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Pulmonology

Using Antisense Oligonucleotides to Improve CFTR Function in Cystic Fibrosis

oligotherapeutics research

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.

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.

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.