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Inside Pediatrics, Pulmonology

Solving the Mystery of Lung Disease in Children with Sickle Cell Disease

Dr-Saadoon-Ammar-Pulmonology-Headhsot-Resized

Children’s of Alabama pulmonologist Ammar Alishlash, M.D.

If lung disease is the leading cause of death in children with sickle cell disease, then why aren’t pulmonologists more involved in their care earlier? That’s a question Children’s of Alabama pulmonologist Ammar Alishlash, M.D., wanted to answer. “I felt for us to take care of those patients, especially those with underlying lung disease, would serve them better clinically,” Dr. Alishlash said. 

In the past, the leading cause of death in those with sickle cell disease was infections. But the use of prophylactic antibiotics changed that. Today, it’s acute chest syndrome (ACS), marked by shortness of breath, low oxygen levels and fever. Many patients progress to respiratory failure, and some die. Yet lung specialists are not usually involved in their care while in the hospital or after discharge. Instead, in most children’s hospitals they are managed solely by hematologists. 

“The problem is, we don’t have any specific treatment targeted for acute chest syndrome,” said Dr. Alishlash. Instead, patients are managed with supportive therapy, including oxygen, fluids, antibiotics and sometimes invasive or non-invasive ventilation. 

Now Dr. Alishlash is on a mission to change that dynamic. He’s launched a three-pronged research initiative: identifying risk factors for ACS to proactively recognize children with a higher risk, developing clinical pathways to prevent progression and mortality and researching novel therapies to treat the condition. 

“I became interested in this condition because I feel that, as pulmonologists, we have experience with other lung diseases,” he said. “We can apply our knowledge from other lung diseases to the sickle cell population, which could open a lot of doors for diagnosis and new treatments.” 

So far, Dr. Alishlash has instituted a clinical pathway to standardize the care children with ACS receive after admission. The pathway has been in place for about 18 months, and the results are encouraging, with a nearly 50 percent reduction in length of stay. In addition, all patients have survived. Previously, one out of every 100 children would die. “That’s pretty significant, especially when you’re talking about children, who are typically between 2 and 4 years of age when they are most likely to develop ACS,” he said. 

Dr. Alishlash has also made progress in identifying risk factors for ACS in children with sickle cell disease. One is nocturnal hypoxemia, when oxygen levels drop at night. This seems to induce the sickling and is associated with increased risk of ACS.1 He also found a correlation between the neighborhood where patients live and ACS, due to, he thinks, air quality, socioeconomic factors and greater stress.2 

On the laboratory side, Dr. Alishlash and his team are using a sickle cell mouse model to test potential treatments as well as identify triggers. One interesting finding is that chlorine can cause sickling, leading to the release of heme from red blood cells, which is toxic to the lung endothelium and subsequent development of ACS. A medication called hemopexin, however, scavenges the free heme. When given to mice exposed to chlorine who developed ACS, hemopexin reduced the death rate from 80 percent to 20 percent.3 

At the same time, Dr. Alishlash has started a twice-monthly clinic for sickle cell patients with underlying lung disease. The clinic is very busy, he said. “And patients’ outcomes are improving, which is very encouraging.” 


1 Nourani AR, Rahman AKMF, Pernell B, et al. Nocturnal hypoxemia measured by polysomnogram is associated with acute chest syndrome in pediatric sickle cell disease. J Clin Sleep Med. 2021;17(2):219–226.

2 Alishlash, AS, Rutland, SB, Friedman, AJ, et al. Acute chest syndrome in pediatric sickle cell disease: Associations with racial composition and neighborhood deprivation. Pediatr Blood Cancer. 2021; 68:e28877

3 Alishlash AS, Sapkota M, Ahmad I, et al. Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin. Redox Biol. 2021;44:102009. doi:10.1016/j.redox.2021.102009

Cardiology, Inside Pediatrics, Pulmonology

Saving Children with Pulmonary Hypertension – One Patient at a Time

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Children’s of Alabama cardiologist Frank Bennett Pearce, M.D.

When the cardiology team at Children’s of Alabama heard the family history of a 6-year-old boy who presented with an episode of syncope, they knew immediately what was wrong. His father had undergone a double lung transplant at the University of Alabama at Birmingham to cure his pulmonary hypertension (PH). Now his son had been diagnosed with the same thing.  

