Posted on by Dr. Francis Collins
More than 30 years ago, I co-led the Michigan-Toronto team that discovered that cystic fibrosis (CF) is caused by an inherited misspelling in the cystic fibrosis transmembrane conductance regulator (CFTR) gene . The CFTR protein’s normal function on the surface of epithelial cells is to serve as a gated channel for chloride ions to pass in and out of the cell. But this function is lost in individuals for whom both copies of CFTR are misspelled. As a consequence, water and salt get out of balance, leading to the production of the thick mucus that leaves people with CF prone to life-threatening lung infections.
It took three decades, but that CFTR gene discovery has now led to the development of a precise triple drug therapy that activates the dysfunctional CFTR protein and provides major benefit to most children and adults with CF. But about 10 percent of individuals with CF have mutations that result in the production of virtually no CFTR protein, which means there is nothing for current triple therapy to correct or activate.
That’s why more basic research is needed to tease out other factors that contribute to CF and, if treatable, could help even more people control the condition and live longer lives with less chronic illness. A recent NIH-supported study, published in the journal Nature Medicine , offers an interesting basic clue, and it’s visible in the image above.
The healthy lung tissue (left) shows a well-defined and orderly layer of ciliated cells (green), which use hair-like extensions to clear away mucus and debris. Running closely alongside it is a layer of basal cells (outlined in red), which includes stem cells that are essential for repairing and regenerating upper airway tissue. (DNA indicating the position of cell is stained in blue).
In the CF-affected airways (right), those same cell types are present. However, compared to the healthy lung tissue, they appear to be in a state of disarray. Upon closer inspection, there’s something else that’s unusual if you look carefully: large numbers of a third, transitional cell subtype (outlined in red with green in the nucleus) that combines properties of both basal stem cells and ciliated cells, which is suggestive of cells in transition. The image below more clearly shows these cells (yellow arrows).
The increased number of cells with transitional characteristics suggests an unsuccessful attempt by the lungs to produce more cells capable of clearing the mucus buildup that occurs in airways of people with CF. The data offer an important foundation and reference for continued study.
These findings come from a team led by Kathrin Plath and Brigitte Gomperts, University of California, Los Angeles; John Mahoney, Cystic Fibrosis Foundation, Lexington, MA; and Barry Stripp, Cedars-Sinai, Los Angeles. Together with their lab members, they’re part of a larger research team assembled through the Cystic Fibrosis Foundation’s Epithelial Stem Cell Consortium, which seeks to learn how the disease changes the lung’s cellular makeup and use that new knowledge to make treatment advances.
In this study, researchers analyzed the lungs of 19 people with CF and another 19 individuals with no evidence of lung disease. Those with CF had donated their lungs for research in the process of receiving a lung transplant. Those with healthy lungs were organ donors who died of other causes.
The researchers analyzed, one by one, many thousands of cells from the airway and classified them into subtypes based on their distinctive RNA patterns. Those patterns indicate which genes are switched on or off in each cell, as well as the degree to which they are activated. Using a sophisticated computer-based approach to sift through and compare data, the team created a comprehensive catalog of cell types and subtypes present in healthy airways and in those affected by CF.
The new catalogs also revealed that the airways of people with CF had alterations in the types and proportions of basal cells. Those differences included a relative overabundance of cells that appeared to be transitioning from basal stem cells into the specialized ciliated cells, which are so essential for clearing mucus from the lungs.
We are not yet at our journey’s end when it comes to realizing the full dream of defeating CF. For the 10 percent of CF patients who don’t benefit from the triple-drug therapy, the continuing work to find other treatment strategies should be encouraging news. Keep daring to dream of breathing free. Through continued research, we can make the story of CF into history!
 Identification of the cystic fibrosis gene: chromosome walking and jumping. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Science.1989 Sep 8;245(4922):1059-65.
 Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Carraro G, Langerman J, Sabri S, Lorenzana Z, Purkayastha A, Zhang G, Konda B, Aros CJ, Calvert BA, Szymaniak A, Wilson E, Mulligan M, Bhatt P, Lu J, Vijayaraj P, Yao C, Shia DW, Lund AJ, Israely E, Rickabaugh TM, Ernst J, Mense M, Randell SH, Vladar EK, Ryan AL, Plath K, Mahoney JE, Stripp BR, Gomperts BN. Nat Med. 2021 May;27(5):806-814.
