Steps in the Journey: CFTR mutation to sweat chloride concentration to survival

Associations between “salty” sweat and early mortality can be found in the scientific literature dating back to the 17th century [1], hundreds of years before a comprehensive medical description of cystic fibrosis (CF) [2]. Insightful observation of excessive dehydration and deaths among children during a 1948 New York City heat wave suggested that salt homeostasis was a fundamental cellular problem in CF [3], with identification of supranormal sweat chloride concentrations remaining fundamental to the diagnosis of CF today. Since identification of the mutated gene associated with CF (the cystic fibrosis transmembrane conductance regulator; CFTR) [4], pieces of the CF puzzle seem to have, for the most part, fallen into place. Continue reading Steps in the Journey: CFTR mutation to sweat chloride concentration to survival

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

Advancing the GI frontier for patients with CF

The care of patients with Cystic Fibrosis (CF) has seen amazing advances in the past few years, made in part through the development of CFTR modulators. However, the recognition of the frequency of gastrointestinal (GI) symptoms in our patients is just beginning to emerge. Only recently have publications noted the excessively high frequency of GI issues. Continue reading Advancing the GI frontier for patients with CF

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

Vertex Plans To Eradicate Cystic Fibrosis, And Go From There

Vertex Pharmaceuticals: Going From ‘Crisis’ To Blockbuster

Jeffrey Leiden, chief executive for Vertex Pharmaceuticals, plans to eradicate cystic fibrosis. (Vertex) Continue reading Vertex Plans To Eradicate Cystic Fibrosis, And Go From There

4D Molecular Receives $3 Million from Cystic Fibrosis Foundation Therapeutics

http://www.raredr.com/

A year removed from its initial grant of $525,000, Cystic Fibrosis Foundation Therapeutics (CFFT) is providing $3 million in additional funding to 4D Molecular Therapeutics (4DMT). Continue reading 4D Molecular Receives $3 Million from Cystic Fibrosis Foundation Therapeutics

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