But that wasn’t the only problem. The boy had also developed a supraventricular tachycardia requiring radiofrequency ablation, which was successful. 

“So we cured that,” said Children’s cardiologist Frank Bennett Pearce, M.D., the boy’s cardiologist. But then the patient continued having episodes of syncope, particularly during exertion. “When that happens in patients with PH, it’s because the blood can’t get through the lungs to the left side of the heart, limiting cardiac output,” said Dr. Pearce. To address that problem, Dr. Pearce and his team performed an atrial septostomy, creating a tiny hole between the atria in the atrial septum. Second problem fixed. 

Discharged on oral medications, the child did well with close follow up for several years, said Dr. Pearce, although he was vulnerable to pneumonia and other infections.  

Then in 2020, at age 13, he took a turn for the worse. “There are three principal metabolic pathways involved in treatment of PH,” said Dr. Pearce. Two—endothelin and phosphodiesterase—have effective oral drugs for treatment. The third, the prostaglandin pathway, is more difficult to address, he said. In the past, it required a central line for IV infusions of treprostinil, a prostaglandin pathway medication. “Most families are very reluctant to go to the central line because it creates major problems in their lifestyle and is a quantum leap in terms of the negative effects on these children,” he said. 

However, treprostinil can also be administered subcutaneously through a small catheter and external pump, much like an insulin pump. Unfortunately, the day the teen was scheduled for cardiac cath and initiation of subcutaneous treprostinil, he became very cyanotic. “We didn’t think it was safe,” Dr. Pearce said. Instead, the boy was admitted to the CVICU on inhaled and oral prostacyclin inhibitors. Despite increasing the dosage, his disease progressed. Finally, the team put him on the intravenous form of treprostinil, and he improved. Eventually, they were able to transition him to the subcutaneous form of the drug via the pump, and he became the first patient at Children’s to be initiated onto subcutaneous treprostinil. 

He’s now home and undergoing evaluation for a lung transplant. “He’s a typical teenage kid but able to deal with all these challenges and keep a pretty good attitude, thanks to support from his family,” said Dr. Pearce. “He just hangs in there.” 

Inside Pediatrics, Pulmonology

Study Shows Long-Term Effectiveness of Ivacaftor in Children and Adults with Cystic Fibrosis

The world of cystic fibrosis was radically changed in 2012 with the approval of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, which targets certain genetic mutations responsible for the disease. Now, a recently published study by the Cystic Fibrosis Foundation’s multi-center Observational Study in People with CF with the G551D Mutation (GOAL) trial (conducted through the Therapeutics Development Network and funded through the Cystic Fibrosis Foundation) finds that ivacaftor remains effective for at least 5.5 years. Study investigators included Children’s of Alabama pediatric pulmonologist Jennifer S. Guimbellot, M.D., Ph.D, Scott Sagel, M.D., Ph.D., at the University of Colorado, and Steven M. Rowe M.D., who directs the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama Birmingham (UAB), as well as other GOAL investigators,

The study followed patients who participated in the drug’s original six-month study. Although a small study with 96 participants, 81% continued as throughout the study duration. “To follow them over five years is a big feat,” said Guimbellot. But it allowed the team to understand whether ivacaftor is helpful with long-term use.

While the study found the drug remained effective overall, with clinically important improvements in lung function, pulmonary exacerbations, quality of life, weight gain, and P. aeruginosa infection, there were some differences based on age and baseline lung function. Adults and those with lower baseline lung function experienced greater improvements in lung function at 5.5 years than children and those with higher baseline lung function. As might be expected, quality-of-life improvement was greater in and more sustained in adults who had lower baseline quality of life scores. Importantly, this was the first study to show quality-of-life improvement beyond 2 years.

Another important finding is that while the overall cohort maintained an average lung function above the pre-ivacaftor level, some continued to experience lung function decline, particularly children. Some also continued to experience infections and remained underweight.

This suggests that “there’s something going on that we need to understand better,” Guimbellot said. “It doesn’t mean that ivacaftor doesn’t work for children; it definitely does work for children. It’s just something we don’t understand and there’s still room for improving care.”

