Omega-3 Compound Reduces Inflammation in Cystic Fibrosis Patients in New Pilot Study

By Jennifer Prince

A marine omega-3 compound comprising a docosahexaenoic acid (DHA) sn1-monoacylglyceride (MAG-DHA) may act as an anti-inflammatory for subjects with cystic fibrosis, according to a new pilot study1 published in the journal Marine Drugs. In the study, MaxSimil (Neptune Wellness Solutions; Laval, QC, Canada) increased omega-3 red blood cell levels, helped moderate the ratio of arachidonic acid (AA) to docosahexaenoic acid, and reduced key inflammatory biomarkers in subjects with cystic fibrosis. Continue reading Omega-3 Compound Reduces Inflammation in Cystic Fibrosis Patients in New Pilot Study

Vertex Pharmaceuticals opens expanded San Diego research center with focus on cystic fibrosis

By Bradley J. Fikes

Vertex Pharmaceuticals opened its new San Diego research center Monday, starting a new chapter in a decades-long quest to not only treat but cure cystic fibrosis.

In 18 years, three drugs for the lung-ravaging disease have emerged from Vertex’s San Diego center and more are in the pipeline.

The first, Kalydeco, was approved in 2012. It is the first drug that treats the underlying cause of the disease. The second, Orkambi, was approved three years later. And the third, Symdeko, was approved in February.

These drugs can benefit about half of all patients with the incurable disease. In the next several years, Boston-based Vertex hopes its drugs can help nearly all patients live longer, healthier lives.

Cystic fibrosis is caused by a genetic defect that allows a buildup of thick mucus in the lungs, and other internal organs. This mucus clogs airways and promotes the growth of bacteria. The average lifespan of patients is 37 years, up from 20 years in 1980. Treatments include antibiotics to fight lung infections and mucus-thinning drugs.

The new 170,000 square-foot building on Torrey Pines Mesa more than doubles the company’s space. The center includes cell culturing equipment to grow lung cells from patients, to be used for drug screening. A 4,000 square-foot incubator suite will serve outside collaborators.

Asides from cystic fibrosis, the staff will work on other serious diseases.

Among the speakers Monday morning was a veteran in the fight against cystic fibrosis: Jennifer Ferguson, who has two children with the disease, Ashton and Lola. Both her children are taking Vertex drugs, and both were present with her at the event.

With these drugs and the promise of better therapies ahead, she says Ashton and Lola have a good chance of growing up and leading their own lives. She urged all Vertex employees to think of themselves as part of a team to cure the disease.

Ferguson, of San Diego, found out about the work from the Cystic Fibrosis Foundation. The foundation had invested $30 million in startup Aurora Biosciences to find therapies.

In 2001, Vertex purchased Aurora for $592 million in stock, the same year Ashton was diagnosed. The research went on under Vertex, and Ferguson became quite familiar with the research team.

“The Cystic Fibrosis Foundation asked me to come speak, to show them what it’s like to have a little child with CF,” she said. “So I came here about 17 years ago with him as a 6-month-old.”

At that time, many cystic fibrosis patients never reached adulthood.

“I had a hard time keeping it together,” Ferguson told the audience of that long-ago visit.

“But I looked in the staff’s faces — and some of you are still here — and I thought, I’m going to put my faith and trust in your hands, in your brains. And I was able to let go of my worry, because you were on the case.”

Ferguson started visiting every few years to check on what progress was being made, first with Ashton, and later including Lola. She also raises money for the Cystic Fibrosis Foundation.

Both her children have shown improvement since starting the Vertex drugs, Ferguson said. But they still need to go through a daily regimen of clearing out their lungs.

From medications, the research frontier has advanced to investigations into a cure. That means fixing the genetic defect, which can come in several variations, inside living patients.

That cure might come from the hot new gene editing technology called CRISR. In 2015, Vertex allied with startup CRISPR Therapeutics to develop curative therapies.

