Newly Discovered CF Mutations Could Be Why Some People with CF are Living Longer

Researchers hypothesize that the newly-discovered mutations help re-hydrate the airways, discouraging bacterial build-up in the lungs.

Despite a narrow average lifespan, there is a big range in how severely cystic fibrosis (CF) affects the lungs and other organs depending on an individual’s specific genetic variation, and even in how long patients sharing the same, most common genetic mutation are able to survive with CF.

This led researchers at Boston Children’s Hospital to wonder if other genetic mutations could be protective against CF’s effects. Recent findings published in the American Journal of Respiratory Cell and Molecular Biology suggest that may be the case.

“There are some patients at one end of extreme severity who need a lung transplant very early in life, then others whose clinical presentation seems to stabilize so that they can live into the fifth and sixth decades of life,” says Pankaj Agrawal, MBBS, MMSc, principal investigator and medical director of The Manton Center’s Gene Discovery Core at Boston Children’s, who was the co-first author on the study.

To find out why, Agrawal and researchers at Boston Children’s — including Ruobing Wang, MD, a pulmonologist, and Craig Gerard, MD, PhD, chief of the Division of Respiratory Diseases — conducted the first-ever longitudinal analysis of genetic modifiers related to CF.

They combed through a population of nearly 600 CF patients registered at the Boston Children’s Cystic Fibrosis Center and found five individuals who stood out because of their advanced age — in their 50s or 60s — and relatively normal lung function.

“Given the large size of our center’s patient population, we were able to find a number of individuals at this rare ‘extreme,'” says Wang, who was co-first author on the paper.

A new hypothesis for mitigating cystic fibrosis

To discover the genetic variants, the researchers collected blood from these patients and performed whole exome sequencing on their DNA, analyzing the “coding” section of the genome that is responsible for most disease-related mutations.

Sequencing the genes of these five Boston Children’s patients — a cohort known as “long-term non-progressors” — the researchers found a set of rare and never-before-discovered genetic variants that might help explain their longevity and stable lung function.

The gene variants are related to so-called epithelial sodium channels (ENaCs), semi-permeable cellular pathways responsible for reabsorbing sodium in the kidney, colon, lung and sweat glands.

“Our hypothesis is that these ENaC mutations help to rehydrate the airways of CF patients, making it less likely for detrimental bacteria to take up residence in the lungs,” says Wang.

The discovery brings ENaCs into the limelight as a potential new therapeutic target.

“For example, if we could target ENaCs with a small molecule or an antibody-based drug, we might be able to incur a protective effect against CF’s progression,” says Agrawal, who is also a physician in the Boston Children’s Division of Newborn Medicine.

Based on their findings, the team is now doing further studies to analyze the genetics of patients at the other end of the CF spectrum — those with extremely severe clinical presentation of symptoms at a young age.

Story Source:

Boston Children’s Hospital. “Some people with cystic fibrosis might live longer because of genetic mutations: Researchers hypothesize that the newly-discovered mutations help re-hydrate the airways, discouraging bacterial build-up in the lungs.” ScienceDaily. ScienceDaily, 25 October 2017. <>.

Materials provided by Boston Children’s HospitalNote: Content may be edited for style and length.

Please Join Us for a Free Private Screening of Up for Air at CUMC

Please join us for a FREE private film screening of

Tuesday, May 9, 2017
6:00 – 8:00 PM

Reception followed by screening and Q & A with Jerry Cahill and the film’s Continue reading Please Join Us for a Free Private Screening of Up for Air at CUMC

Stream My Documentary, Up For Air, FREE this week!

We’re still celebrating Jerry Cahill’s 5 year post transplant anniversary by giving away his documentary, Up For Air, for FREE through April 30th!

Use discount code “BigAir” to stream!

Phase 2a CF corrector study

Galapagos doses first patient with novel CF corrector GLPG2222

Galapagos NV (Euronext & NASDAQ: GLPG) announces dosing of the first patient with cystic fibrosis (CF) Class III (F508del and a gating mutation like G551D) with novel CF corrector GLPG2222 as an add-on to Kalydeco®[1] in a Phase 2a study. Galapagos further announced the opening of an Investigational New Drug (IND) file with the US Food & Drug Administration for GLPG2222, triggering a $10 million milestone payment.
Continue reading Phase 2a CF corrector study

Hopeful new clinical trails for nonsense mutations

Translarna’s Turn In Cystic Fibrosis And Brodalumab’s Approval Tardiness

Welcome to your weekly digest of approaching regulatory and clinical readouts. PTC Therapeutics (NASDAQ:PTC) is awaiting data in the first quarter with its transcription modulator Translarna in nonsense Continue reading Hopeful new clinical trails for nonsense mutations

Corbus Pharma Completes Phase 2 CF Study

Corbus Pharma (CRBP) Completes Phase 2 CF Study of JBT-101; Expects to Report Results in Q1

Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) completed its Phase 2 study evaluating JBT-101 (“Resunab”) for the treatment of cystic fibrosis. JBT-101, the Company’s novel synthetic oral endocannabinoid-mimetic drug, is designed Continue reading Corbus Pharma Completes Phase 2 CF Study

‘Tis The Season

By Piper Beatty Welsh

The holidays are a time for miracles. We see it everywhere we turn, whether in the birth of a newborn baby, or the oil that lit the Temple light, or just in the warmth of family and friends or the gleam in a child’s eye. The holidays are a season of gathering; a season of celebration, generosity, and forgiveness; and a Continue reading ‘Tis The Season

Galapagos starts SAPHIRA Phase 2 study with GLPG1837 in cystic fibrosis patients

Galapagos NV (Euronext & NASDAQ: GLPG) announced today the first dosing in its Phase 2 exploratory program of GLPG1837 in patients with cystic fibrosis (CF).