One interesting observation is that while most participants gained weight (in part because they didn’t spend as much metabolic energy fighting the lung disease and attendant infections), some gained an unhealthy amount of weight. “This is something we have to pay attention to,” Guimbellot said. This may include revising the typical high-calorie, high-protein, high-fat diet recommended for certain people with CF to a more balanced diet.

The study is important not only because it shows the long-term effects of ivacaftor, she said, but because it can, hopefully, be extrapolated to the newest approved CTFR, a combination of elexacaftor, ivacaftor, and tezacaftor. Unlike ivacaftor, which is effective for just 4% or 5% of the CF population, this combination, approved in 2019, works in up to 90% of people with the disease.

“As a physician who helps diagnose newborns with cystic fibrosis, I am often asked what parents can expect the child’s lifespan to be,” Guimbellot said. Today the median age of survival is 47, but that doesn’t take into account the effect of the CTFR modulators. “With the new drugs,” she said, “we may see a population of children who don’t have the typical findings of cystic fibrosis as long as they adhere to their therapies.”

Inside Pediatrics, Pulmonology

Pulmonology Telehealth Gets Good Reviews

When the pandemic hit in March 2020, most clinics at Children’s of Alabama pivoted to telehealth visits, including pulmonology. Although things have primarily returned to normal with in-person visits, telehealth still has a presence in the outpatient setting.

Given that, an interprofessional team of Pediatric Pulmonary Trainees at the University of Alabama at Birmingham led by Valerie Tarn, MS, RD, LD, training director of the Pediatric Pulmonary Center (PPC), launched a survey to assess how families and clinicians felt about televisits in the pulmonary clinic. “We wanted to evaluate our services and get feedback from our families since many have children with special healthcare needs that require multiple visits per year,” she said. “We wondered if we could do telehealth for every other visit in some populations.”

They surveyed families that had already had a televisit (most used their phones) and those that hadn’t, as well as clinicians who participated in the televisits, to see what, if any, barriers existed as well as collect demographic information.

Most families who had participated in telehealth said they would like to continue for some, but not all, visits. The greatest advantages were avoiding COVID-19 infection and not having to drive to the hospital. The latter is particularly important, Tarn said, since many families drive an hour or more to the clinic. As one parent commented, “This has been wonderful experience! I don’t have to worry about exposing her to COVID or the flu, which is very dangerous for my child. Hope to be able to continue this service in the future!”

About 90 percent of families that hadn’t had a pulmonary televisit reported having Internet access. When asked about potential disadvantages to such visits, they noted the inability to conduct a physical exam. As one parent wrote,  “Please allow the patient to have a choice as to whether or not the appointment is to be in-person or a telehealth appointment.”

Clinicians agreed that telehealth was probably here to stay, Tarn said, but they wanted a more consistent structure. That included prescreening families and finding ways to incorporate other members of the health care team into the visit. “A lot of our patients need to see other health professionals,” she said. “How do you get them to talk with the pharmacist or social worker or nutritionist?” In the spring, the doctors were typically emailing other clinicians or leaving a message in the patient’s secure medical record about the need for follow up.

In the cystic fibrosis clinic, however, nutritionists, social workers, and other allied health professionals rotatedthrough the visit, each taking turns with the iPad. “That worked fairly smoothly,” Tarn said, and could provide a model for other pulmonary clinics.

In the future, the clinicians noted, it would be helpful if patients had home equipment available, such as spirometers, peak flow meters, and weight scales.

But overall, Tarn said, families and healthcare professionals liked telehealth. Now that the surveys have been collected, the PPC trainees plan to present the research results to an interprofessional audience at a local or regional conference.

Inside Pediatrics, Pulmonology

Using Mobile Health To Improve Cystic Fibrosis Care

Gabriela Oates, Ph.D., assistant professor pulmonary and sleep medicine at UAB and Children’s of Alabama, is working to develop a mobile app to to help young children, adolescents and their families manage cystic fibrosis.