Cystic Fibrosis (National Heart, Lung, and Blood Institute/NIH)
Kathrin Plath (University of California, Los Angeles)
Brigitte Gomperts (UCLA)
Stripp Lab (Cedars-Sinai, Los Angeles)
Cystic Fibrosis Foundation (Lexington, MA)
Epithelial Stem Cell Consortium (Cystic Fibrosis Foundation, Lexington, MA)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Cancer Institute; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
When your world has been touched by a life-threatening disease, it’s hard to spend a lot of time dreaming about the future. But that’s exactly what Jenny, an 8-year-old girl with cystic fibrosis (CF), did 30 years ago upon hearing the news that I and my colleagues in Ann Arbor and Toronto had discovered the gene for CF [1,2]. Her upbeat diary entry, which you can read above, is among the many ways in which people with CF have encouraged researchers on the long and difficult road toward achieving our shared dream of effective, molecularly targeted therapies for one of the nation’s most common potentially fatal recessive genetic diseases, affecting more than 30,000 individuals in the United States .
Today, I’m overjoyed to say that this dream finally appears to have come true for about 90 percent of people with CF. In papers in the New England Journal of Medicine and The Lancet [4,5], two international teams, including researchers partly supported by NIH, report impressive results from phase 3 clinical trials of a triple drug therapy for individuals with CF and at least one copy of Phe508del, the most common CF-causing mutation. And Jenny happens to be among those who now stand to benefit from this major advance.
Now happily married and living in Colorado, Jenny is leading an active life, writing a children’s book and trying to keep up with her daughter Pippa Lou, whom you see with her in the photo above. In a recent email to me, her optimistic outlook continues to shine through: “I have ALWAYS known in my heart that CF will be cured during my lifetime and I have made it my goal to be strong and ready for that day when it comes. None of the advancements in care would be what they are without you.”
But there are a great many more people who need to be recognized and thanked. Such advances were made possible by decades of work involving a vast number of other researchers, many funded by NIH, as well as by more than two decades of visionary and collaborative efforts between the Cystic Fibrosis Foundation and Aurora Biosciences (now, Vertex Pharmaceuticals) that built upon that fundamental knowledge of the responsible gene and its protein product. Not only did this innovative approach serve to accelerate the development of therapies for CF, it established a model that may inform efforts to develop therapies for other rare genetic diseases.
To understand how the new triple therapy works, one first needs to understand some things about the protein affected by CF, the cystic fibrosis transmembrane regulator (CFTR). In healthy people, CFTR serves as a gated channel for chloride ions in the cell membrane, regulating the balance of salt and water in the lungs, pancreas, sweat glands, and other organ systems.
People with the most common CF-causing Phe508del mutation produce a CFTR protein with two serious problems: misfolding that often results in the protein becoming trapped in the cell’s factory production line called the endoplasmic reticulum; and deficient activation of any protein that does manage to reach its proper location in the cell membrane. Consequently, an effective therapy for such people needs to include drugs that can correct the CFTR misfolding, along with those than can activate, or potentiate, the function of CFTR when it reaches the cell membrane.
The new triple combination therapy, which was developed by Vertex Pharmaceuticals and recently approved by the Food and Drug Administration (FDA) , is elexacaftor-tezacaftor-ivacaftor (two correctors and one potentiator). This approach builds upon the success of ivacaftor monotherapy, approved by the FDA in 2012 for rare CF-causing mutations; and tezacaftor-ivacaftor dual therapy, approved by the FDA in 2018 for people with two copies of the Phe508del mutation.
Specifically, the final results from two Phase 3 multi-center, randomized clinical trials demonstrated the safety and efficacy of the triple combination therapy for people with either one or two copies of the Phe508del mutation—which represents about 90 percent of people with CF. Patients in both trials experienced striking improvements in a key measure of lung capacity (forced expiratory volume in 1 second) and in sweat chloride levels, which show if the drugs are working throughout the body. In addition, the triple therapy was generally safe and well tolerated, with less than 1 percent of patients discontinuing the treatment due to adverse effects.
This is wonderful news! But let’s be clear—we are not yet at our journey’s end when it comes to realizing the full dream of defeating CF. More work remains to be done to help the approximately 10 percent of CF patients whose mutations result in the production of virtually no CFTR protein, which means there is nothing for current drugs to correct or activate.
