Low Level of Zinc Ions in Lungs Contribute to Buildup of Mucus in CF

When two channels that are supposed to move chloride and sodium ions out of cells in the lungs fail to function properly, it leads to the mucus buildup seen in cystic fibrosis.

Japanese researchers have discovered that the channel dysfunctions also reduce the amount of zinc ions going into the lungs, further contributing to the thick mucus accumulation.

Their study, published in the journal EBioMedicine, is titled “Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells.Continue reading Low Level of Zinc Ions in Lungs Contribute to Buildup of Mucus in CF

Therapy for Reducing P. Aeruginosa Lung Infections Planned Phase 1 Trial

Arch Biopartners recently completed a good manufacturing practice (GMP) production campaign for AB569, a potential inhalation treatment for antibiotic-resistant bacterial lung infections in people with cystic fibrosis (CF) chronic obstructive pulmonary disease (COPD) and other conditions. The campaign, intended to ensure the quality of the investigative therapy, was directed by Dalton Pharma Services.

AB569 is composed of ethylenediaminetetraacetic acid (EDTA) and sodium nitrite, two compounds approved by the U.S. Food and Drug Administration (FDA) for use in people. AB569 can be administered alone or in combination with other compounds to treat multi-drug resistant bacterial infections that can cause reduced lung function.

Pseudomonas aeruginosa is one of the most common bacterial infections in patients with respiratory diseases, including CF, COPD, and pneumonia.

In preclinical studies, AB569 was shown to be capable of killing drug-resistant bacteria like P. aeruginosa and other common pathogens associated with chronic lung infections.

The company also announced that a Phase 1 clinical trial to investigate the safety and pharmacokinetic profile of AB569, planned to start in January, will be conducted at the Cincinnati Veterans Affairs Medical Center (CVAMC). According to an Arch Biopartners press release, Ralph Panos, chief of medicine at CVAMC, will lead the trial.

Three escalating doses of nebulized AB569 will be used to evaluate tolerance to the treatment in about 25 healthy volunteers. Each will be given a single administration of nebulized AB569  to characterize the pharmacokinetic profile of plasma nitrite and nitrate metabolites, exhaled nitric oxide, and circulating hemoglobin.

Pharmacokinetics studies how a drug is absorbed, distributed and metabolized in, and expelled by, the body.

Should the Phase 1 trial in volunteers be successful, Arch Biopartners plans to move its AB569 program into a Phase 2 trial to test its effectiveness in treating chronic P.aeruginosa infections in COPD patients.

AB569 received orphan drug status by the FDA in November 2015 as a potential treatment of P. aeruginosa lung infections in CF patients. Orphan drug status is given to investigative medicines intended for people with rare diseases to speed their development and testing.

Original article: https://cysticfibrosisnewstoday.com/2017/12/12/arch-biopartners-readies-ab569-potential-treatment-for-cf-copd-lung-infections-for-phase-1-trial/

A Breath of Fresh Air for Biotechs Working on Cystic Fibrosis Therapies

Researchers from the University of Zurich have determined the structure of a chloride channel, which could be a target for new drugs to treat cystic fibrosis.

Researchers at the University of Zurich have found a new target for future cystic fibrosis treatments. The study, published in Nature, has uncovered the structure of a protein that could help to correct the mechanism underlying the buildup of sticky mucus in patients’ lungs. This could give rise to a new wave of therapeutics for the condition, which at the moment lacks disease-modifying treatments.

Cystic fibrosis is a severe genetic disease affecting the lungs, for which there is currently no cure. It is caused by a malfunctioning chloride channel, CFTR, which prevents the secretion of chloride by cells, leading to the production of thick, sticky mucus in the lung. The condition affects around 70,000 people worldwide, who suffer from chronic infections and require daily physiotherapy.