It’s not easy living with cystic fibrosis (CF). The multitude of medications, therapies and nutritional supplements that children and adolescents with the disease require can be exhausting and overwhelming, leading to high rates of nonadherence, particularly in adolescents. That’s why Gabriela Oates, Ph.D., an assistant professor of pulmonary and sleep medicine in the University of Alabama at Birmingham (UAB) Department of Pediatrics at Children’s of Alabama, is working to create a mobile health application designed to bridge the gap between what is and what should be when it comes to managing the disease.

The application builds on one developed in Sweden, which 65 to 87% of CF families in that country now use. Called Genia, the app is used to track symptoms, activities and aspects of daily care and share them with the clinical team.

In modifying Genia for the U.S., Oates and her team didn’t rely on what they thought it should look like. They turned to the experts, holding five focus groups with adolescents with CF, families of younger children with CF and the clinicians who care for them. The approach is called “health care service coproduction” and its central tenet is getting buy-in from both clinicians and patients. It’s part of the movement away from the paternalistic view of health and medicine in which the doctor alone drives the process.

The focus groups showed differences between what the clinicians wanted the app to do and what the families and patients asked for, something Oates said the team expected. “The clinicians don’t have the lived experience of managing the disease on a daily basis; our patients and families provided that. However, the clinicians told us what’s necessary to make it work in the clinic; capturing just the patient perspective would have led to an app that’s not workable in the clinical setting.”

Among the changes the focus group participants requested and the team implemented were adding a mental health tracker, making other trackers (i.e., nutrition, medication, physical activity) more specific, syncing the app with calendars and customizing the app with avatars, images and colors.

One thing parents wanted that the adolescents didn’t: the ability to see their child’s entries. On this point, the team decided that the account holder gets to determine the privacy setting and each family decides who the account holder is. “This is normal,” said Oates. “Our children are supposed to become independent and take over the management of their own health condition.”

She and her team are currently conducting a pilot study about the impact of the app’s use on clinical outcomes, with results expected later this year. So far, they are getting high praise from physicians, families and patients. For instance, the patients/families love that they can use the app to submit pre-visit reports instead of completing long paper forms in the waiting room. The clinical team, on the other hand, appreciates having a detailed view of patients’ symptoms or struggles before seeing them in clinic; it helps them understand what’s going on in their patients’ lives and better tailor treatment plans. The app also flags potential problems and shares them with the CF care team on a weekly basis, which allows for earlier intervention.

With the help of the Children’s CF care team, Oates hopes to transition Genia from research settings to a standard of care. Recently, the app was translated to Spanish and made available for both Android and Apple devices. This will allow it to reach a larger segment of CF families to help them manage daily care and better integrate their experiences in treatment plans.

Inside Pediatrics, Pulmonology

When It Takes A Village: A Unique Multidisciplinary Team For Aerodigestive Disease And Complex Conditions

Children’s of Alabama pediatric pulmonologist Tom Harris, M.D., left, and Reed Dimmitt, M.D., MSPH, right, director of the UAB Division of Pediatric Gastroenterology, are among the multidisciplinary team members who make up Children’s Aerodigestive Clinic.

Break down the word “aerodigestive” and you can understand why the condition is so complex and intertwined. Children with aerodigestive conditions often have overlapping disorders involving the upper airway, larynx, trachea, esophagus and lungs, all of which originally developed embryonically from a common source.

One patient may have symptoms affecting multiple systems. At most pediatric hospitals, each condition is treated separately; subspecialists typically focus on the organ of their expertise and not the child holistically.

At Children’s of Alabama’s Aerodigestive Clinic, families don’t need to make multiple appointments and repeated trips to the hospital to see a slew of medical professionals. Instead, they can see a multidisciplinary team of pediatric subspecialists during a single clinic visit and receive coordinated care. Children’s Aerodigestive Program is the only one in Alabama and one of just a few around the country.

“We felt there was a big gap in care, and that led to frustrations that maybe we weren’t meeting their needs,” explained clinic coordinator Ashley Chapman of why Children’s started the program. Chapman focuses on improving communication and facilitating access.

The result of better care has improved both patient and provider satisfaction. “Families appreciate that they don’t feel ‘bounced’ around the medical system,” said pediatric gastroenterologist Reed Dimmitt, M.D.

