I Inhaled Viruses As A Last-Ditch Effort To Fight A Drug-Resistant Bacterial Infection

By Ella Balasa

A few months ago I tried an experimental treatment called phage therapy to treat the relentless Pseudomonas in my lungs. This treatment was documented by the Associated Press and since then I have received many questions from individuals asking how I feel now. Well, I wrote a piece to tell the story from my perspective and hopefully provide some information that you can’t gather from just a news blurb.

I also discuss the importance of understanding scientific knowledge about treatments and disease prognosis. Without this, I would have shied away from trying this treatment that significantly helped me. It’s a vital aspect of being a receiver of health care ― asking questions, probing for answers, and gaining the knowledge to feel empowered to take an active role in shaping your health journey.

If anyone is interested in learning more about this experience, take a read at HuffPost here.

Patients with lung disease could find relief by breathing in messenger RNA molecules

Original article on Science Daily.

Messenger RNA, which can induce cells to produce therapeutic proteins, holds great promise for treating a variety of diseases. The biggest obstacle to this approach so far has been finding safe and efficient ways to deliver mRNA molecules to the target cells.

In an advance that could lead to new treatments for lung disease, MIT researchers have now designed an inhalable form of mRNA. This aerosol could be administered directly to the lungs to help treat diseases such as cystic fibrosis, the researchers say.

“We think the ability to deliver mRNA via inhalation could allow us to treat a range of different disease of the lung,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study.

The researchers showed that they could induce lung cells in mice to produce a target protein — in this case, a bioluminescent protein. If the same success rate can be achieved with therapeutic proteins, that could be high enough to treat many lung diseases, the researchers say.

Asha Patel, a former MIT postdoc who is now an assistant professor at Imperial College London, is the lead author of the paper, which appears in the Jan. 4 issue of the journal Advanced Materials. Other authors of the paper include James Kaczmarek and Kevin Kauffman, both recent MIT PhD recipients; Suman Bose, a research scientist at the Koch Institute; Faryal Mir, a former MIT technical assistant; Michael Heartlein, the chief technical officer at Translate Bio; Frank DeRosa, senior vice president of research and development at Translate Bio; and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute.

Treatment by inhalation

Messenger RNA encodes genetic instructions that stimulate cells to produce specific proteins. Many researchers have been working on developing mRNA to treat genetic disorders or cancer, by essentially turning the patients’ own cells into drug factories.

Because mRNA can be easily broken down in the body, it needs to transported within some kind of protective carrier. Anderson’s lab has previously designed materials that can deliver mRNA and another type of RNA therapy called RNA interference (RNAi) to the liver and other organs, and some of these are being further developed for possible testing in patients.

In this study, the researchers wanted to create an inhalable form of mRNA, which would allow the molecules to be delivered directly to the lungs. Many existing drugs for asthma and other lung diseases are specially formulated so they can be inhaled via either an inhaler, which sprays powdered particles of medication, or a nebulizer, which releases an aerosol containing the medication.

The MIT team set out to develop a material that could stabilize RNA during the process of aerosol delivery. Some previous studies have explored a material called polyethylenimine (PEI) for delivering inhalable DNA to the lungs. However, PEI doesn’t break down easily, so with the repeated dosing that would likely be required for mRNA therapies, the polymer could accumulate and cause side effects.

To avoid those potential side effects, the researchers turned to a type of positively charged polymers called hyperbranched poly (beta amino esters), which, unlike PEI, are biodegradable.

The particles the team created consist of spheres, approximately 150 nanometers in diameter, with a tangled mixture of the polymer and mRNA molecules that encode luciferase, a bioluminescent protein. The researchers suspended these particles in droplets and delivered them to mice as an inhalable mist, using a nebulizer.

“Breathing is used as a simple but effective delivery route to the lungs. Once the aerosol droplets are inhaled, the nanoparticles contained within each droplet enter the cells and instruct it to make a particular protein from mRNA,” Patel says.

The researchers found that 24 hours after the mice inhaled the mRNA, lung cells were producing the bioluminescent protein. The amount of protein gradually fell over time as the mRNA was cleared. The researchers were able to maintain steady levels of the protein by giving the mice repeated doses, which may be necessary if adapted to treat chronic lung disease.

