiple organs, including the sinuses, liver, intestines, pancreas, and reproductive system.

More than 2,000 known variants of the CFTR gene exist, and at least 700 can cause disease. The most common, found in in about 70% of people with CF, removes three letters from the CFTR code. That deletion causes the incorrect formation and premature breakdown of the CFTR protein that secretes chloride and bicarbonate from the cell. Without this protein, the altered secretions lead to a buildup of thick, sticky mucus and reduced airway defenses. In the lungs, bacteria can get caught in the mucus and cause infection and inflammation.

A ground-breaking standard of care emerges - with caveats

A little over 10 years ago, new treatment options became available to people living with CF. Medications known as CFTR modulators hit the market and revolutionized CF care. Life expectancy and lung function became near normal for those on the medications.

"The medical literature is full of dramatic stories of how people responded," said McCray. "Before we started using the CFTR modulators to treat patients, there were typically 200-300 people with CF on the transplant list at any given time. Since these drugs became available, this number has been reduced by more than 75%."

The CFTR modulators work by partially restoring function to the defective CFTR protein. For example, some of the mutations in the CFTR gene still make a protein, but the protein gets stuck inside the cell and can't get to where it needs to go, explained Marrah Lachowicz-Scroggins, Ph.D., chief of the lung development and pediatric diseases branch in NHLBI's Division of Lung Diseases.

Yet, while the modulators have greatly improved patient care, they aren't perfect. People on them are required to take them twice per day, and some estimates suggest they can cost upwards of $300,000 per patient per year. People living in low-resourced countries with little access to the medications face an even more profound barrier. But perhaps the biggest drawback is that for 10% of people with CF, these medications don't work at all. Some simply don't have the right kind of mutation that can be fixed by the modulators; others cannot tolerate the side effects the medication causes.

Lachowicz-Scroggins explained that the variants for which the drugs are ineffective are predominately found in individuals of non-Caucasian descent who have more uncommon mutations in the CFTR gene. "These are the people who are already dealing with health disparities and are being left behind by the advancement of these new drugs," she said. But gene editing technology may one day be able to change that.

Lachowicz-Scroggins says not only might the new technology help those who don't have other treatment options; it holds the promise of being a lifelong one-time treatment for anybody with CF, regardless of which mutation in the CFTR gene they have.

Challenges on the horizon

Though researchers are moving at breakneck pace to improve these gene editing technologies, obstacles in using them on actual patients remain.

"The most challenging hurdle for gene editing techniques for lung diseases is to find efficient ways to deliver the technology to the right place in the body where it can work its magic," said McCray. "We have these amazing tools at our disposal, but how to get the tool to the target cells of interest is really where our focus is now."

Despite that CF can impact multiple organs, previous research has shown that even just targeting the cells in the lungs could result in an upswing in a patient's prognosis. McCray and his team are currently working on testing multiple delivery tools in the lab to figure out which one reaches the cells in the lungs best. And NHLBI is at the forefront of ensuring innovative solutions to this problem through partnering on the Targeted Genome Editor Delivery (TARGETED) Challenge, led by NIH Common Fund, which plans to award a total of $6 million to scientists who figure out how gene editing tools can get to the cells and tissues that need them most.

"This is exactly the type of novel innovation that we need from our scientists," said Lachowicz-Scroggins. "If we figure this out, then we're really on the precipice of testing more of these types of technologies in clinical trials, because they're already so advanced in preclinical models. It's exciting work."