However, one potential approach to treat cystic fibrosis is to activate the calcium-activated chloride channel, TMEM16A, as an alternative route for chloride efflux. As TMEM16A is located within the same epithelium as CFTR, its activation could rehydrate the mucus layer. The research group used cryo-electron microscopy to decipher the structure of TMEM16A, which is part of a protein family that facilitates the flow of negatively charged ions or lipids across the cell membrane.

The changes that occur in the lungs of cystic fibrosis patients.

TMEM16A is found in many of our organs, playing a key role in muscle contraction and pain perception, as well as in the lungs. It forms an hourglass-shaped protein-enclosed channel, which when bound by positively charged calcium ions, opens to let chloride ions to pass through the membrane.

Current treatments for cystic fibrosis include bronchodilators, mucus thinners, antibiotics, and physiotherapy, which only control symptoms. However, biotechs around Europe are beginning to make progress, with ProQR completing a Phase Ib trial and Galapagos and Abbvie’s triple combination therapy entering Phase I. Antabio has also received €7.6M from CARB-X to develop a new antibiotic against Pseudomonas infections.

The identification of a new target provides patients and biotechs alike with renewed hope of new and effective cystic fibrosis treatments, or even a cure. It will be interesting to see whether small molecules or gene therapy specialists could take advantage of this information.

Original article: https://labiotech.eu/cystic-fibrosis-treatment-target/

Cancer gene plays key role in cystic fibrosis lung infections

PTEN is best known as a tumor suppressor, a type of protein that protects cells from growing uncontrollably and becoming cancerous. But according to a new study from Columbia University Medical Center (CUMC), PTEN has a second, previously unknown talent: working with another protein, CFTR, it also keeps lung tissue free and clear of potentially dangerous infections.

The findings, published in Immunity, explain why people with cystic  are particularly prone to respiratory infections—and suggest a new approach to treatment.

A quarter-century ago, researchers discovered that cystic fibrosis is caused by mutations in the CFTR gene, which makes an eponymous protein that transports chloride ions in and out of the cell. Without ion transport, mucus in the lung becomes thicker and stickier and traps bacteria—especially Pseudomonas—in the lung. The trapped bacteria exacerbate the body’s inflammatory response, leading to persistent, debilitating infections.

But newer research suggests CFTR mutations also encourage infections through a completely different manner.

“Recent findings suggested that  with CFTR mutations have a weaker response to bacteria, reducing their ability to clear infections and augmenting inflammation,” said lead author Sebastián A. Riquelme, PhD, a postdoctoral fellow at CUMC. “This was interesting because it pointed to a parallel deregulated immune mechanism that contributes to airway destruction, beyond CFTR’s effect on mucus.”

That’s where PTEN comes into play. “We had no idea that PTEN was involved in cystic fibrosis,” said study leader Alice Prince, MD, professor of pediatrics (in pharmacology). “We were studying mice that lack a form of PTEN and noticed that they had a severe inflammatory response to Pseudomonas and diminished clearance that looked a lot like what we see in patients with cystic fibrosis.”

Delving deeper, the CUMC team discovered that when PTEN is located on the surface of lung and immune cells, it helps clear Pseudomonas bacteria and keeps the inflammatory response in check. But PTEN can do this only when it’s attached to CFTR.

And in most cases of cystic fibrosis, little CFTR finds it way to the cell surface. As a result, the duo fail to connect, and Pseudomonas run wild.

As it happens, the latest generation of cystic fibrosis drugs push mutated CFTR to the cell surface, with the aim of improving chloride channel function and reducing a buildup of mucus. The new findings suggest that it might be beneficial to coax nonfunctional CFTR to the surface as well, since even abnormal CFTR can work with PTEN to fight infections, according to the researchers.

“Another idea is to find drugs that improve PTEN membrane anti-inflammatory activity directly,” said Dr. Riquelme. “There are several PTEN promotors under investigation as cancer treatments that might prove useful in cystic fibrosis.”