Broad distribution

Further analysis of the lungs revealed that mRNA was evenly distributed throughout the five lobes of the lungs and was taken up mainly by epithelial lung cells, which line the lung surfaces. These cells are implicated in cystic fibrosis, as well as other lung diseases such as respiratory distress syndrome, which is caused by a deficiency in surfactant protein. In her new lab at Imperial College London, Patel plans to further investigate mRNA-based therapeutics.

In this study, the researchers also demonstrated that the nanoparticles could be freeze-dried into a powder, suggesting that it may be possible to deliver them via an inhaler instead of nebulizer, which could make the medication more convenient for patients.

TranslateBio, a company developing mRNA therapeutics, partially funded this study and has also begun testing an inhalable form of mRNA in a Phase 1/2 clinical trial in patients with cystic fibrosis. Other sources of funding for this study include the United Kingdom Engineering and Physical Sciences Research Council and the Koch Institute Support (core) Grant from the National Cancer Institute.

Juggling Responsibilities and Compliance – Guest blog by LMK Scholarship Winner

By: Mike Miccioli

I went to high school in Nashville, Tennessee and am currently a freshman at Harvard. Growing up in Nashville, I always focused on academics and staying healthy. On the academic side, I have always had an interest in mathematics, and physics is a fascinating way to apply math to science and the universe. I took all the toughest courses in math and science, and I competed in every math competition and Science Olympiad contest available. I did applied mathematics research at Vanderbilt University the summer after my junior year of high school, and different research during my senior year in condensed matter physics. On top of this hefty workload, my school required all its students to play sports after school year-round. With all of these obligations and many hours of homework each night after sports, working in my CF therapies was not easy; however, from an early age I learned the lesson that I had to prioritize my CF therapies that were necessary to keep me healthy and enable me to pursue my academics and sports. I had to be disciplined, and I got up early each day before school to make sure I did all my vests and nebulizers in the morning. There was a second round each evening, and I would always try to combine homework with both the morning and evening sessions. If a special circumstance would throw my schedule off and interfere with my therapies, I always made them up at different times during the same day; it was a given that I couldn’t miss therapies.

Compliance with the therapies that are available to us nowadays is crucial to having a good outcome with CF. There is generally a vast difference between the outcomes of patients who do their best to comply with their therapies every day and those who have a hard time completing theirs on a regular basis. I have always stayed aware of this fact and used it to motivate me to be compliant, and I believe it has paid off.

This fall I made the transition to my first semester in college, 1200 miles away from home and my support network. The first adjustment was being responsible for remembering to do everything without prompting from my parents. That wasn’t too difficult, and a bigger challenge was learning how to be more flexible in how I achieved my full compliance despite the fact that my schedule was different every day. Reflecting back on my years prior to college, my schedule was the same nearly every day, and this helped me stay disciplined in keeping up with my therapies. In college, I have had to look at each day and determine when I am going to fit in my routine as I meet all my academic obligations. Having completed my first semester, while it was frustrating at first, I eventually fell into a rhythm — from having nighttime labs one day to having an overloaded afternoon the next, eventually I encountered all the different scenarios I would be faced with, and it became easier to deal with each day’s changes.

I am continuing my studies of math and physics at Harvard and am currently in the process of applying for research opportunities for this summer. At this point, I am thinking that I want to pursue a career in scientific research. I guess one of the main reasons I feel this way is because I have personally benefited from modern advancements in medicine. I currently take one of the CFTR modulator drugs and have had good results with it, and it reminds me every day of how people can benefit from cutting edge research and have their lives changed in meaningful ways. I hope to be able to contribute back to the scientific community and perhaps some day make a difference for others.

This also relates back to the point I was making before about working hard to be as compliant as possible with your CF therapies. CF research has made amazing strides, and it appears that significantly improved CFTR modulators will be available to as many as 90% of those of us with CF sometime in 2019. The healthier we are when these new therapies become available, the better positioned we will be to take advantage of their benefits to the maximum degree possible. That is the other big reason to try and stay compliant. So, in conclusion, I want to encourage everyone to remember that while it is difficult to make compliance a priority day after day, without a break, particularly when you are in college with new vistas to explore and great demands for your time, it is worth it, and you will reap the benefits in the short run and even more so down the road when new therapies become available.