This post was originally published on The San Diego Union-Tribune

Jerry Cahill’s CF Podcast: Stem Cell Research with Dr. Hans-Willem Snoeck

In this feature of The Path Forward with CF series, Dr. Hans-Willem Snoeck, Professor of Medicine (Microbiology and Immunology) at CUMC, sits down to discuss stem cell research as it relates to CF.

Because lung cells regenerate and repair themselves regularly, researchers believe that – some day – stem cell technology could be a one-time therapy to cure cystic fibrosis. Research is ongoing, but in the meantime, scientists can currently use human pluripotent stem cells to create lung organoids (tiny, 3-D structures that mimic features of a full-sized lung), introduce various mutations, and apply technologies to learn more about those mutations’ characteristics.

This video was originally published on JerryCahill.com

Vertex Employees Donate $1M to CF and Other Communities via Matching Gift Program

By Carolina Henriques

Vertex Pharmaceuticals employees have raised more million $1 million  using  the Vertex Foundation‘s matching gift program in a show of commitment to causes that include the cystic fibrosis (CF) community, a company press release states.

The dollar-for-dollar matching gift program is being run through the nonprofit Vertex Foundation, established by the company in November 2017 as part of it’s charitable giving goal of donating $500 million to qualified nonprofits and other causes worldwide over 10 years.

To date, more than 500 Vertex employees have used the program to support 753 charities around the globe working to advance work in areas that include healthcare, human services, education, and disaster relief.

Vertex’s charitable commitment has four primary goals: supporting CF patients and caregivers worldwide, including enabling access to Vertex’s medicines; helping underserved students and young women with STEAM (science, technology, engineering, arts and math) education; supporting young doctors and scientists; and strengthening and fostering innovation in local communities through health and wellness programs.

“Giving back is in our DNA at Vertex, and our employees have a long history of going the extra mile to improve the lives of patients, students and their neighbors,” Jeffrey Leiden, president, chairman and chief executive officer of Vertex, said in the release. “I’m proud that The Vertex Foundation is able to help extend the impact of our employees’ giving and look forward to seeing the reach of these investments in the causes they care about most.”

Also as part of its 10-year commitment, Vertex awarded $400,000 in scholarships to eligible CF patients and their family members in May as part of its second “All in for CF” scholarship program. In total, 80 scholarships worth $5,000 each were awarded for the upcoming academic year.

Vertex, which specializes in cystic fibrosis, has three approved CF therapies: Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), and Symdeko (tezacaftor/ivacaftor).

The company is also testing potential triple combination treatments for CF.

For the rest of this article, click here.

Cystic Fibrosis Disease Severity Linked to Immune Overreaction to Fungus, Study Reports

By Ana Pena

Disease severity in cystic fibrosis (CF) may be associated with an overreaction of the immune system to the fungus Aspergillus fumigatus, particularly due to a type of white blood cell called a phagocyte — which ingests and kills invading organisms — a study suggests.

U.K. researchers found that phagocytes from CF patients release higher amounts of harmful reactive oxygen species in response to Aspergillus fumigatus, a common cause of lung infection in these patients.

The study, “Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity,” was published in the journal ERC Open Research.

Recent studies have supported the idea that the widespread environmental fungus Aspergillus fumigatus may play a critical role in CF lung disease.

Up to 58% of CF patients are colonized with this fungus, and an estimated 47.7% of adult patients are affected by either allergic reactions or infection caused by the fungus.

Persistent infections with A. fumigatus are also known to be adversely correlated with lung function and hospitalization in CF patients.

Researchers hypothesized that the anti-fungal defense mechanism in CF patients might be altered and have an impact on the progression of lung disease.

To investigate this hypothesis, the team compared the immune response of phagocytes from CF patients with those of healthy individuals used as controls, and tried to correlate them to clinical metrics of disease severity.

For original article please visit CF News Today.