The study also raises the possibility that PTEN might have something to do with the increased risk of gastrointestinal cancer in . “With better clinical care, these patients are living much longer, and we’re seeing a rise in gastrointestinal cancers,” said Dr. Prince. “Some studies suggest that CFTR may be a tumor suppressor. Our work offers an alternative hypothesis, where CFTR mutations and lack of its partner, PTEN, might be driving this cancer in patients with .”

The paper is titled, “Cystic fibrosis transmembrane conductance regulator attaches tumor suppressor PTEN to the membrane and promotes anti Pseudomonas aeruginosa immunity.”

For journal article click here:

http://www.cell.com/immunity/fulltext/S1074-7613(17)30487-9

Why Aspiration Is a Silent, Hidden Danger for Cystic Fibrosis Patients

Dr. Gwen A. Huitt is an infectious disease doctor at National Jewish Health with a special interest in mycobacteria, bronchiectasis, and cystic fibrosis. Here, she talks to us about the hidden dangers of a major medical issue she feels doesn’t receive the attention it needs in the CF community — aspiration.

Q: What is aspiration? What is silent aspiration?

A: Aspiration is defined as any liquid, substance, or foreign body that gains access (below the vocal cords) to the airways. Many times when we have an overt aspiration, a cough is triggered. Think, “something went down the wrong pipe.” This may occur when folks drink fluids too quickly, toss their head back to take pills, etc. A small amount of liquid trickles down the windpipe, irritating it and causing a cough. Additionally, overt aspiration may occur in some folks with neurologic disorders that impair the ability to swallow appropriately (think stroke, Parkinson’s disease, etc.).

Silent aspiration may also occur in many neuromuscular disorders as well in “normal” hosts. This is where my patient population lives for the most part. There are two distinct situations that may occur. The first would be that when we take a drink, some small amounts of liquid “pools” in a recess around the vocal cords and then little amounts can trickle over the vocal cords down into the airway, but it does not trigger a cough or any sensation that something has just gained access to the airway. The second scenario is when we silently or overtly reflux up liquids from the stomach or esophagus and they reach high enough in the esophagus that they then trickle into the airway.

Q: What contributes most to aspiration?

A: For our patient population, we believe that overdistending the stomach with too much liquid, bending forward or lying too flat on your back, stomach, or on your right side contributes to most of our silent reflux episodes.

Q: What are the dangers of aspiration for a CF patient?

A: The dangers of aspiration for CF or non-CF patients are that you are sending not only germs such as pseudomonas or non-tuberculosis mycobacteria (NTM) into the airway that contribute to infection, but also that digestive enzymes and acids cause significant inflammation in the airways. This situation worsens inflammation and infection in the vulnerable airway.

MORE: Three travel considerations if you have a lung disease

Q: What are telltale signs of aspiration damage in the lungs?

A: We know that aspiration can lead to bronchiectasis. Additionally, by looking at microbiology of the sputum, we may find many organisms that are predominantly only supposed to be found in the digestive tract. When we see certain organisms such as citrobacter or E. coli we know for sure that these organisms were translocated from the digestive tract to the airway via aspiration. In all likelihood, other organisms such as pseudomonas, NTM, and Klebsiella are also primarily acquired in the airway via this mechanism. Much more research needs to be done in this area though.

Q: What is something about aspiration you think people would be surprised to learn?

A: That so much of aspiration is silent and we currently don’t have any good test to assess for intermittent reflux that may lead to aspiration. Also, there is no medication that stops reflux (which then leads to aspiration). Medications such as PPI (i.e., Nexium) or H2 blocker (i.e., Zantac) medications suppress acid production, which certainly can help with heartburn or cough, but they do not stop the physical action of reflux.

Q: Should reflux medication be a last resort or is it enough of a danger that it should be used as soon as a patient begins exhibiting reflux/aspiration symptoms?