Aridis Enrolling CF Patients to Test AR-501 in Chronic Lung Infections

By:
ALICE MELÃO

Aridis Pharmaceuticals has enrolled the first healthy participant in its Phase 1/2a clinical trial to evaluate the antibacterial potential of its investigational candidate, AR-501 (gallium citrate), against chronic lung infections in patients with cystic fibrosis (CF).

The study (NCT03669614) is expected to enroll approximately 48 healthy adult volunteers and 48 adult CF patients with chronic lung infections across 15 sites in the United States.

Participants will be randomized to receive one of three doses of AR-501, or a placebo, self-administered once a week using a hand-held nebulizer.

The company expects to announce results from Phase 1 during the fourth quarter of 2019, and from Phase 2a in the fourth quarter of 2020.

“We are pleased to initiate this exciting program with the first subject enrolled,” Wolfgang Dummer, MD, PhD, chief medical officer of Aridis, said in a press release. “Through this trial, we anticipate safety, pharmacokinetic, and exploratory efficacy data that will enable us to further explore the potential of AR-501 in the treatment of life-threatening bacterial infections in cystic fibrosis patients.”

AR-501 is an inhalable formulation of gallium being developed to treat pulmonary bacterial infections. It works by starving bacteria of iron, and inhibiting their iron-dependent metabolic processes necessary for the infection to progress, a mechanism very different from that of common antibiotics.

Preclinical studies have demonstrated that AR-501 holds a broad antibacterial activity with unique benefits, compared to current standard-of-care antibiotics, working against antibiotic-resistant strains such as Pseudomonas aeruginosa and B. cepaciaaccording to the company.

Also, data from a Phase 2 clinical trial (NCT02354859) showed that intravenous gallium is safe and can effectively improve the lung function of CF patients.

“The recent safety and efficacy demonstration of intravenous gallium from a Phase 2 clinical study in CF patients gives us optimism of the prospect inhaled delivery of gallium (AR-501), which is a more direct, local route of delivery to the site of infection in the lungs and less systemic exposure,” Dummer said.

The new Phase 1/2a trial is being conducted in collaboration with the Cystic Fibrosis Foundation (CFF), and is led by Noah Lechtzin, MD, director of the Adult Cystic Fibrosis Program and associate professor of medicine at Johns Hopkins University.

The U.S. Food and Drug Administration recently granted Fast Track Designation and Qualified Infectious Disease Product Designation (QIDP) to AR-501. These are expected to support and expedite the therapy’s development and regulatory review.

Original article: https://cysticfibrosisnewstoday.com/2018/12/14/aridis-started-enrolling-in-phase-1-2a-trial-to-test-ar-501-antibacterial-potential/

Catastrophizing and Cystic Fibrosis: Fear of Breathlessness Impacts Quality of Life

By Carisa D. Brewster

A new study has found an association between the cognitive process of breathlessness catastrophizing (BC) and poor health-related quality of life (HRQoL) in patients with cystic fibrosis.

Breathlessness is common in patients with cystic fibrosis and does impact HRQoL, even when pulmonary function is in normal ranges. Catastrophizing is a cognitive distortion where irrational thought patterns dominate, and the worst outcome is expected regarding a real or anticipated issue.

Advances in treatment have increased life expectancy for people with cystic fibrosis, but there remains a need to better examine and understand the psychological issues related to quality of life, according to researchers of this study.

“Following in the footsteps of other researchers who have begun to examine breathlessness catastrophizing in respiratory populations, such as those with COPD, we were curious to examine breathlessness catastrophizing among adults living with cystic fibrosis and how it relates to quality of life,” Danijela Maras, MA, lead researcher and doctoral student in clinical psychology at the University of Ottawa, told MD Magazine®.

Participants were recruited from a small observational cohort within the pilot project, “The Ottawa Cystic Fibrosis Treatment Knowledge and Adherence Program”, from May 2011 to June 2013. Patients were excluded if they had received a lung transplant or had an expected survival of less than one year. Final sample size was 45 adults.

