Oct 25, 2017 Veronique De Turenne
Incurable. Degenerative. Terminal. For decades, those terms have lingered in the ears of patients with a little-known lung disease while they have listened in vain for good news from the scientific community. Finally, investigators are breathing new life into the quest for novel treatments.
He knows it sounds odd, but Paul Giordano says he was lucky in 2014, the year he was diagnosed with a rare and deadly lung disease.
The first bit of good fortune came when his family doctor detected a slight crackling sound in Giordano's breath during a routine physical, and then sent him to a lung specialist for further testing. Her vigilance meant his illness was caught early. The second bit was when he saw the specialist. The pulmonologist delivered a bleak piece of news: Most people with this condition don't live more than three years.
"He was pretty cavalier about it," Giordano says. "He sure didn't offer me much hope other than 'Take some prednisone and see you in 30 days.' But then after telling me there's no cure and that at age 71 I'm probably too old for a lung transplant, he said that a Dr. Noble at Cedars-Sinai is doing some advanced studies in this disease," Giordano recalls. "I called his assistant, and it seemed like there was, maybe, some hope."
The diagnosis that upended Giordano's life was idiopathic pulmonary fibrosis (IPF), a fatal lung disease. For reasons that are not yet fully understood — that's the "idiopathic" part — the disease causes progressive scarring, or fibrosis, within the lungs that gradually destroys their ability to function.
In IPF, an ever-expanding barrier of scar tissue makes delicate structures deep in the lungs become thick and stiff. Breathing is increasingly difficult. Oxygen cannot pass from the lungs to the blood to fuel muscles and organs. The disease also affects the pathways that clear the waste product carbon dioxide from the blood and prevent an unhealthy buildup of the gas.
Pulmonary fibrosis slowly robs patients of breath and finally life. We are working to change that."
— Paul Noble, MD
What begins as an unexpected bit of breathlessness — the stairs you breezed up last week are suddenly a difficult climb — worsens progressively. Starved for oxygen, the body grows weak. Patients with advanced IPF struggle to breathe, and eventually succumb to lung and heart failure, and sometimes cancer.
The referral to Cedars-Sinai, though, put Giordano in a position to beat the odds. Paul W. Noble, MD — director of the Women's Guild Lung Institute, and the Vera and Paul Guerin Family Distinguished Chair — is a renowned leader in interstitial lung diseases. He was the moving force behind a landmark series of clinical trials that, for the first time, identified specific medications to combat the progression of IPF. As a result of those trials, in October 2014 the FDA approved the drugs nintedanib and pirfenidone, which slow the disease's advance by interfering with the cellular pathway that causes scarring.
To call these new therapies game-changers is an understatement. Before they became available, all patients faced a dark future: either a lung transplant or a slow and painful death. While neither medication cures IPF, patients now have therapies that can extend their lives for the first time since the mid-1800s, when the condition was identified by German physicians.
"Noble deserves a lot of credit for his work in moving pirfenidone, which was the first [IPF] drug to be approved by the FDA, into the clinic," says Victor Thannickal, MD, director of the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Alabama. "Without a doubt, he is one of the pioneers [in combatting] this disease."
Giordano had never heard of IPF before learning he had it. That's because the disease has a public relations problem. Each year about 50,000 new cases are diagnosed in the U.S., and the condition results in up to 40,000 deaths annually. Twenty times as many people are diagnosed with IPF as with cystic fibrosis, yet IPF remains all but invisible in awareness. This makes accurate diagnosis and early intervention more difficult, and also makes it harder for scientists to garner research funding.
"One of our biggest challenges is that virtually no one knows about this disease," Noble says. "We have suffered from a lack of interest and motivation, in part because it does affect mostly older men. But the people I take care of are in their early 70s, are otherwise perfectly fit, and would give anything to enjoy another 10 years."
For Giordano, the timing of his diagnosis could not have been better. Just two days after his initial phone call to Cedars-Sinai — made the same month as the FDA approvals — he was in Noble's office. That's when a whole new world of treatment options opened up.
"Dr. Noble was so kind and gracious and reassuring," Giordano says. "His first words to me were 'I want you to know that we're going to be with you all the way through on this.'"
After a lung biopsy and additional tests, Giordano was cleared to begin a regimen of pirfenidone, which he tolerates well despite the drug's known adverse side effects. He has the added comfort of knowing that, unlike what he previously was told, he is not too old for a lung transplant. If the time comes, Noble says the lifesaving procedure may indeed be an option. Cedars-Sinai is one of the few medical centers in Southern California with Medicare certification for lung transplants. The expertise of the Women's Guild Lung Institute teams enables older and sicker patients to be accepted for care.