“Our team is a fun, collaborative group,” added pediatric pulmonologist Tom Harris, M.D. “Previously, we each treated the patients in a general clinic but were limited by our individual skill set. This approach allows us to lean on one another’s expertise, asking, ‘How can we improve care by working together?’”

Consider the triple endoscopy (direct laryngoscopy bronchoscopy, flexible bronchoscopy and esophagogastroduodenoscopy) with the ENT surgeon, pulmonologist and gastroenterologist all in the procedure room. Before, patients would need three separate procedures, requiring three times under general anesthesia with separate interpretations. Now, the three physicians meet together with the family post-procedure to discuss findings and deliver the management plan.

“It’s an additive model, but there’s also a synergy that occurs with everyone meeting together, which contributes to better outcomes,” said Dimmitt. “Collaborating with the multidisciplinary team,” he said, “pushes me to think outside the GI box.” The aerodigestive coordinator, speech pathologist and dietician are central to management plans, providing additional non-M.D. layers of coordination, expertise and pragmatic considerations.

The clinic offers in-person as well as telemedicine visits, and is growing fast, with referrals doubling in the past two years. “That’s also led to more complex patients,” added Dimmitt. “To meet these many needs, we spend a lot of time with the parents.”

The team receives referrals from a variety of sources, including inpatient subspecialists, community pediatricians and speech pathologists, among others. “My favorite referrals,” Harris said, “are families telling friends. That’s when we know we have succeeded.”

“What we hear from parents is that they are so thankful for the collaborative care, the time everyone spends and that their concerns are heard,” said Chapman.

Inside Pediatrics, Pulmonology

New Faculty Expands Pulmonary and Sleep Medicine Division

The UAB Division of Pediatric Pulmonary and Sleep Medicine at Children’s of Alabama welcomed two new faculty in July 2020.

The University of Alabama at Birmingham (UAB) School of Medicine Division of Pediatric Pulmonary and Sleep Medicine at Children’s of Alabama continues to expand, with two new faculty joining in July.

Pedro Anis Nourani, M.D., anassistant professor in the division, earned his medical degree at the University of São Paulo and completed his pediatric residency at Texas A&M’s Driscoll Children’s Hospital. He finished his sleep medicine and pulmonary fellowships at UAB and decided to stay.

“It’s definitely the people that work here,” he said of his decision to remain in Birmingham. “The collaboration between everyone, the excellent support from not just the physicians, but everyone in the department. This group has extensive expertise on subspecialities within pulmonary medicine, which provides good support for someone just starting their career.”

He was drawn to pulmonology medicine, he said, because it’s the “best that pediatrics has to offer.” That includes long-lasting relationships with patients; continuity of care; a strong inpatient presence and the ability to perform procedures. And he was drawn to UAB for his fellowship because of its large pediatric sleep lab. He interviewed at other institutions upon finishing his fellowships, “but there just wasn’t the support and excellence.”

He and his wife have three children, the youngest of whom was born at UAB.

Guillermo Beltran Ale, M.D., an assistant professor in pulmonology, was born and raised in Peru, where attended Universidad Peruana Cayetano Heredia medical school. He completed his pediatric residency at Cincinnati Children’s Hospital Medical Center, then stayed for his pediatric pulmonary fellowship. “I’ve been interested in pulmonology forever,” he said. First because of asthma and cystic fibrosis, with its complex management system and physiology. Then because of the strong bronchoscopy program at Cincinnati and its relationship with chronic ventilator management.

He chose Children’s because it offered a place to grow his skills and continue his research on the pathology of long-term ventilation. He moved to Birmingham with his wife and dog in the summer and started his new career at Children’s July 1.

COVID-19 has, of course, changed the experience of moving to a new city. “We meet a lot of people but we can only see their eyes,” he said. Nonetheless, “we enjoy Birmingham so far.”

Inside Pediatrics, Pulmonology

Children’s of Alabama Muscular Dystrophy Care Center Offers Life-Saving Treatment for Rare, Fatal Disease

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Brad Troxler, M.D., director of the Muscular Dystrophy Care Center (MDA) at Children’s of Alabama, chats with a patient. The MDA Care Center is the only MDA clinic in Alabama and one of only a few in the region.