Ex Vivo Lung Perfusion for Transplant

Cystic Fibrosis Podcast 186:
In the latest edition of The Path Forward with Cystic Fibrosis, Dr. Frank D’Ovidio – the Surgical Director of the Lung Transplant Project and Director of the Ex Vivo Lung Perfusion Program at CUMC – explains exactly what the Ex Vivo program is and what its end goals are.
Because so many donor lungs are damaged at the time of death, only 20-30% of donated lungs are usable for transplantation. The ex vivo lung perfusion (EVLP) is a process of evaluating and preparing donor lungs outside the body prior to transplant surgery. In EVLP, the lungs are warmed to normal body temperature, flushed of donor blood, inflammatory cells and potentially harmful biologic factors, and treated with antibiotics and anti-inflammatory agents.
Eventually, as this process is perfected, it could expand the available donor pool by restoring and repairing donor lungs that have sustained damage and eventually create a sort of ‘ICU for organs.’

This video podcast was made possible through an unrestricted educational grant from Columbia University Medial Center and the Lung Transplant Project.

Antioxidant Supplement Helps Cystic Fibrosis Patients, Study Finds

By Carolina Henriques

A special formulation of an antioxidant-enriched multivitamin helped decrease the frequency of pulmonary exacerbations in patients with cystic fibrosis (CF), according to a new study.

The findings, by researchers at Children’s Hospital Colorado and the University of Colorado School of Medicine, were published in the American Journal of Respiratory and Critical Care Medicine under the title “Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis: Randomized, Controlled, Multicenter Trial.”

Inflammation is an important contributor to lung damage and to progressive lung function decline in CF. In the study, researchers looked at the effects of a “cocktail” of multiple antioxidants on inflammation and health outcomes in CF patients.

“Single oral antioxidant formulations have been tested previously in CF with mixed results. However, there had not been a well-designed, randomized controlled trial of an antioxidant ‘cocktail’ that included multiple antioxidants in a single formulation,” Scott Sagel, MD, PhD, said in a University of Colorado news story. Sagel is the study’s first author and a pediatric pulmonologist at Children’s Colorado.

The 16-week study (NCT01859390) was conducted from September 2013 to October 2015 at 15 U.S. CF centers affiliated with the CF Foundation’s Therapeutics Development Network.

The study included 73 pancreatic-insufficient CF patients, 10 years and older (average age 22), who could not adequately absorb important dietary antioxidants such as beta-carotene, coenzyme Q10 (CoQ10), tocopherols (vitamin E), and selenium, which help neutralize inflammation in the body.

Participants received either capsules of antioxidant-enriched multivitamins, or control multivitamins without antioxidant enrichment. The capsules were designed specifically for people with difficulties in absorbing fats and proteins, like CF patients.

The investigational antioxidant-enriched multivitamin supplement, called AquADEKs-2, contains standard amounts of fat-soluble vitamins (A, D, E, K) plus several antioxidants, including beta-carotene, mixed tocopherols, CoQ10, mixed carotenoids (lutein, lycopene and zeaxanthin), and the minerals zinc and selenium.

Sagel and his team found that the antioxidant-enriched multivitamin supplement increased the concentration of antioxidants in the bloodstream, and temporarily reduced inflammation at four weeks, even though these results were not sustained through the end of the 16 weeks of the study.

In addition, antioxidant supplementation was found safe and well-tolerated by study participants.

Researchers also observed that antioxidant treatment appeared to prolong the time to the first pulmonary exacerbation requiring antibiotics, and also to reduce the frequency of pulmonary exacerbations altogether.

For the full article, please visit CF News Today.

Toothpaste ingredient may bust up cystic fibrosis biofilms

By Chris Waters and Sarina Gleason

A common antibacterial substance in toothpaste may combat life-threatening diseases such as cystic fibrosis when combined with an with an FDA-approved drug, researchers report.