Prior to 2014, when the FDA approved the two anti-scarring drugs, treatment for IPF consisted mainly of corticosteroids to reduce inflammation and agents to thin mucus. Whether treatment with steroids was useful or perhaps even harmful was open to debate. Now, researchers in the Noble Laboratory at Cedars-Sinai are moving the science forward once again. Their latest inquiries are shining new light on the molecular mechanisms behind IPF.
"Idiopathic pulmonary fibrosis is primarily a disease of the cells that line the gas exchange regions of the lung, or the alveoli," Noble says, referring to the millions of tiny, balloon-shaped sacs where the oxygen we inhale is transferred to the blood, and from which we receive carbon dioxide that we exhale.
The lining cells are called type 2 alveolar epithelial cells, or AEC2 cells. "These recently have been shown to function as stem cells, which means IPF is, in part, a disease of stem cell failure," Noble says.
In a healthy lung, these liner AEC2 stem cells are constantly renewing themselves with the help of worker cells known as fibroblasts. The Noble Laboratory recently discovered a mechanism by which the AEC2 stem cells regenerate. But in IPF, AEC2s weaken and begin to die off — the regenerative ability is lost. This appears to trigger the fibroblasts to malfunction: Instead of helping to rebuild the lung, they attack the delicate lining of the alveoli, which causes IPF's signature scarring.
"We are starting to get clues on how to target these cells," Noble says. "We think what we need are two different pills — one that stimulates the tired stem cells to grow, and one that targets these bad fibroblast cells that almost behave like cancer cells."
By pioneering this line of inquiry, Noble and his colleagues hope to parse the mysteries of IPF at the cellular level. They also are looking at any genetic predispositions that may play a role in its development in certain individuals. This could lead not just to the formulation of new medications to manage the disease but perhaps even to a cure.
Among the many people rooting for Noble to succeed is Don Yuhas, who was 55 when he learned he had IPF in 2013. While on a family vacation to Hawaii, the shortness of breath that Yuhas had noticed for several months suddenly became severe.
"One day we were out snorkeling in a cove with no waves and no wind, and I was struggling and running low on breath," he recalls. "I was 30 feet from the beach and it felt like it was 300 feet. I had fins on and I'm a strong swimmer, but when my foot hit the sand, I had just about run out of gas."
Unlike Giordano, who got a swift diagnosis, Yuhas' doctors struggled to identify his condition. First he was told he had walking pneumonia, then that he had experienced a mild heart attack. It wasn't until a visit to a pulmonologist seven months after the Hawaii vacation that the diagnosis was in: IPF.
Yuhas' girlfriend immediately went into research mode. From the American Lung Association, she learned that the best doctor in the field was in their own backyard.
"What I liked about Dr. Noble from the first day I met him was his optimism," Yuhas says. "Before that, everyone was very grim."
When it became clear that the initial treatment Noble prescribed was not working, Yuhas was added to the waiting list at the Lung Transplant Program at Cedars-Sinai. A little over a month later, he received a new set of lungs. Within eight days he was home again, his oxygen levels in the normal range for the first time in years.
"Every breath I take now, I think of and thank my donor. I will never let him down!" he says.
Although a nonsurgical treatment did not work for Yuhas, he has greatly contributed to the push to decode the origins of IPF: He donated his diseased lungs to the Noble Laboratory, where they now are being studied. Cells from the lungs are cultured for use in experiments to learn how and why IPF develops, and to seek pathways to stop or even reverse its progress.
"Our research is now moving toward screening a large number of drugs that can either stimulate stem cell renewal or kill the pathologic fibroblasts" — those worker cells that go rogue, Noble says.
"One of the ways that our investigators discover new treatments is by using an approach where we grow something like mini lungs in a dish from healthy or diseased cells. We can use these organoids to test compounds." The long-term goal is to use this personalized approach to treat patients.
The Noble Laboratory's work has been funded through grants from the National Institutes of Health (NIH), the California Institute for Regenerative Medicine, and philanthropic funds from grateful patients and donors. "One of the challenges is that the NIH budgets have been severely stressed, compromising research moving forward," Noble says. His team has a number of research grants under review, including an additional NIH grant, and is hoping for positive news to fund the IPF research program. In the meantime, he is directing research, seeing patients, and giving hope to a desperately ill population.
"Pulmonary fibrosis slowly robs patients of breath and finally life," Noble says. "We are working to change that."
And for that, Giordano is profoundly grateful. Thanks to the new drugs Noble's work has made available, Giordano remains active. He walks, rides his bike, and enjoys life with Suszann, his wife of 50 years. He doesn't mince words when saying how he feels about Noble and his work.
"We went from despair to hope," he says. "Dr. Noble gave me my life back."