The Muscular Dystrophy Care Center (MDA) at Children’s of Alabama sees about 280 patients a year with a wide variety of neuromuscular conditions. They require multidisciplinary care from neuromuscular specialists, neurologists, pulmonologists, genetic counselors and cardiologists, among others. They also need respiratory, physical and occupational therapies, nutritional counseling and social work support.

One of the most devastating conditions the clinic sees is spinal muscular atrophy (SMA), a rare autosomal recessive genetic disorder that is the leading cause genetic cause of death in infants. It is characterized by degeneration and loss of lower motor neurons, leading to muscle atrophy. Infants with the most serious form of the disease, Type 0, can be diagnosed prenatally and typically die before 6 months, while those with Type 1 begin showing symptoms around 6 months, require ventilation and typically die before age 2. Other types of SMA may not manifest until childhood or even adulthood and are less severe, although all of those affected experience some neuromuscular effects.

Until recently, SMA was primarily treated with supportive care. Today, however, there are two groundbreaking treatments and Children’s is the only MDA clinic in the state, and one of only few in the region, to offer both: nusinersen (Spinraza), approved for children and adults, which is administered in several doses the first year and annually after that; and onasemnogene abeparvovec-xioi (Zolgensma), a single-dose treatment approved for use in children with SMA Type 1 under age 2.

Both are gene therapies designed to address genetic mutations in the SMN1 and/or SMN2 genes, which make the protein required to control muscle movement. Both are also extremely expensive, with the first 10 years of treatment with Spinraza estimated at $4 million and a single dose of Zolgensma costing $2.1 million, making it the most expensive drug ever marketed.[1]

The cost could be worth it, though, given the benefits of the drugs. “Clinical trials showed huge improvement,” said Brad Troxler, M.D., who MDA Care Center director. Indeed, after four years, infants treated with Spinraza before they turned 6 weeks were still achieving and maintaining motor milestones such as walking and sitting without assistance, things SMA babies would not normally be able to do.[2]

Participants in the Zolgensma trials were demonstrating similar results, with all children who received the drug still alive at 2 years and none requiring ventilation.[3]

Don’t call the treatments cures, however, says Troxler. “‘Cure’ is a hard word to define,” he said. While improved, patients still don’t have normal neuromuscular function after receiving the drug, with some muscle weakness remaining and an increased risk of scoliosis and other issues related to the disease. “But if we give it early enough, they are able to walk and talk and eat so it’s pretty close to a cure,” he said.

The earlier the drugs are administered, the greater the benefit. “Time is neurons,” said Shelley Coskery, MSN, CRNP-AC, MDA Care Center coordinator. However, Alabama is one of the few states that doesn’t screen newborns for SMA, which could delay treatment until symptoms appear. “We’re working on it,” Coskery said. “We need to start treating these patients before they develop symptoms and then, hopefully, we will see fewer and fewer affected with the disease.”

Becoming one of the first centers to offer SMA treatments, she said, “puts us at the forefront of the gene replacement movement.” Indeed, the center is also beginning clinical trials for genetic therapies for children with Duchenne, one of the most common neuromuscular diseases.

The ability to provide such effective treatments to children who otherwise would have died before age 2 “is very profound,” Troxler said. “You can see the difference it makes on individual families in a really powerful way. Conversations historically been about how ‘this is a terrible disease that will likely end in your child’s death.’” Now, Troxler said, the conversation has changed to, “‘Your child has a horrible disease, but we have some therapies that are going to change what this looks like.’ It’s completely different.”

“There is a lot of excitement throughout the SMA community,” Coskery said. “We are very grateful when the parents send emails of the child standing and achieving milestones we didn’t think they would.”


[1] Thomas K. his New Treatment Could Save the Lives of Babies. But It Costs $2.1 Million. The New York Times. May 24, 2019.

