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cystic fibrosis

Pulmonology

CF Research Cooperative Expands Patients’ Options

A mother helps her son use a nebulizer. (Stock photo)

In the last few decades, scientific collaboration has played a vital role in improving quality of life and extending life expectancy for patients with cystic fibrosis (CF). Now, the members of a new cooperative hope that sharing their research and expertise will lead to more progress. The Southeast Cystic Fibrosis Research Cooperative connects specialists from about two dozen high-volume centers across the Southeast region, including Children’s of Alabama. Members have been meeting for the last year with the goal of advancing a sea change in available CF treatments.

Launched by the Cystic Fibrosis Foundation, the research cooperative blends a social component with the work of effectively treating CF, for which breakthrough therapies targeting gene defects have transformed care in just the last several years. Members of the cooperative—who, in many cases, have attended the same medical conferences over the years—have held virtual meetings in recent months but hope to gather in person as more join the group.

“Our region is big, and our patients are spread out—all the way from eastern Texas to the tip of Florida,” Children’s of Alabama pulmonologist and sleep medicine specialist Christopher “Miles” Fowler, M.D., said. “Every big center is working on different research and has different strengths to offer, so I think we’re all bringing something different to the table.”

About 600 CF patients are receiving treatment at any given time from the combined adult and pediatric program at Children’s and the University of Alabama at Birmingham (UAB). “There are more than 30,000 patients with CF in the United States, and the Southeast represents a big percentage of those patients,” Fowler said.

Accordingly, each CF center in the Southeast is tackling diverse aspects of CF, from groundbreaking gene therapy studies to clinical trials assessing new infection-fighting protocols or ways to optimize nutrition or exercise. UAB will soon be enrolling patients for gene therapy trials, but other centers in the region will be analyzing both similar and different gene therapy endpoints.

“There are going to be different options: The drugs will be different, and the risks will be different,” Fowler explained. “There’s a need to disseminate information about the trials being offered and educate providers about the risks and benefits of the drugs we’re still learning about. That’s been part of our focus.”

Ultimately, CF patients here and elsewhere should greatly benefit from the research cooperative’s efforts, Fowler said. The collaboration makes it easy for patients to learn about trial options and for centers to refer patients to other studies.

“There’s so much going on with cystic fibrosis that I think it’s impossible for any one center to do all of this,” he said. “We all have different resources and expertise that allow us to do the studies we do, so one way the regional cooperative helps is by making more types of studies available to patients in our region.”

August 25, 2023 by childrensal

Inside Pediatrics, Pulmonology

New Pulmonary Faculty Join Children’s of Alabama

Left to right, Spencer Poore, M.D., Ryne Simpson, M.D., and Christopher Fowler, M.D. All three are assistant professors in the Division of Pediatric Pulmonary & Sleep Medicine, University of Alabama at Birmingham Department of Pediatrics.

The Division of Pulmonary and Sleep Medicine at Children’s of Alabama has added three physicians to its team.

Christopher Fowler, M.D.

Christopher Fowler, M.D., is used to the South, having completed medical school at the Medical College of Georgia, his pediatric residency in South Carolina, and his pediatric pulmonary fellowship at the University of Alabama at Birmingham. So leaving simply wasn’t on the table. “I enjoyed being here so much as a fellow that I really wanted to stay and keep working with this awesome team,” he said.

Dr. Fowler entered pediatrics because, as his wife put it, when he was on the pediatrics rotation in medical school, he was happiest and most excited to come home and tell her about his day.

The pulmonology specialty came after caring for his first cystic fibrosis (CF) patients, all of whom were hospitalized with pneumonia. “These kids had a lot going on. And they were very smart. They taught me all about their disease and how they take care of themselves when they’re at home and then how I should take care of them while they were in the hospital. I enjoyed getting to know them and learn from them so much that I decided pulmonology was the thing for me.”

His research focuses on investigating adrenal complications from steroids CF patients take. Chronic use leads to adrenal insufficiency, with symptoms mimicking a respiratory disease. Studies in adults with CF show that about 8 percent develop adrenal problems over a 10-year period, but there are no studies in children, he said. “I don’t know if it’s going to be as big a problem in children as it is in the adults. But I think it’s a good question to answer.”

When he’s not trying to answer complex research questions, Dr. Fowler can be found corralling his own children and playing the drums.

