A cystic brosis success story — over 30 years | Health – The Union Leader

In August 1989, scientists made a blockbuster discovery: They pinpointed the faulty gene that causes cystic fibrosis, a cruel lung disease that killed many of its victims before they reached 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 had intended his talk to be technical and prophetic, but he was overwhelmed by the surging thrill in the room that science was about to save peoples lives.

It was one of the most amazing experiences that Ive ever had, Wilson said, adding, The expectations were through the roof.

The importance of the cystic fibrosis gene discovery went far beyond a single illness. It helped build the case for the $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 that no one could have anticipated back then. 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, from an exuberant moment of insight to a major success, would take 30 years of persistent, methodical work: a feat of science, business, fundraising and patience that has become a model for other diseases.

I specifically remember sitting with my doctor in the exam room, having the conversation that the gene was discovered, said Josh Taylor, 48, of Virginia Beach, who has cystic fibrosis. And him telling me the cure is just he literally said, In 5 to 10 years, were going to beat this.

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 percent 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. Back then, there was no test to detect whether a parent carried a defective gene because no one even knew what the gene was.

As scientists developed new tools to probe human genetics, cystic fibrosis quickly became one of the top targets. It is the most common inherited disease among Caucasians, afflicting 30,000 Americans, 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 didnt know what the genes were, or where they were located, said Robert Nussbaum, a medical geneticist who was hunting genes for other diseases.

Francis Collins, now director of the National Institutes of Health and then a scientist at the University of Michigan working on cystic fibrosis, was photographed for the universitys graduates magazine sitting in a haystack holding a needle, to convey the magnitude of the technical challenge.

Almost everybody knew some family where it had happened, and it was heartbreaking to see what these kids go through, Collins said.

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 holding joint lab meetings at a midway point on the long drive, in London, Ontario.

After years of work, Tsuis lab had narrowed the search to ever smaller stretches of DNA, pioneering new techniques in the search for the gene. Collins had invented a method to speed up the process called chromosome jumping, which allowed scientists to leap over sections of DNA something he compares to leaping from one street corner to the next to initiate searches. Jack Riordan, another scientist in Toronto, discovered a bit of DNA that looked like it might be a part of the gene, providing an essential lead.

In May, a scientist in Tsuis lab found a tantalizing clue three missing letters of DNA in a patient with cystic fibrosis. The team would need to confirm that this genetic mutation was the cause of the disease. Collins and Tsui were at a scientific conference at New Haven, Conn., a month later when they got more evidence.

One rainy night after the days program was over, the pair raced to Tsuis 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, Ive got to see more data, Collins recalled. I bought it, that was it. I wanted to scream and jump up and down.

The news report triggered frantic preparations to present the findings officially, and the work was published in Science magazine that September in three papers.

Collins would testify before Congress that it was necessary to fund the human genome project because the flat-out effort to find the cystic fibrosis gene simply would not be scalable in trying to understand thousands of other diseases.

Gene therapy, the thinking went, would soon cure cystic fibrosis, marking a turning point in the treatment of genetic diseases. The idea was relatively straightforward: Use a virus to ferry a good, functioning copy of the gene into patients lung cells.

But human biology turned out to have all sorts of ways of resisting 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 Wilsons 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. That understanding made it possible to develop ways to screen chemicals, to see if any showed promise as a drug.

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 nonprofit world in 2000 by awarding the company $40 million, a new kind of venture philanthropy arrangement in which if the company was successful, the nonprofit 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 couldnt do its essential job in the cell. The protein didnt fold correctly, which interfered with its ability to reach the surface of the cell. And it didnt function well once there, where it was supposed to work as a gate. That meant theyd need multiple drugs to help patients one to get the protein to the right spot, the other one to open the gate.

Vertexs first drug candidate was focused on just one of the problems getting the gate to work better. Alone, it would help only about 4% 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.

Then, Vertexs main product a hepatitis C drug was eclipsed by a better treatment from a competitor, and the future of the company and its cystic fibrosis research was cast in doubt.

It obviously created an incredible crisis here at Vertex, said Jeff Leiden, chief executive of the company.

Vertexs board decided to bet 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; Orkambis launch price was $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.

Ten percent of cystic fibrosis patients, or about 3,000 people in the United States, 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.

Im so excited for the community. Im 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 cant help but wonder when is it going to be my turn?

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A cystic brosis success story -- over 30 years | Health - The Union Leader