Researchers have found that when triclosan, a substance that reduces or prevents bacteria from growing, combines with an antibiotic called tobramycin, it kills the cells that protect the CF bacteria, known as Pseudomonas aeruginosa, by up to 99.9 percent.

CF is a common genetic disease with one in every 2,500 to 3,500 people diagnosed with it at an early age. It results in a thick mucus in the lungs, which becomes a magnet for bacteria.

These bacteria are notoriously difficult to kill because a slimy barrier known as a biofilm, which allows the disease to thrive even when treated with antibiotics, protects them.

“The problem that we’re really tackling is finding ways to kill these biofilms,” says Chris Waters, lead author of the study and a microbiology professor at Michigan State University.

According to Waters, there are many common biofilm-related infections that people get, including ear infections and swollen, painful gums caused by gingivitis. But more serious, potentially fatal diseases join the ranks of CF including endocarditis, or inflammation of the heart, as well as infections from artificial hip and pacemaker implants.

Waters and his coauthors grew 6,000 biofilms in petri dishes, added in tobramycin along with many different compounds, to see what worked better at killing the bacteria. Twenty-five potential compounds were effective, but one stood out.

“It’s well known that triclosan, when used by itself, isn’t effective at killing Pseudomonas aeruginosa,” says coauthor Alessandra Hunt, a postdoctoral associate of microbiology and molecular genetics. “But when I saw it listed as a possible compound to use with tobramycin, I was intrigued. We found triclosan was the one that worked every time.”

Triclosan has been used for more than 40 years in soaps, makeup, and other commercial products because of its antibacterial properties. Recently, the FDA ruled to limit its use in soaps and hand sanitizers due to insufficient data on its increased effectiveness and concern about overuse. Clear evidence has shown, though, that its use in toothpaste is safe and highly effective in fighting gingivitis, and it is still approved for use.

“Limiting its use is the right thing to do,” says coauthor Michael Maiden, a graduate student in medicine. “The key is to avoid creating resistance to a substance so when it’s found in numerous products, the chances of that happening increase.”

Tobramycin is currently the most widely used treatment for CF, but it typically doesn’t clear the lungs of infection, Waters says. Patients typically inhale the drug, yet still find themselves chronically infected their whole lives, eventually needing a lung transplant.

“Most transplants aren’t a viable option though for these patients and those who do have a transplant see a 50 percent failure rate within five years,” he says. “The other issue is that tobramycin can be toxic itself.” Known side effects from the drug include kidney toxicity and hearing loss.

“Our triclosan finding gives doctors another potential option and allows them to use significantly less of the tobramycin in treatment, potentially reducing its use by 100 times,” Hunt says.

Within the next year, Waters and his colleagues will begin testing the effectiveness of the combination therapy on mice with hopes of it heading to a human trial soon after since both drugs are already FDA approved.

Just brushing your teeth with toothpaste that has triclosan won’t help to treat lung infections though, Maiden says.

“We’re working to get this potential therapy approved so we can provide a new treatment option for CF patients, as well as treat other biofilm infections that are now untreatable. We think this can save lives,” he says.

The research appears in the journal Antimicrobial Agents and Chemotherapy.

The National Institutes of Health, Cystic Fibrosis Foundation, and Hunt for a Cure in Grand Rapids, Michigan funded the research.

Source: Michigan State University

Defining chronic Pseudomonas aeruginosa infection in cystic fibrosis

By Valerie Waters and Keith Grimwood

Cystic fibrosis (CF) is a genetic, multi-system disease due to mutations in the cystic fibrosis conductance regulator (CFTR) gene, leading to ineffective anion channel activity [1]. The resulting impaired mucociliary clearance permits initial acquisition of Pseudomonas aeruginosa and, if untreated, the establishment of persistent infection in the CF airways. It has long been recognized that chronic infection, often characterized by a mucoid P. aeruginosa phenotype, is associated with more rapid lung function decline and earlier death in individuals with CF [[2], [3], [4]]. Defining chronic P. aeruginosa infection is, therefore, an important step in identifying CF patients most at risk of lung disease progression. Traditionally, the Leed’s criteria has been used to define chronicity (as having >50% of sputum cultures being P. aeruginosa positive in the preceding 12 months), as it is the only clinically validated definition [5]. However, the Leed’s criteria are difficult to implement in young children unable to provide sputum and further limited by the required number of sputum samples and follow-up time [6].