Beyond that, wouldn’t it be great if biomedical science could figure out a way to permanently cure CF, perhaps using nonheritable gene editing, so no one needs to take drugs at all? It’s a bold dream, but look how far a little dreaming, plus a lot of hard work, has taken us so far in Jenny’s life.
In closing, I’d like to leave you with the chorus of a song, called “Dare to Dream,” that I wrote shortly after we identified the CF gene. I hope the words inspire not only folks affected by CF, but everyone who is looking to NIH-supported research for healing and hope.
Dare to dream, dare to dream,
All our brothers and sisters breathing free.
Unafraid, our hearts unswayed,
‘Til the story of CF is history.
. Identification of the cystic fibrosis gene: chromosome walking and jumping. Rommens JM, Iannuzzi MC, Kerem B, et al. Science 1989; 245:1059-1065.
. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Riordan JR, Rommens JM, Kerem B, et al. Science 1989; 245:1066-73. Erratum in: Science 1989; 245:1437.
 Realizing the Dream of Molecularly Targeted Therapies for Cystic Fibrosis. Collins, FS. N Engl J Med. 2019 Oct 31. [Epub ahead of print]
. Elexacaftor-Tezacaftor-Ivacaftor for CF with a Single Phe508del Mutation. Middleton P, Mall M, Drevinek P, et al.N Engl J Med. 2019 Oct 31. [Epub ahead of print]
 Efficacy and safety of the elexacaftor/tezacaftor/ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Heijerman H, McKone E, Downey D, et al. Lancet. 2019 Oct 31. [Epub ahead of print]
 FDA approves new breakthrough therapy for cystic fibrosis. FDA News Release, Oct. 21, 2019.
Cystic Fibrosis (Genetics Home Reference/National Library of Medicine/NIH)
Research Milestones (Cystic Fibrosis Foundation, Bethesda, MD)
Wheezie Stevens in “Bubbles Can’t Hold Rain,” by Jennifer K. McGlincy
NIH Support: National, Heart, Lung and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
As NIH Director, I often hear stories of how people with serious diseases—from arthritis to Zika infection—are benefitting from the transformational power of NIH’s investments in basic science. Today, I’d like to share one such advance that I find particularly exciting: news that a combination of three molecularly targeted drugs may finally make it possible to treat the vast majority of patients with cystic fibrosis (CF), our nation’s most common genetic disease.
First, a bit of history! The first genetic mutation that causes CF was discovered by a collaborative effort between my own research lab at the University of Michigan, Ann Arbor, and colleagues at the Hospital for Sick Children in Toronto—more than 25 years ago . Years of hard work, supported by the National Institutes of Health and the Cystic Fibrosis Foundation, painstakingly worked out the normal function of the protein that is altered in CF, called the cystic fibrosis transmembrane regulator (CFTR). Very recently new technologies, such as cryo-EM, have given researchers the ability to map the exact structure of the protein involved in CF.
Among the tens of thousands of CF patients who stand to benefit from the next generation of targeted drugs is little Avalyn Mahoney of Cardiff by the Sea, CA. Just a few decades ago, a kid like Avalyn—who just turned 2 last month—probably wouldn’t have made it beyond her teens. But today the outlook is far brighter for her and so many others, thanks to recent advances that build upon NIH-supported basic research.
Posted on by Dr. Francis Collins
It’s been more than a quarter-century since my colleagues and I were able to identify the gene responsible for cystic fibrosis (CF), a life-shortening inherited disease that mainly affects the lungs and pancreas . And, at a recent event in New York, I had an opportunity to celebrate how far we’ve come since then in treating CF, as well as to honor a major force behind that progress, Dr. Bob Beall, who has just retired as president and chief executive officer of the Cystic Fibrosis Foundation.
Thanks to the tireless efforts of Bob and many others in the public and private sectors to support basic, translational, and clinical research, we today have two therapies from Vertex Pharmaceuticals that are targeted specifically at CF’s underlying molecular cause: ivacaftor (Kalydeco™), approved by the Food and Drug Administration (FDA) in 2012 for people with an uncommon mutation in the CF gene; and the combination ivacaftor-lumacaftor (Orkambi™), approved by the FDA in July for the roughly 50 percent of CF patients with two copies of the most common mutation. Yet more remains to be done before we can truly declare victory. Not only are new therapies needed for people with other CF mutations, but also for those with the common mutation who don’t respond well to Orkambi™. So, the work needs to go on, and I’m encouraged by new findings that suggest a different strategy for helping folks with the most common CF mutation.