T. Spencer Poore, M.D.

Spencer Poore, M.D., is quite familiar with Children’s of Alabama, having completed his pediatric internship and residency in Birmingham. Now, after three years in Colorado for his pulmonology fellowship, he’s back as one of the pulmonology division’s newest faculty.

He chose Children’s for his first academic position because it provides the opportunity to treat a wide variety of patients, from urban to rural, with common conditions like asthma to extremely rare pulmonary conditions. “I wanted a big program that could expose me to anything and everything,” he said, “as well as springboard me into any direction I wanted to go given its world-renowned experts.”

He brought with him his research on fungal infections and lung inflammation in children with cystic fibrosis. “Fungus is an interesting organism in that in some people it causes infection and in some an allergic reaction,” he said. “And there’s probably some degree of overlap, but we don’t know the pathways. So it feels like chipping away at an iceberg.”

Whatever they find, he said, the recognition should go to the patients. “If it weren’t for the patients willing to help people they’ll never even meet, we couldn’t do this,” he said.

Outside of work, Dr. Poore enjoys cycling, both mountain biking and road biking.

Ryne Simpson, M.D.

Having grown up in Chattanooga, Tennessee, and attended medical school at the University of Tennessee in Memphis, Ryne Simpson, M.D., was not quite prepared for the weather when he completed his residency in Kansas City, Missouri, and his fellowship in Cincinnati, Ohio. So Children’s of Alabama — with its warm climate and proximity to his family — was a perfect fit. “I was tired of the cold Midwestern winters that never ended,” he said.

His focus on pediatric pulmonology comes from the “complex nature of the patients,” he said. “I enjoy that we get to do procedures like bronchoscopy, and also the continuity of working with the patients.”

Dr. Simpson’s prior research focused on identifying best practices for flexible bronchoscopy and chronic ventilation in children based on outcomes and readmission rates. He enjoys such quality improvement and systems process studies, he said, given their more immediate impact on clinical outcomes compared to basic or clinical research. “I don’t always have the mindset for multi-year longitudinal studies,” he said.

Since coming to Birmingham, he’s enjoyed trying new restaurants. Now that he has his own house, he said, he’s looking forward to getting a set of drums “and playing when I want.”

February 15, 2022 by childrensal

Pulmonology

Using Antisense Oligonucleotides to Improve CFTR Function in Cystic Fibrosis

Therapeutic development in cystic fibrosis (CF), a fatal pediatric lung disease affecting 1 in 3500 newborns annually, is rapidly advancing. “Although exciting progress has been made,” said Children’s of Alabama pediatric pulmonologist William T. Harris, M.D., an associate scientist at the Gregory Fleming James CF Research Center at the University of Alabama at Birmingham (UAB) who treats patients at Children’s of Alabama, “we are just midstream.”

Where previous advances focused on the downstream consequences of disease, such as malnutrition, chronic infection and mucopurulent secretion, recent drug developments target genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein itself. Dr. Harris’ research focuses on improving the efficacy of these agents, called CFTR modulators.

One key therapeutic clue is to identify why certain children with exactly the same CFTR genotype have widely different disease trajectories. Dr. Harris has studied the mechanisms behind this disease disparity and has discovered the mechanism through which transforming growth factor beta (TGF-β), a leading gene modifier of CF lung disease severity, inhibits CFTR functional expression. Dr. Harris now targets this mediator of disease progression as a therapeutic opportunity to optimize CFTR modulator response.

His research discovered that small, non-coding nucleotide sequences called microRNA (miRNA) regulate CFTR function. miRNA diminish gene expression by degrading the gene transcript or inhibiting protein translation. In CF, TGF-β stimulates miR-145 expression, which binds to and degrades the CFTR gene transcript. This prevents protein expression and diminishes channel function. Both TGF-β and miR-145 are markedly increased in CF lungs and airway epithelia, posing a significant barrier to effective intervention.

Introducing miR-145 antagonists to airway epithelia reverses TGF-β suppression of CFTR and potentiates CFTR modulator response. However, TGF-β signaling and miR-145 activity are involved in multiple functions throughout the body, raising concern for off-target consequences. “As CF outcomes improve, the tolerance for side effects becomes very low,” he said. “Thus, the therapeutic intervention must be highly specific with a clearly defined target that only blocks the effects on CFTR.”

Antisense oligonucleotides (ASOs) offer that option. These short nucleic acid sequences bind to specific molecules of RNA, regulating expression of the gene. The FDA has already approved a handful of ASOs to treat congenital pediatric diseases such as Duchenne muscular dystrophy and spinal muscular atrophy.