The following was assessed for all participants: lung function (FEV1%), depression (Center for Epidemiological Studies Depression Scale), anxiety (7-item Generalized Anxiety Disorder scale), pain (Cystic Fibrosis Symptom Scale, developed by researchers this for study), BC (Breathlessness Catastrophizing Scale, adapted from the Pain Catastrophizing Scale), and HRQoL (Cystic Fibrosis Quality of Life questionnaire).

After controlling for lung function, depression, anxiety, and pain, there was a significant correlation between breathlessness catastrophizing and poor HRQoL (P <.05). In addition, 40% had clinical depression and 13.3% had moderate levels of anxiety.

While results are preliminary and warrant further exploration, Maras said this highlights the importance of assessing and treating mental health difficulties in individuals with cystic fibrosis.

“For example, breathlessness catastrophizing could be targeted in psychological interventions to improve mental health, quality of life, and/or treatment,” she said. “Findings are also relevant for other populations that experience breathlessness, such as those with asthma and other respiratory diseases, neuromuscular conditions, and cancer.”

Maras said that further research should center on longitudinal designs to examine breathlessness catastrophizing in larger and more diverse populations and explore how it plays a role in treatment uptake and adherence.

The study, “Breathlessness catastrophizing relates to poorer quality of life in adults with cystic fibrosis”, was published in the Journal of Cystic Fibrosis.

Click here for original article.

CFReSHC meeting on Aging, Menopause and CF

What is menopause? I’m 30 years old and have heard it groused about for years, but I really don’t know what it is. I have heard from older women with CF that maybe it starts earlier in CF women and that the experience could be different from the non-CF population. I know it has something to do with hormonal changes, more estrogen, maybe? But I have no idea how it will impact my health in the future or what signs and symptoms I should be on the lookout for. On this one, I will follow the girl scouts’ mantra “always be prepared.”

Luckily, CFReSHC is hosting their next Patient Task Force meeting about the menopause experience. It is a great opportunity for any adult woman with CF to learn about what to expect in a few years’ time or to share your wisdom and questions if you’re experiencing or have experienced it.

The meeting will be December 10th from 2-4pm EST.  Laura Mentch, Health Educator, will be sharing her knowledge on the subject.

Please email info@CFReSHC.org, or follow us on facebook for more information.

As Both Patient and Scientist, I’m Putting Nature’s Medicine to the Test

By Ella Balasa

I peered into one of the incubators that stored my petri dishes for 24 hours, anxious to see whether I would discover discoloration and unevenness on the surface, which would have indicated that my experiment produced favorable results. I wanted to see a visual representation of whether manuka honey kills the stubborn Pseudomonas bacterium, which dwells in nearly half of the lungs affected by CF.

I’m a microbiology lab scientist, plus an inquisitive writer. I also consider myself an informed, self-advocating realist. Life experiences have taught me that I am solely responsible for my health. I strive to keep my health stable through prescribed medications, healthy diet, and some natural supplements.

During my college years, I focused on the environment, especially the living parts that we can’t see but that are essential to the cycle of life — bacteria. It just so happens that certain ones are, understatedly, little pests for people with CF. The lung bacteria of people with CF birth many symptoms and infections.

I continually fight Pseudomonas aeruginosa, my nemesis bacterium that spikes fevers within days of overwhelming my immune system and that has caused countless infections, leaving my lungs with pockets of dead tissue. I take antibiotics frequently, but I also believe that naturally derived compounds can have positive effects. So, despite my disdain and nausea, I sometimes supplement garlic, which contains the antibacterial compound ajoene. I’ve also consumed manuka honey; this I’ve done more religiously, as it tastes more like candy than any “medication.” Manuka honey contains the natural antibiotic methylglyoxal, a compound that fights relentless Pseudomonas by causing its cells to burst and die. I took a spoonful a day for a few years until recently. Maybe I stuck to this exorbitantly priced, palatable remedy merely because of its taste and the flawed logic that expensiveness is indicative of effectivity.

I had the idea to test the effectiveness of the honey on my sputum. My mucus grows many species of bacteria, but Pseudomonas is a primary component, so it’s easy to propagate in the lab setting.

