A Dutch Company on the Quest Against Cystic Fibrosis

An interview by:  Clara Rodríguez Fernández

Daniel de Boer founded ProQR in 2012 following a strong determination to improve the lives of people with cystic fibrosis. We started ProQR Therapeutics for a very personal reason,” he told me. “Eight years ago, my son was born, and diagnosed with cystic fibrosis. At that time, I was a serial entrepreneur in IT. I decided to make a career switch and start a company to develop drugs for cystic fibrosis, but then also for other genetic diseases.”

One would think that a person without a background in biotech might have it difficult to succeed, but de Boer is not the only to have so far successfully undertaken this endeavor. Over in France Karen Aiach built Lysogene to treat her daughter’s rare genetic disorder, while in the US the story of John Crawley and his company Amicus Therapeutics, founded to help his two children’s diagnosis, went so far as to inspire a movie. The determination and motivation of these parents seem to overdrive any challenges they might have faced because of their limited experience.

De Boer set out to create a business plan for his new company and found out that there was already quite a lot of activity, especially in approaches using small molecules or gene therapy.“We decided that we really wanted to add something new to the space, and take a completely novel approach.”

So he started looking for a new technology, and he found it. “Around that time, I met for the first time with some people in biotech, including the CEO at Alnylam, John Maraganore, and we talked about how they used RNA approaches for genetic diseases,” says de Boer.

Technologies targeting RNA are quite new compared to those that target DNA such as gene therapy. But RNA-based treatments have started to gain traction in the last few years. There are multiple ways that RNA can be used as a therapeutic, but its distinctive advantage over gene therapies and the likes is that it does not permanently change our genetic makeup, making it possible to reverse its effects.

Today, RNA technology is being tested in multiple rare diseases caused by genetic mutations, such as hemophilia, porphyria, or iron overload disorders. I thought, ‘if you can do that for all these other genetic diseases, why not for cystic fibrosis?’” says the Boer. “With that in mind, we started ProQR.”

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Potential Nitric Oxide Treatment for Resistant Bacterial Infections Gets Patent

A possible inhalable treatment for antibiotic-resistant bacterial infections in people with cystic fibrosis due to Pseudomonas aeruginosa now has a U.S. patent and is being readied for a first clinical trial, Novoclem Therapeutics announced.

The patent (No. 9,850,322) was issued to the University of North Carolina (UNC) at Chapel Hill where the potential therapy, BIOC51, was discovered, and covers a technology known as water-soluble polyglucosamine compositions that release nitric oxideContinue reading Potential Nitric Oxide Treatment for Resistant Bacterial Infections Gets Patent

Clinical Trial Opportunity for Phase IV Airway Clearance System

Med Systems is sponsoring a Phase IV clinical study to measure the
effectiveness of the Electro Flo 5000 Airway Clearance System for
people who have been diagnosed with cystic fibrosis. The goal of the
study is to provide health insurers and Medicare with comprehensive
information regarding the system’s performance. The study is designed
to measure the efficacy of the system, which includes the FDA510K
(K031876) device under current indications. The study will last 30 days
and involve using the system for lung clearance and recording the
results in a digital journal. The study should take about 10 minutes per
day to record measured results in the morning after waking. You will
also be asked to use a spirometer and a digital pulse oximeter to
evaluate your lung function after using the Electro Flo 5000 Airway
Clearance System.

Interested participants must be:
 Between the ages of 18-55 years of age
 Diagnosed with cystic fibrosis
 Prescribed chest physical therapy for airway clearance
 Able to perform self-treatment- having manual dexterity
 Residing in the United States

Contact- Dr. Leigh Mack: CFtrial@mackbio.com or Phone 888-935-
8676 ext. 706

Vitamin D3 deficiency and its association with nasal polyposis in patients with cystic fibrosis

This trial ascertained if the deficiency of vitamin D3 (VD3) correlated with the presence of nasal polyposis (NP) in patients with cystic fibrosis (CF) and patients with chronic rhinosinusitis (CRS). VD3 deficiency appeared to be related to the presence of nasal polyps in the patients with CRS and in the patients with CF in a similar manner. It was inferred that the lower the level of serum VD3, the more severe the mucosal disease was disclosed in the imaging studies and the more frequent microbial colonization of the patients with CF and the patients with CRS. Continue reading Vitamin D3 deficiency and its association with nasal polyposis in patients with cystic fibrosis

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

Introduction of New Therapies Affects Pregnancy Rates in Women With CF

The overall rate at which women with cystic fibrosis are becoming pregnant dropped slightly in recent years — coinciding with the introduction of CFTR modulators and the clinical trials that led to their approval as CF therapies — but appears to be rising again to pre-trial levels, a study reports.  Continue reading Introduction of New Therapies Affects Pregnancy Rates in Women 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

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

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