“ASOs are appealing in CF because they can be delivered directly to the lungs (via inhalation) to bypass systemic side effects,” Dr. Harris said. He is partnering with Ionis Pharmaceuticals, a leader in the development of ASOs, to test an ASO that prevents miR-145 binding to the CFTR transcript. This approach is called target site blockade (TSB).

“TSB offers a nuanced strategy to address the problem of CFTR inhibition without interrupting TGF-β/miR-145 availability for other regulatory processes,” he explained. “I expect oligotherapeutics to benefit CF patients across genotype and improve next-generation therapeutics whether that be small molecule correctors or evolving gene editing strategies.”

Get More Information
Learn more about the Cystic Fibrosis Center’s resources for physicians.

August 20, 2019 by childrensal

Pulmonology

Secondhand Smoke Exposure in Kids with Cystic Fibrosis May Impact Treatment Efficacy, Researchers Suspect

The introduction of cystic fibrosis transmembrane conductance regulator (CTFR) modulators, which target the basic genetic defect in cystic fibrosis (CF), has revolutionized the treatment of the disease over the past five years. With a new, triple CTFR modulator expected to be approved by the end of 2019, in the next year, 90% of those with CF may benefit from these new drugs. However, studies of currently available modulator therapies find that between 20% to 25% of patients who should respond based on their disease’s genetic fingerprint don’t.[1][2]

Researchers from the University of Alabama at Birmingham (UAB) think they may know why: patients’ exposure to secondhand smoke. Now they have embarked upon a study to test this hypothesis.

While it might seem counterintuitive that families with a child with CF would expose them to secondhand smoke, approximately one-third of pediatric CF patients are exposed to tobacco smoke, half of whom have been around a smoker in the past 3 months.[3] And yet, said Gabriela Oates, Ph.D., assistant professor in the UAB Division of Pediatric Pulmonary and Sleep Medicine at Children’s of Alabama and an associate scientist in the UAB Cystic Fibrosis Research Center, “many think their child isn’t exposed to the smoke if the family member is smoking outside.”

But that’s simply not true.

“We’re not just talking about secondhand smoke but also about thirdhand smoke exposure,” Oates said. Tobacco particulates remain on the hair, skin and clothes of the smoker, even if he or she smokes outside, and are also found on household surfaces. “You can find relatively high level of nicotine metabolites in the urine of kids whose parents smoke out of doors,” she said. In fact, children demonstrate exposure even if their household members do not smoke but they live in multifamily housing that shares a wall with a smoking household.

This all ties into the new CFTR modulators because in-vitro, animal and non-CF studies indicate that “even indirect exposure to tobacco smoke actually blunts the effect of the drug,” she said. So while the CFTR modulators are designed to correct the underlying genetic mutation that causes the disease, “the smoke exposure undermines that.”

Her project will define the consequences of secondhand smoke on CF respiratory decline and CFTR modulator response using both self-reported and objective measures of exposure such as urine biomarkers. Results will underscore the necessity of clinically driven smoking cessation programs for CF families and will inform recommendations for smoke exposure screening and control.

Given that most children exposed to smoke are clustered in the low-income segment of the CF population, this becomes a health equity issue, Oates said. “It’s particularly concerning because the smoke exposure may be outside of the household and there’s nothing the family can do about it,” she said. “I worry that in the era of CFTR modulators we may see an increased gap in CF outcomes between kids living in poorer environments and their advantaged counterparts. This issue needs to be watched carefully.”

Oates also fears that if her hypothesis is supported, payers may institute smoke exposure screening programs and base drug coverage on the results. This creates quite the conundrum for researchers like herself. “As scientists, we have a responsibility to determine why drugs work or don’t work,” she said, “yet we have little control over how the results of our science are used.” If her study does show that smoke exposure limits the benefits of CFTR modulators, she said, “the very first step is major education on several levels, including CF families, clinicians and insurance providers.”

Her team is being proactive in this regard, already holding interviews with current and former smokers who have a family member with CF, as well as with CF clinicians and other stakeholders. The goal is to develop materials to better inform caregivers and clinical providers about the impact of second-hand smoke and to test a smoking cessation intervention tailored to CF families. “You would be amazed that there is not a single U.S. study evaluating smoking cessation programs in the CF community,” Oates said.

[1] Hebestreit H, Sauer-Heilborn A, Fischer R, Kading M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros. 2013;12(6):599-603.