A: As I said earlier, we currently have no medication to stop the action of reflux. In many ways, taking these medications may actually make reflux worse because you don’t feel heartburn symptoms but most certainly are still refluxing. Also, part of what PPIs and H2 blockers do is lower acid. Part of the action of acid in digestive juices is to kill some proportion of germs that we swallow. If you are still refluxing (while taking PPIs) and you then aspirate some of this digestive “soup,” you are actually aspirating more germs per aliquot of gastric contents. [But] you should definitely take a medication to help with heartburn symptoms or if you have been seen by a [gastro doctor] and they have diagnosed ulcer disease or Barrett’s esophagus.

Q: Do you believe aspiration is taken as seriously in the CF health care setting as it should be?

A: No, I do not think that aspiration is taken seriously at all in the CF community. Nor is it taken as seriously in the non-CF world.

Original article found at: https://cysticfibrosisnewstoday.com/2017/12/14/aspiration-risks/?utm_source=Cystic+Fibrosis&utm_campaign=a772c5a83f-RSS_THURSDAY_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_b075749015-a772c5a83f-71418393

Tips for Surviving a Holiday Admission

Guest Blog By: Lauren Jones Hunsaker

Most of us have had to suffer through a holiday admission at one point.  It’s a reality of our disease, which, for most of us, never made a habit of consulting our social calendars before burdening us with an exacerbation.  I’ve spent several Christmases, birthdays, wedding anniversaries and many-a-Thanksgiving admitted.  As far back as middle school, most of my holidays were spent in the hospital simply because it was an advantageous time for an admission.

It’s not an easy thing to endure for kids or adults.  On a good day, being in the hospital is boring, uncomfortable and tedious.  The holidays magnify our misery by adding self-pity and a serious case of F.O.M.O. to the litany of grievances.  However, there are a few easy things you can do to weather the emotional storm of a holiday admission:

  1. Make a To Do List. While a day of nothing but channel-changing can seem never ending, a daily to-do list can help compartmentalize your day and alleviate the monotony of an admission.  Reading, exercising, playing games or journaling at specific times can be helpful distractions and keep you from staring wistfully out of your window.
  2. Enjoy Holiday T.V. Ordinarily, I don’t watch a lot of television.  But during the holidays there are so many classic movies, parades and specials on, allow yourself to indulge in the holiday deluge.  If nothing else, it helps pass the time and connects you to the outside world (“Hey, did you catch It’s a Wonderful Life for the sixteenth time on NBC?”  “I sure did!” “I don’t really understand why ‘Hee Haw!’ is funny.” “Me either, but Clarence is my favorite.”).
  3. Schedule Holiday Events Post-Discharge. The holidays are the holidays because of family.  The pilgrims will not cast a pox on your house if you host Thanksgiving the following weekend so ask family members if they are willing to attend a second family gathering after your discharge.  This gives you something to look forward to and helps temper loneliness while your family memorializes turkey carving on Facebook Live.
  4. Try a Little Empathy. No one wants to be in a hospital on Christmas, including doctors, nurses and nurse’s assistants.  I know what you’re thinking – “they’re getting paid to be there.”    And so as to preempt your next argument, yes, some are getting paid a higher wage for working on a holiday.  But remember that many don’t have a choice in their work schedules, just as we don’t have a choice as to when we’re admitted.  Staff are away from their families and missing holiday gatherings so they can take care of patients.  Take a moment to tell a favorite nurse thank you for working on the holiday.  Sometimes making someone else feel better makes you feel better too.
  5. Order in a Special Meal. Diet restrictions permitting, indulge in a holiday craving (i.e., turkey with stuffing, Chinese takeout, multiple desserts).  Your doctors will love that you’re packing in some extra calories and it’ll give you a break from repetitious hospital food.
  6. Take Advantage of Tech. Twenty years ago, when we would emerge from an admission (shielding our eyes from the blazing sun, unaccustomed to human life), we had no idea what had occurred during our fourteen days of solitude.  Gone are the days.  With social media and constant connectivity, we rarely experience the same isolation we once did.  Use today’s technology to cyber-attend family events from afar—FaceTime into family dinner or Skype into religious celebrations.  Social media can sometimes (and ironically) exacerbate loneliness, but use its advantages to stay connected during the holidays.  Feeling included can boost morale and help you power through an admission.