Yes, I took a sputum cup of mucus into work. When inoculating the vials with the bacteria, I was slightly anxious that my lab mates might freak out at the sight of the hazardous and vile-looking green blobs. Then again, they work with wastewater from treatment plants, so it really shouldn’t phase them.

I tested a concentration of 15 percent weight per volume of manuka honey, a choice informed by published studies. I tested half of the petri dishes with honey mixed into the nutrients for the bacteria and the other half without the honey. The dishes with the honey should have less bacterial growth if the treatment works. (If you want more detail on the process, drop a comment below this column.)

The yellow dish has the honey added and the white dish doesn’t. (Photo by Ella Balasa)

After the 24-hour incubation period, I was excited to see the results of science that we as patients typically do not participate in. We provide our sputum samples during doctor’s appointments, then labs perform antibiotic resistance tests, and results are returned as values on a piece of paper indicating resistance or susceptibility. We don’t see the process. I was doing this same research on my own, and in a sense, taking the utmost control of my health.

To continue reading, click here.

Antibiotic plus probiotic combination may kill off superbugs

By 

Every year, over 2 million people in the United States develop infections that are resistant to treatment, and approximately 23,000 people die as a result.

These statistics have prompted the Centers for Disease Control and Prevention (CDC) to deem drug resistance “one of the biggest public health challenges of our time.”

Therefore, researchers are hard at work trying to develop ingenious ways of tackling so-called superbugs — bacteria that have become immune to antibiotic treatment.

Lately, researchers have added probiotics to their arsenal against superbugs. Probiotics are beneficial bacteria found in foods, such as yogurt, kefir, pickles, or miso soup.

Only a month ago, for example, a study suggested that simply consuming probiotics on a regular basis could reduce the need for antibiotics, thus helping to curb the drug resistance crisis. Continue reading Antibiotic plus probiotic combination may kill off superbugs

Have you talked to your CF Team about your sexual and reproductive health?

By: Georgia Brown

I often say that there is no modesty in medicine.  I mean, we routinely talk with medical professionals who are used to gross anatomy.  But I realized I was wrong when I broached sexual and reproductive health (SRH) issues with my CF physician.

After I attended the CFF MiniCon on SRH, I was so energized by the honest discussions that I had handwritten notes to share at clinic the next day.  After giving an overview of the event, I listed items clinics should be talking about and offered my notes for use as a reference. Continue reading Have you talked to your CF Team about your sexual and reproductive health?

Be Involved in a Meeting with FDA on CF!

On October 29th, individuals with cystic fibrosis and their families will have a unique and pivotal opportunity to share their experiences with representatives of the FDA during a live-streamed interactive meeting.

CFRI is very honored to host an Externally-Led Patient-Focused Drug Development Meeting on Cystic Fibrosis with the FDA on Monday, October 29th. This is an amazing and singular opportunity to share the patient experience with FDA representatives. They want and need to know the impacts and burden of the disease, your hopes for new therapies, and what you are willing to go through to find these new drugs.

PLEASE register to participate in this free live-streamed meeting! We need your input and participation You will have the opportunity to participate in live polling, and to email and call in to share your experiences. Those who do not have CF/a family member with CF should also feel free to join us.

You can register and log in for any or all of the day’s presentations and discussions. The day begins at 9:45 am. Please note: all times listed are East Coast time, as the meeting will be held at the College Park Marriott Hotel and Conference Center in Hyattsville, Maryland.

Here is the link:  http://cfri.org/advocacy/advocacy-events/

Speakers/Panelists
Jen Caruso
Lise-Courtney D’Amico
Boomer Esiason
Gunnar Esiason
Joseph Klausing, JD
Emily Kramer-Golinkoff
Robert Lim, MD
Jane Mitchell
Anna Payne
Kat Quinn Porco, MS
Tejashri Purohit-Sheth, MD
Arek Puzia, CPA, MBA
Emily Schaller
Isa Stenzel Byrnes, LCSW, MPH
Ahmet Uluer, DO, MPH
James Valentine, JD, MHS

Thank you for having an impact upon those who are assessing the safety and efficacy of new CF therapies, and making recommendations for their movement to market. 

Your voices matter!