Another Milestone in the Cystic Fibrosis Journey

Avalyn Mahoney

Caption: Two-year-old Avalyn is among the cystic fibrosis patients who may be helped by targeted drugs.
Credit: Brittany Mahoney

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 [1]. 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.

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Cystic Fibrosis: Keeping the Momentum Going

Cystic Fibrosis: 1989 and 2015

Caption: Lower left, me, Lap-Chee Tsui, and John Riordan celebrating our discovery of the cystic fibrosis gene. Right, Robert J. Beall, me, and Doris Tulcin at a November Cystic Fibrosis Foundation event honoring Dr. Beall.

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 [1]. 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.

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Targeting Cystic Fibrosis: Are Two Drugs Better than One?

Cystic Fibrosis Patient

Caption: Doctor with a child with cystic fibrosis who is taking part in clinical research studies. Credit: Colorado Clinical and Translational Sciences Institute

To explain the many challenges involved in turning scientific discoveries into treatments and cures, I often say, “Research is not a 100-yard dash, it’s a marathon.” Perhaps there is no better example of this than cystic fibrosis (CF). Back in 1989, I co-led the team that identified the cystic fibrosis transmembrane conductance regulator (CFTR) genethe gene responsible for this life-shortening, inherited disease that affects some 70,000 people worldwide [1]. Yet, it has taken more than 25 years of additional basic, translational, and clinical research to reach the point where we are today: seeing the emergence of precise combination drug therapy that may help about half of all people with CF.

CF is a recessive diseasethat is, affected individuals have a misspelling of both copies of CFTR, one inherited from each parent; the parents are asymptomatic carriers. The first major advance in designer drug treatment for CF came in 2012, when the Food and Drug Administration (FDA) approved ivacaftor (Kalydeco™), the first drug to target specifically CF’s underlying molecular cause [2]. Exciting news, but the rub was that ivacaftor was expected to help only about 4 percent of CF patients—those who carry a copy of the relatively rare G551D mutation (that means a normal glycine at position 551 in the 1480 amino acid protein has been changed to aspartic acid) in CFTR. What could be done for the roughly 50 percent of CF patients who carry two copies of the far more common F508del mutation (that means a phenylalanine at position 508 is missing)? New findings show one answer may be to team ivacaftor with an experimental drug called lumacaftor.

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Ferreting Out Genomic Secrets

Ferret

Ferret in a Colorado conservation center, U.S. Fish and Wildlife Service

Not only is the ferret (Mustela putorius furo) adept at navigating a dirt field or threading electrical cables through piping (in New Zealand, ferrets can be registered as electrician assistants), this furry 5-pounder ranks as a real heavyweight for studying respiratory diseases. In fact, much of our current thinking about influenza is influenced by research with ferrets.

Now, the ferret will stand out even more. As reported online in Nature Biotechnology, NIH-funded researchers recently sequenced the genome of the sable ferret, the type that is bred in the United States as a pet. By studying this genetic blueprint like an explorer would a map, scientists can perform experiments to learn more systematically how the ferret copes biologically with common or emerging respiratory pathogens, pointing the way to improved strategies to preserve the health and well being of humans and ferrets alike.

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Creative Minds: Interpreting Your Genome

Artist's rendering of a doctor with a patient and a strand of DNA

Credit: Jane Ades, National Human Genome Research Institute, NIH

Just this year, we’ve reached the point where we can sequence an entire human genome for less than $1,000. That’s great news—and rather astounding, since the first human genome sequence (finished in 2003) cost an estimated $400,000,000!  Does that mean we’ll be able to use each person’s unique genetic blueprint to guide his or her health care from cradle to grave?  Maybe eventually, but it’s not quite as simple as it sounds.

Before we can use your genome to develop more personalized strategies for detecting, treating, and preventing disease, we need to be able to interpret the many variations that make your genome distinct from everybody else’s. While most of these variations are neither bad nor good, some raise the risk of particular diseases, and others serve to lower the risk. How do we figure out which is which?

Jay Shendure, an associate professor at the University of Washington in Seattle, has an audacious plan to figure this out, which is why he is among the 2013 recipients of the NIH Director’s Pioneer Award.

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