New Promising Results from Phase 3 of Combination Therapy

Findings from a phase 3 trial evaluating the efficacy and safety of tezacaftor in combination with ivacaftor in patients with cystic fibrosis (CF) who were homozygous for the Phe508del mutation were published in the New England Journal of Medicine.

The Phe508del mutation has been known to result in greatly reduced conductance regulator (CFTR) protein activity and a loss of chloride secretion, which can lead to impaction of mucus in the airways, gastrointestinal tract, and exocrine organs, with the potential for severe clinical consequences including gradual loss of lung function, nutritional deficits, pulmonary exacerbations, and respiratory failure. It is the most prevalent CFTR mutation worldwide, and affects approximately 46% of American CF patients.

Previous data has shown Ivacaftor’s association with a rate of progressive decline in lung function that is lower than that in untreated patients. In a phase 2 clinical trial involving patients who were homozygous for the Phe508del mutation or heterozygous for the Phe508del and G551D mutations, when combined with the investigational CFTR corrector tezacaftor, it has exhibited enhanced CFTR function and improved lung function.

In August, just one month removed from Vertex’s announcement of positive datafrom Phase 1 and Phase 2 studies, Rare Disease Report covered the acceptance of applications for the use of the tezacaftor/ivacaftor combination treatment in this patient population by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

The phase 3 trial enrolled a total of 510 patients 12 years and older with CF who were homozygous for the Phe508del CFTR mutation at 91 sites in the U.S., Canada, and Europe from January 30, 2015 to January 20, 2017. Patients were randomly assigned to be administered either tezacaftor and ivacaftor (administered as a fixed-dose combination tablet containing 100 mg of tezacaftor and 150 mg of ivacaftor in the morning and a tablet containing 150 mg of ivacaftor in the evening) combination therapy or placebo for 24 weeks.

In total, 475 patients completed the full 24 weeks of the trial, with 93.6% (n=235) in the tezacaftor-ivacaftor group and 93% (n=240) in the placebo group. While no significant difference in the body mass index (BMI) was experienced between the groups at week 24, the use of the combination therapy led to a significantly greater absolute change from baseline in the predicted forced expiratory volume in 1 second (FEV1) than placebo. Despite advances in standard-of-care therapy, patients with CF continue to lose lung function at a rate of an estimated 1% to 3% per year. This trial exhibited a significant effect of the combination therapy compared to the placebo, as the mean absolute change from baseline in FEV1 through week 24 was 3.4 percentage points in the former, compared to 0.6 in the latter.

The most common adverse events (AEs) among the enrolled patients included infective pulmonary exacerbation, cough, headache, nasopharyngitis, increased sputum production, pyrecia, hemoptysis, oropharyngeal pain, and fatigue. The incidence of AEs was similar in both the group for combination therapy and the placebo group, however, those treated with lumacaftor-ivacaftor in the phase 3 did not experience an increased incidence of respiratory events (33 patients [13.1%] vs. 41 patients [15.9%]).

This improved safety profile of the tezacaftor-ivacaftor combination supports its use in a broad range of patients with CF, and, if approved, the therapy will be the third of Vertex’s drugs approved for CF patients, and the second intended specifically to treat patients with F508del mutations (Orkami [lumacaftor/ivacaftor]).

For original article please visit: http://www.raredr.com/news/phase-3-combination-therapy-cystic-fibrosis?t=physicians

For the published study please visit: http://www.nejm.org/doi/full/10.1056/NEJMoa1709846?query=genetics#t=articleDiscussion

Study Links PPI Use to Treat Gastroesophageal Reflux with More Frequent Hospitalizations

Doctors should frequently re-evaluate the use of protein pump inhibitors (PPIs) for cystic fibrosis (CF) patients, urges a University of Florida study which warns that long-term PPI use leads to a higher risk of hospitalization for pulmonary exacerbations.

