A CYSTIC FIBROSIS SUCCESS STORY
THE QUEST FOR A CURE TO CRUEL LUNG DISEASE ELUDED DEDICATED RESEARCHERS FOR YEARS
In August 1989, scientists made a blockbuster discovery: They pinpointed the faulty gene that causes cystic fibrosis, a cruel lung disease that kills many of its victims before they reach adulthood. The human genome was uncharted territory, and the gene hunt had become an all- out international race, with laboratories in three countries searching for the root of the disease.
That fall, biologist James Wilson stood before an audience of researchers, physicians, and cystic fibrosis patients and their families and described gene therapy, a way to replace the faulty gene with a good copy. Wilson was overwhelmed by the surging thrill in the room that science was about to save people’s lives.
“It was one of the most amazing experiences that I’ve ever had,” Wilson said.
The importance of the cystic fibrosis gene discovery went far beyond a single illness. It helped build the case for the US$ 3 billion project to sequence the entire human genome, which would alter understanding of human biology and shed light on rare and common diseases.
But the story of cystic fibrosis has been illustrative in a way no one could have anticipated. In the early days of human genetics, the path seemed straightforward: Find the gene, fix the gene and repeat for other diseases. The cystic fibrosis journey would take 30 years of persistent, methodical work: a feat of science, business, fundraising and patience that has become a model for other diseases.
It was not until late 2019 that another breakthrough fulfilled many of the hopes of 1989. Now, Taylor has what he has been waiting for all these decades — a new drug, Trikafta, that is effective for 90 per cent of patients. Doctors marvel at what they think will be possible if it is given at an early age: a full life span.
Cystic fibrosis developed when a child had the bad luck to inherit two faulty genes, one from each parent. It is the most common inherited disease among Caucasians, and its motivated patient group spurred the work forward with funding.
“All these human disease genes were floating around. We knew they were inherited, but we knew very little. We didn’t know what the genes were, or where they were located,” said Robert Nussbaum, a medical geneticist who was hunting genes for other diseases.
Meanwhile, families were desperate for advances.
“Almost everybody knew some family where it had happened, and it was heartbreaking to see what these kids go through,” said Francis Collins, now director of the National Institutes of Health and then a scientist at the University of Michigan working on cystic fibrosis.
Robert Beall, then an executive vice- president at the Cystic Fibrosis Foundation, which was funding the work, was also “the most impatient human being I ever met — to his credit,” Collins said.
Collins partnered with biologist Lap- Chee Tsui in Toronto and another Toronto scientist, Jack Riordan. In May, a scientist in Tsui’s lab found a tantalizing clue — three missing letters of DNA in a patient with cystic fibrosis. Collins and Tsui were at a scientific conference a month later when they got more evidence.
The pair raced to Tsui’s room, where he had installed a portable fax machine to receive updates from the lab. Among the papers that had spilled onto the floor was a table showing those three letters of DNA missing in multiple patients with cystic fibrosis, while they were present in healthy people.
“Lap- Chee was a little more skeptical, ( saying) ‘ I’ve got to see more data,’” Collins recalled. “I bought it, that was it. I wanted to scream and jump up and down.”
Tsui and Collins later presented their results to the scientific community at a major genetics meeting, where the audience rose to its feet in excitement.
Collins would testify before Congress it was necessary to fund the human genome project.
Scientists already were beginning to look for ways to transform the knowledge of the gene into a treatment.
“Such an approach was absolutely impossible until the gene was in hand,” Collins told Congress. “But now it is.”
Gene therapy, the thinking went, would soon cure cystic fibrosis, marking a turning point in the treatment of genetic diseases. Use a virus to ferry a good, functioning copy of the gene into patients’ lung cells.
Wilson teamed up with Collins and corrected cystic fibrosis in cells in a dish, a proof- of- concept experiment that became front-page news. Wilson gave another presentation to the cystic fibrosis conference.
“The year before, I talk prophetically about gene therapy. And now I show up and say we cured cystic fibrosis in the test tube. And I’m talking about expectations ... at that time, with a lay audience, if you cured in a test tube — ‘ Wow, let’s go,’ ” Wilson recalled.
Several teams raced to test the therapy in people, appearing before a special federal committee that evaluated the safety, science and ethical issues of such clinical trials. There were fears of “an Andromeda Strain virus that wiped out Bethesda ( Maryland),” recalled Ronald Crystal, a pulmonologist who led a trial at the National Institutes of Health.
The first patients spent weeks inside two negative-air-pressure rooms built at NIH to ensure that didn’t happen.
But human biology turned out to resist an easy fix, and it quickly became clear that gene therapy would not be simple in real lungs. Then the entire gene therapy field screeched halted in 1999 with the death of Jesse Gelsinger, a teenager with a metabolic disorder who died after being treated for the disorder in one of Wilson’s gene therapy trials.
As the hope for a high- profile gene therapy success crashed, research continued on the basic, less glamorous work to untangle what went wrong with the cystic fibrosis gene. Beall and Preston Campbell of the Cystic Fibrosis Foundation visited Aurora Biosciences, a San Diego biotech company that used robotics to massively speed up such testing.
“Bob and I were like kids in a candy shop,” Campbell recalled. After a small initial investment, the foundation stunned the non- profit world in 2000 by awarding the company $ 40 million, a new kind of venture philanthropy arrangement in which if the company was successful, the non- profit group would receive a share of the royalties.
A Massachusetts company, Vertex Pharmaceuticals, acquired Aurora in 2001, and although the cystic fibrosis work continued, it was considered a long shot, called the “fantasy project” internally, recalled Fred Van Goor, a scientist who joined the company around that time and became the biology lead for the cystic fibrosis program.
The scientific problem was huge: The most common gene mutation in cystic fibrosis created a protein that couldn’t do its essential job in the cell. The protein didn’t fold correctly, which interfered with its ability to reach the surface of the cell. And it didn’t function well once there, where it was supposed to work as a gate. That meant they’d need multiple drugs to help patients — one to get the protein to the right spot, the other one to open the gate.
Vertex’s first drug candidate was focused on just one of the problems — getting the gate to work better. Alone, it would help only about four per cent of patients, whose disease was caused by a rare mutation. That drug, Kalydeco, was approved in 2012, but it remained unclear whether a drug could be made that would work for a larger group of patients.
After a business loss, Vertex’s board decided to focus on cystic fibrosis, and in 2015, a two- drug combination called Orkambi, was approved for a larger group of cystic fibrosis patients. Excitement about the drugs began to yield to a societal debate about their high prices; Orkambi’s launch price was US$259,000 a year.
Meanwhile, the company would need to develop a third drug to treat more patients.
Drug trials are “blinded” so that neither the patients nor the scientists know which people are receiving the drug and which are receiving a placebo. When Trikafta, the triple drug combination that would ultimately be approved, was unblinded from one trial in October 2018, researchers finally saw the slide showing how the drug affected lung function.
There was a stunned silence in the room for a full minute. The drug worked.
“There was the heart and the mind ... Our minds said, ‘ Yup, just as expected,’ and our guts said, ‘ Could this be true?’“said David Altshuler, Vertex’s chief medical officer.
After such a long wait, 10 per cent of cystic fibrosis patients, are still waiting for a therapy that works for them.
Stacy Carmona, who was born just three years before the gene was discovered, is one of them.
“I’m so excited for the community. I’m so excited for the CF friends I have who so desperately need the drug. There are so many people hanging on by a thread, waiting for this,” Carmona said. “The flip side of that is you can’t help but wonder: When is it going to be my turn?”