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. <https://www.sciencedaily.com/releases/2017/10/171025150620.htm>.

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

Positive Results for Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced that the New England Journal of Medicine (NEJM) published two articles with results from two Phase 3 studies of the tezacaftor/ivacaftor combination treatment, a medicine in development that is designed to treat the underlying cause of cystic fibrosis (CF) in people ages 12 and older who have certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Continue reading Positive Results for Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment

Live Stream the North American CF Conference Tomorrow for Free!

The North American CF Conference (NACFC) provides a collaborative and educational forum for all CF professionals. The educational elements of the meeting program are targeted to physicians, nurses, research scientists, respiratory therapists, physical therapists, nutritionists, social workers, and pharmacists. Continue reading Live Stream the North American CF Conference Tomorrow for Free!

Phase 1a study for drug to treat CF regardless of CF Mutation

http://www.businesswire.com/news/home/20171018005403/en/Synspira-Announces-Patient-Dosed-Phase-1a-Study

Synspira Announces First Patient Dosed in Phase 1a Study of SNSP113 in Cystic Fibrosis
— First-in-class drug candidate for treatment of cystic fibrosis regardless of genetic mutation — Continue reading Phase 1a study for drug to treat CF regardless of CF Mutation

Antifungal Drug Candidate Receives a Second “Qualified Infectious Disease Product” Designation

Pulmatrix Antifungal Drug Candidate Receives a Second “Qualified Infectious Disease Product” (QIDP) Designation from the FDA

http://markets.businessinsider.com/news/stocks/Pulmatrix-Antifungal-Drug-Candidate-Receives-a-Second-Qualified-Infectious-Disease-Product-QIDP-Designation-from-the-FDA-1002944255 Continue reading Antifungal Drug Candidate Receives a Second “Qualified Infectious Disease Product” Designation

Phase III study starts AVAIL study

Savara Announces Start of Pivotal Phase III AVAIL Study of AeroVanc

http://markets.businessinsider.com/news/stocks/Savara-Announces-Start-of-Pivotal-Phase-III-AVAIL-Study-of-AeroVanc-1002569033

Savara, Inc.(NASDAQ: SVRA), a clinical-stage specialty pharmaceutical company focused on the development Continue reading Phase III study starts AVAIL study

Phase 1b Trial of QR-010

https://globenewswire.com/news-release/2017/08/29/1101646/0/en/ProQR-Completes-Dosing-of-Cystic-Fibrosis-Patients-in-QR-010-Phase-1b-Trial.html

ProQR Completes Dosing of Cystic Fibrosis Patients in QR-010 Phase 1b Trial

Key Updates
• Last patient received their final dose in the PQ-010-001 Phase 1b clinical trial of QR-010 in CF patients with the F508del mutation.
Top-line trial data are expected to be issued in a press release Continue reading Phase 1b Trial of QR-010

Vertex Drug Gets Priority Review for Cystic Fibrosis

http://www.empr.com/drugs-in-the-pipeline/tezacaftor-ivacaftor-vertex-cystic-fibrosis-priority-review-nda/article/684284/

Tezacaftor/Ivacaftor Gets Priority Review for Cystic Fibrosis

The Food and Drug Administration (FDA) has granted Priority Review to the New Drug Application (NDA) of tezacaftor/ivacaftor (Vertex) for the treatment of patients ≥12yrs old with cystic fibrosis (CF) who have two copies of the F508del mutation or one F508del mutation and one residual function mutation.

The NDA submission was based on positive results from 2 global Phase 3 trials, which showed statistically significant improvements in lung function (percent predicted forced expiratory volume in one second, or ppFEV1) in patients treated with tezacaftor/ivacaftor.

The combination treatment consists of ivacaftor (marketed under the brand name Kalydeco), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, and tezacaftor, a novel CFTR corrector. Tezacaftor is designed to address the processing defect of F508del-CFTR to enable it to reach the cell surface, where ivacaftor can further enhance the protein’s function.

The FDA has set a Prescription Drug User Fee Act (PDUFA) target date of February 28, 2018 to make a decision on the NDA.

For more information visit Vrtx.com.

Two clinical trials presented at the European Cystic Fibrosis Conference

https://globenewswire.com/news-release/2017/08/17/1088301/0/en/Fluidigm-Licenses-CFTR-Next-Generation-Sequencing-Assay-From-Baylor-Genetics-for-Use-With-the-Juno-System.html

ProQR Announces Results for the Second Quarter of 2017

Key updates
• Data from two clinical trials of QR-010 presented at the European Cystic Fibrosis Conference. Enrollment completed in the Phase 1b clinical trial in cystic Continue reading Two clinical trials presented at the European Cystic Fibrosis Conference

Phase Two Clinical Trials to treat NTM

http://www.nasdaq.com/press-release/ait-therapeutics-announces-enrollment-of-first-patient-into-its-nontm-abscessus-phase-2-trial-in-20170807-00641

AIT Therapeutics Announces Enrollment of First Patient into Its NO-NTM abscessus Phase 2 Trial in Nontuberculous Mycobacteria (NTM)

10 patients with Mycobacterium Abscessus Complex (MABSC) are expected to enroll in the trial Continue reading Phase Two Clinical Trials to treat NTM