In this issue of the Journal, studies by Heltshe et al. and Boutin et al. aim to re-define what chronic P. aeruginosa infection means in CF. In a retrospective cohort study using data from the US CF Foundation Patient Registry, Heltshe et al. followed close to 6000 early-diagnosed CF children for approximately 6 years [7]. Two-thirds acquired P. aeruginosa infection and of those, 6% had an initial mucoid phenotype. Furthermore, the majority (87%) of children who developed mucoid infection did so before meeting the definition of chronic infection (at least 3 yearly quarters P. aeruginosa positive in the preceding year). Initial P. aeruginosa infection with a mucoid phenotype has been previously described and is a recognized risk factor for failure of antimicrobial eradication therapy [[8], [9], [10]]. Whether this initial acquisition of a mucoid phenotype represents prior adaptation of P. aeruginosa in the CF host (either undetected or transmitted from a patient with chronic infection) or simply infection with an environmental strain particularly well-suited to the CF airways, is as of yet unknown [11]. It is clear, though, that mucoid P. aeruginosa does have an adaptive advantage in early CF infection as mucoidy was associated with an almost three-fold increased risk of transition to chronic infection in this current study. Despite the presence of this risk factor, however, only 13% of P. aeruginosa infected patients went on to develop chronic infection. Although Heltshe et al. did not provide details as to eradication strategies used in this cohort, this low incidence of persistent infection does speak to the overall effectiveness of current antimicrobial treatment for early P. aeruginosa infection.

Boutin et al. took their investigation a step further by using molecular methods, specifically quantitative polymerase chain reaction (qPCR), to define chronic P. aeruginosa infection [12]. In their study, patients with chronic infection had significantly higher levels of P. aeruginosa as measured by qPCR compared to those with intermittent infection. A single P. aeruginosa qPCR measurement in sputum had a sensitivity of 84% (with a specificity of 85%) in detecting chronic infection using a threshold of 103.4 colony forming units (CFU)/ml. A single sputum PCR measure had the advantage of not requiring 12 months of culture results as per the Leed’s criteria [5]. Furthermore, in their small study sample size, PCR was more discriminatory than mucoidy status in predicting chronicity, not surprisingly, given that alginate production (conferring mucoidy) is only one of several virulence factors contributing to the establishment of persistent P. aeruginosa infection in CF [13]. When used in throat swab samples, qPCR had a considerably lower sensitivity (82%) and specificity (56%) in detecting chronic infection, likely due in part to the lower bacterial burden observed in this specimen, compared to sputum. The low specificity of PCR in this setting (positive PCR, negative culture) may reflect the fact that a molecular signal may precede culture positivity. Early detection of P. aeruginosa infection, before culture conversion, in CF patients was originally suggested decades ago using serologic and, more recently, molecular methods [[14], [15], [16]]. Serology, however, has proven disappointing at identifying early P. aeruginosa infection [17]. Nevertheless, early detection may still be possible using highly-sensitive PCR techniques for identifying lower airway P. aeruginosa infection in a young, non-expectorating child. In the study by Boutin et al., P. aeruginosa detection in throat swabs by PCR alone was linked to a positive culture in sputum in three-quarters of cases. Previous studies comparing oropharyngeal cultures to bronchoalveolar lavage (BAL) cultures in children with CF demonstrated that oropharyngeal cultures had a positive predictive value of only 44%, but a negative predictive value of 95% in diagnosing lower airway P. aeruginosa infection [18]. Performing P. aeruginosa qPCR on culture negative throat swabs may further improve the diagnosis of lower airway infection in young children with CF who are unable to produce sputum, but this approach will still need to be validated by comparative studies employing BAL fluid samples. Unfortunately, using confirmatory induced sputum samples as suggested by Boutin et al., may produce unreliable results as these specimens are poor predictors of lower airway pathogens cultured from BAL specimens in young children with CF [19]. Finally, it is yet to be determined whether an earlier diagnosis of P. aeruginosa infection leads to improved eradication success rates and superior clinical outcomes.