GLPG1837 is a candidate CFTR potentiator drug in clinical development for the treatment of Class III mutations in cystic fibrosis. The SAPHIRA Phase 2 Continue reading Galapagos starts SAPHIRA Phase 2 study with GLPG1837 in cystic fibrosis patients

KaloBios Reports Top-Line Data for Phase 2 Study of KB001-A to Treat Pseudomonas Aeruginosa Lung Infections in Cystic Fibrosis Patients

Study Does Not Meet Primary Endpoint

SOUTH SAN FRANCISCO, Calif., Jan. 6, 2015 /PRNewswire/ — KaloBios Pharmaceuticals, Inc. (Nasdaq: KBIO) today announced top-line data from the randomized, double-blind, placebo-controlled Phase 2 study of KB001-A, an anti-PcrV monoclonal

antibody (mAb) fragment, to treat Pseudomonas aeruginosa (Pa) lung infections in subjects with cystic fibrosis (CF). While the data from this study showed KB001-A was generally safe and well-tolerated, the primary endpoint of increased time to need for antibiotics for worsening respiratory tract signs and symptoms (an indicator of reduction of the risk to develop pulmonary exacerbations) was not met.

The company also evaluated time to need for antibiotics in a number of pre-specified subgroup analyses known to be associated with such risk and none demonstrated an improvement for KB001-A versus placebo. In addition, secondary endpoints such as improvements in FEV1 and subject-reported outcomes as measured by Cystic Fibrosis Respiratory Symptom Diary (CFRSD) did not show an advantage with KB001-A treatment.

“The study did demonstrate a non-significant reduction in Pa titer in sputum measured post dosing and a 3% improvement in FEV1 (p=0.0029) at Week 16 for the KB001-A arm compared to placebo; however, these effects were not accompanied by improvements in other clinically significant end-points such as exacerbations or symptoms,” said Nestor A. Molfino, MD, MSc., KaloBios’ Chief Medical Officer. “The KaloBios team is still collecting all of the patient data and working to further understand the  results and plan to submit our comprehensive findings to a scientific meeting or journal.”

“We are very disappointed that KB001-A did not demonstrate a clinically significant effect on Pa infections in these CF patients, but we are thankful to all of them for volunteering to participate in this study,” said David W. Pritchard, KaloBios’ President and Chief Executive Officer.  “Based on these top line data, we intend to discontinue our development of KB001-A in cystic fibrosis.”

“Going forward, KaloBios will focus resources and efforts on advancing our oncology programs.  Specifically, we are working to advance our KB004 oncology program as well as to expand the oncology development portfolio with the possible introduction of additional oncology indications for KB004 or for KB003, our anti-GM-CSF antibody. Currently, the KB004 Phase 2 cohort expansion study evaluating subjects with myelofibrosis, myelodysplastic syndrome, and acute myeloid leukemia is actively enrolling,” said Mr. Pritchard.

Conference Call with Management
Management will host a teleconference and webcast to provide an overview of the trial results later today, January 6, 2015, at 4:30PM Eastern Time (1:30PM Pacific Time). Interested parties can listen to the live teleconference by dialing (800) 514-4861 from the U.S. and Canada or +1 (678) 809-2406 for international callers. Individuals may access the live audio webcast by visiting the event URL at:  A replay of the webcast will be available on the company’s website for 90 days following the live event.

KB001-A Trial Design
The Phase 2 clinical study of KB001-A in CF subjects with Pa lung infections was a randomized, double-blind, placebo controlled study in which 182 subjects were randomized one to one between treatment with KB001-A or placebo. Eligible subjects were identified as CF patients whose lungs were colonized with Pa at the time of entry into the study, and who had been compliant in taking their antibiotics for at least the preceding two cycles. Subjects enrolled in the 16 week study were allowed to continue on their antibiotics in the first four weeks of the study, after which antibiotics were withdrawn for the remainder of their time on the study. Throughout the 16 week study duration, subjects received either placebo or KB001-A dosed at 10 mg/kg every four weeks via intravenous administration with one additional loading dose at Week 2. The primary endpoint of the study was the time to need for antibiotics for respiratory signs and symptoms and was analytically expressed as a hazard ratio.

Inhaled Mannitol Found to be Helpful for Those With Cystic Fibrosis

Several studies have recently been released looking at the use of dry mannitol powder in an inhalation device for the management of cystic fibrosis. One study, entitled “Optimising inhaled mannitol for cystic fibrosis in an adult population,” Continue reading Inhaled Mannitol Found to be Helpful for Those With Cystic Fibrosis