[2] Taylor-Cousar J, Niknian M, Gilmartin G, Pilewski JM, investigators VX. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States. J Cyst Fibros. 2016;15(1):116-122.

[3] Ong T, Schechter M, Yang J, et al. Socioeconomic Status, Smoke Exposure, and Health Outcomes in Young Children With Cystic Fibrosis. Pediatrics. 2017;139(2).

Breathe Easier

Learn more about the Cystic Fibrosis Center at Children’s of Alabama.

August 20, 2019 by childrensal

Pulmonology

Network for Change

Pulmonology_CFTN-LA

From his office on the south side of Birmingham, Alabama, pediatric pulmonologist Hector Gutierrez, M.D., shares his passion to help cystic fibrosis (CF) patients around the world. In addition to being director of the University of Alabama at Birmingham (UAB) Division of Pediatric Pulmonology and the Cystic Fibrosis Center at Children’s of Alabama, Gutierrez is also principal investigator of the Cystic Fibrosis Training Network for Latin America (CFTN-LA). He leads a specialized team whose goal is to establish CFTN-LA as a permanent presence in Latin America.

“Unlike the United States, most Latin American countries lack a center network to provide shared information and collaboration to help improve the care of patients. Because of this, they have been at a great disadvantage,” Gutierrez said. “A sustainable training program for CF centers can help improve quality of care, clinical outcomes and life expectancy for Latin American CF patients.”

The CFTN-LA strives to meet the same goals of the CF Foundation, which over the past 60 years has established itself as a global leader in rare disease research and advancement of new CF therapies in the U.S. The network aims to provide high-quality care for thousands of Latin American patients, to establish comprehensive, multidisciplinary CF centers and to address preventive barriers. Gutierrez said the network would open important avenues for future research and drug development.

“Several factors limit the optimal CF delivery of care in these countries,” Gutierrez said. “Whereas diagnostic testing and medications are increasingly available here in the United States, there has been a paucity of expert manpower and a lack of multidisciplinary team approach in Latin America.”

Gutierrez said the CFTN-LA would lay the foundation for a well-integrated infrastructure for CF centers and their teams, with future training efforts led in qualified Latin America centers, ensuring continued growth and sustainability of the network. Since 2014, Gutierrez has led eight benchmarking visits to Chile to help ensure access to high-quality care and establish the CFTN-LA. In turn, the Santiago, Chile-based Hospital Clínico San Borja Arriaran (HCSBA) CF team, among the partners in this endeavor, visited Birmingham for a two-week training to accelerate the project.

Because the current Latin America healthcare delivery systems do not integrate or share information, patients may change from one system to another without proper follow-up and data acquisition. In addition, some health professionals essential to the CF team work as independent contractors to both public and private systems, resulting in higher costs to insurers and families.

The CF Center at Children’s has proposed establishing a multidisciplinary CF Center in Santiago, Chile, providing care adhering to CF Foundation standards. Collaborative work has led to significant improvement in clinical outcomes and team expertise for a number of hospitals in Chile. In 2015, the HCSBA CF team was approached by five other Santiago-based hospitals that are now part of the project as affiliate hospitals. After the incorporation of the affiliate hospitals, the HCSBA CF Center renamed itself Regional CF Center Santiago.

“This project started with one center, one hospital, and other hospitals in Santiago started to get interested,” Gutierrez said. “They joined by participating in our visits in Chile, and we provided similar information and feedback, but the first center (HCSBA) that came to Birmingham became their leader and the point group for the others to learn from them.”

Efforts thus far have shown a marked improvement in nutritional outcomes, lung function and microbiology among CF patients cared for by the participating hospitals in Chile, Gutierrez said.

“We have been in discussion for two years with the government officials in Chile and other Latin American countries to work toward developing a solid CF network similar to what we have in the United States,” Gutierrez said. “We have explained the benefits, however, the structure of care deliveries, health care benefits, et cetera are different. Although we have started small, we feel we are making progress and hope to continue to do so in the years to come.”

A mentorship by high-performing, U.S.-based CF teams, namely Children’s, UAB and the Baylor College of Medicine in Houston, plans to expand and train Latin America-based CF teams in Chile, Mexico and Uruguay. The mentorship would continue the development of an effective, adaptable and scalable training program for both mentors and trainees, and adapt transformative care management to local resources, culture, customers and healthcare delivery.

Pulmonary Clinics
Learn more about some specialized pulmonary services at Children’s of Alabama.

December 28, 2018 by childrensal