In summary, the recent studies by Heltshe et al. and Boutin et al. further our understanding of how chronic P. aeruginosa infection develops in CF and how to better recognize it [7,12]. Ultimately, prevention of chronic P. aeruginosa infection and its deleterious effects on lung function and survival is the goal.

Original article in Journal of Cystic Fibrosis here.

CF Foundation ‘Venture Philanthropy’ Model Crucial to CF Breakthroughs

By Larry Luxner

When the Cystic Fibrosis Foundation (CFF) was established in 1955, most people with cystic fibrosis (CF) didn’t make it to their sixth birthday. Today, the average life expectancy of a CF patient is 47 years.

To date, the U.S. Food and Drug Administration has approved 12 CF therapies. Three of them are CFTR modulators that treat the basic disease-causing defect, benefiting 60 percent of all patients, and more therapies are on the way.

Preston W. Campbell III, the CFF’s president and CEO, directly attributes this dramatic improvement to the foundation’s philosophy of “venture philanthropy.”

“We are now in Phase 3 CFTR trials that, if successful, will mean that as early as next year, more than 90 percent of all individuals with CF will have a highly effective therapy targeting CF’s basic defect,” he said. “More therapies that treat the complications of CF are in the pipeline than ever before.

“It begs the question: how did all of this happen?”

Campbell answered that during his March 26 presentation, “Patient advocates taking a real stand in drug development: How the CFF worked with biotech and pharma to find a cure,” at the 2018 World Orphan Drug Congress USA in Oxon Hill, Maryland.

Back in 1960, the Bethesda, Maryland-based foundation broke ground by establishing a Care Center Network to provide multidisciplinary care. Within five more years, it had formed a patient registry.

With only $400,000 in the bank, it would also commit $11 million to research, Campbell said. “Five years later, in 1985, the basic CF defect was identified, and in 1989, the CFTR gene was discovered. That opened the floodgates,” he added.

Campbell’s predecessor, Robert J. Beall, created the Therapeutics Development Program — now called its Venture Philanthropy Model — in 1998 to entice industry to focus on CF, and specifically on CFTR as a target. Its three components were financial assistance, research tools and scientific advice, and a clinical trials network.

“We would lower the risk for industry to come into the CF space. We also made our research tools and scientific advice freely available, and we also embedded the best scientists in the world in these industry programs,” said Campbell, who took over from Beall as head of the CFF in January 2016. “Finally, in order to make sure clinical trials were safely and efficiently done, we created a clinical trials network that originally had seven centers and now has 89.”

In the beginning, CFF’s investments were typically in the $1.5 million range. Ultimately, the foundation invested more than $100 million in Aurora and its successor, Vertex Pharmaceuticals, whose headquarters are in Boston.

To date, the FDA has approved three Vertex CFTR modulators: Kalydeco (ivacaftor) for patients with the G551D mutation in the CFTR gene (2012); Orkambi (lumacaftor/ivacaftor)for patients who are homozygous for F508del, the most common mutation in the CFTR gene (2015); and Symdeko (tezacaftor/ivacaftor) for homozygous F508del patients as well as others (2018).

“Payments are milestone-based, so we pay for success,” Campbell said. “A scientific advisory committee determines if milestones are met and if the project should continue. Successful programs offer a return on our investment, so if the program is foundering, we shake hands and walk away.”

To continue to full article, please click here.