Identifying risk factors associated with pulmonary exacerbations is critical since they cause a decline in pulmonary function and survival rates among CF patients.

PPI use, in particular, is believed to cause community-acquired pneumonia (CAP). Even though most CF patients use PPIs to control gastroesophageal reflux (GER), scientists still don’t fully understand the link between PPIs and pulmonary exacerbations in CF.

In the study, “Proton Pump Inhibitor Use Is Associated With an Increased Frequency of Hospitalization in Patients With Cystic Fibrosis,” which appeared in the journal Gastroenterology Research, researchers investigated that link and the risks it entails.

The study involved 114 adults who had been seen at UF’s Adult Cystic Fibrosis Center in Gainesville, Florida, between January and December 2016. Researchers collected data on PPI use and hospitalization during a one-year follow-up.

Results showed that 59 of the 114 patients (51.7 percent) used PPI for six or more months, and that exactly the same proportion (51.7 percent) had been hospitalized at least once during the one-year follow-up period. Among those who were hospitalized, PPI use was closely linked with the number of hospitalizations for pulmonary exacerbation, though researchers observed no link between frequency of hospitalization and PPI dosage.

No significant difference was found in GER between hospitalized and non-hospitalized patients.

The UF study is limited, in that it’s retrospective and therefore doesn’t establish a cause-effect relationship between PPIs and pulmonary exacerbation. Researchers say there’s still a possibility that GER itself — rather than the subsequent use of PPIs — causes increased pulmonary exacerbations. Yet they point out that the prevalence of GER was similar among hospitalized and non-hospitalized patients, supporting a causative link between PPI and pulmonary exacerbations.

Based on their findings, the UF team suggests that “prescribers of PPI therapy should exercise pharmacovigilance; frequently re-evaluating indications and appropriateness of therapy and in the setting of GER considering alternate management modalities such as anti-reflux surgery where appropriate.”

For original article please visit: https://cysticfibrosisnewstoday.com/2017/12/07/proton-pump-inhibitor-use-is-associated-with-an-increased-frequency-of-hospitalization-in-patients-with-cystic-fibrosis/

Deadline to Enroll in a 2018 Marketplace Plan Ends Friday December 15th!!

The deadline to enroll in a 2018 Marketplace health insurance plan is Friday, December 15, 2017.  A person can visit www.HealthCare.gov to create an account and review options for coverage.  Then the person can apply for coverage for  2018.  All plans on the government Marketplace offer essential benefits, such as emergency room visits and prescription drug coverage, as well as preventive care including shots and screenings.  The plans offered are run by private insurance companies.  Many states have a variety of plans available.
Some people in the CF community think that the Affordable Care Act has been repealed.  This NOT true.  The Affordable Care Act is still the law of the land.
This means that some people with CF may be eligible for premium help when purchasing a policy on the Marketplace.  The household income cut off is much higher than the cut off for Medicaid which means many people with CF may be eligible for help paying their premiums if their plan is purchased through the Marketplace.
 Some states run their own Marketplaces.  When a person goes to www.Healthcare.gov the site will link them to their state marketplace if the state has their own marketplace.
In some cases the premium help that is available is higher than the help that has been available in prior years.
The only way to enroll in a health plan through the Marketplace after December 15, 2017 is if you qualify for a Special Enrollment Period.  A person qualifies for a Special Enrollment Period if the person has certain life events occur such as losing health coverage, moving, having a change in income, getting married or having a change in family size.
If a person with CF is without health insurance coverage or wants to see if a better more affordable option is available then he or she should go to www.Healthcare.gov to see what is available before time runs out.

Trial to Possibly Treat Nonesense Mutations Begins

Sevion Therapeutics and Eloxx Pharmaceuticals announced that a first healthy subject has been dosed in a Phase 1b clinical trial assessing the safety, tolerability and drug properties of ELX-02 as a potential treatment of several genetic diseases caused by nonsense mutations, including cystic fibrosis (CF).

Continue reading Trial to Possibly Treat Nonesense Mutations Begins