[2] Biogen Announces New Data Further Establishing SPINRAZA® (nusinersen) as a Foundation of Care in Spinal Muscular Atrophy for a Broad Range of Patients. Available at: http://investors.biogen.com/news-releases/news-release-details/biogen-announces-new-data-further-establishing-spinrazar

[3] New Data Shows Long-Term Benefits of Zolgensma in SMA Patients. Available at: https://www.biospace.com/article/in-wake-of-data-manipulation-scandal-avexis-releases-long-term-efficacy-of-zolgensma-at-conference/

Inside Pediatrics, Pulmonology

Using Pharmacogenetics to Help Identify Patients with Cystic Fibrosis Most Likely to Respond to Targeted Therapies

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Children’s of Alabama and the University of Alabama at Birmingham (UAB) are on a mission to determine how patients use Cystic Fibrosis Transmembrane Conductance Regulator modulators at the cellular level.

The discovery of the genetic mutation responsible for cystic fibrosis (CF) and the subsequent development of drugs that target this mutation, called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, together with improved supportive treatments, has revolutionized the management of the disease. Today, the median life expectancy of someone with CF has increased from age 10 in 1962 to 47, with many patients living into their 50s or 60s. With the newer drugs, many expect those with CF will be able to live a normal lifespan.

However, studies of the four currently available CFTR modulator therapies, three of which are combination drugs, find that between 20 and 25 percent of patients who should respond based on their disease’s genetic fingerprint don’t.1,2 Given that the drugs can cost up to $300,000 a year, it is important to find biomarkers to identify which drug will be most effective for which patient.3 Currently, the only option is a rectal biopsy followed by complicated testing or nasal brushing, neither of which are approved by the U.S. Food and Drug Administration, accepted by insurance or widely used.

Children’s of Alabama pulmonologist Jennifer S. Guimbellot, M.D., Ph.D., together with Steven M. Rowe M.D., who directs the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham (UAB), and  Edward P. Acosta, Pharm.D.,  who directs UAB’s Division of Clinical Pharmacology, are on a mission to change that.  Their research focuses on how patients use CFTR modulators at the cellular level.

Until fairly recently, Guimbellot said,We didn’t have the tools to measure levels in the tissue.” Now they can use a simple, minimally invasive test Guimbellot helped develop. The assay measures concentrations of CFTR modulators in plasma and nasal epithelial cells, which, like epithelial cells in the lungs, are the drug’s site of action. Obtaining the cells is simple and inexpensive, requiring only a nasal brush, and can be done repeatedly to monitor drug levels.

After obtaining cells from patients, Guimbellot said, her team found that while plasma concentrations seem to correlate with the drug response, concentrations in tissue differ from those in plasma.

The question is why.

The answer may be related to pharmacogenomics, or the genetic variation in the way individuals metabolize drugs. Thanks to the epithelial tissue assays, she said, “our lab found that there may be substantial differences in the levels of modulators and also of metabolism proteins in people with CF.” Thus, once the drug is delivered to the cell, the effect may differ between patients. For instance, one person may be a fast metabolizer and clear the drug quickly; while the other may be a slow metabolizer and the drug accumulates in the tissue.

The protein known to metabolize CFTR modulators, CYP3A4, is primarily active in the liver. But in about 20 percent of people, it may also be produced in other tissues. While Guimbellot’s team has not found CYP3A4 in the epithelial cells from CF patients they’ve examined, they have found substantial levels of mRNA from the almost identical CYP3A7 protein and its cousin, CYP3A5. “So we hypothesize the CFTR modulator drugs are substantially metabolized by those proteins since it’s so similar to CYP3A4, and that this could affect how well patients respond to the drug.” They also found wide variation in the expression levels of both, which could contribute to the amount of available modulator at the target site.

“By understanding how genetic variation may influence the expression of these proteins and how that might affect the amount of drug available to do its job in the target tissue we can then relate the findings back to whether or not a patient can be expected to respond well to it or not,” she said.

Which is the next step in their research.

The team’s work is currently funded by the Cystic Fibrosis Foundation.


[1] National Institutes of Health. Cystic Fibrosis. 2019; https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=36&key=C.

[2] Cystic Fibrosis News Today. Cystic Fibrosis Statistics. 2019; https://cysticfibrosisnewstoday.com/cystic-fibrosis-statistics/. Accessed June 19, 2019.

[3] Starner CI. How much is too much? Prime Therapeutics. May 31, 2019. Available at: https://www.primetherapeutics.com/en/news/prime-insights/2019-insights/Story_Cystic_Fibrosis_Treatments.html.

 

 

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.”

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