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.

Antibiotic plus probiotic combination may kill off superbugs

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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

For Cystic Fibrosis Lung Infections, How Well Antibiotics Work May be Affected by pH, Oxygen

By Heather Buschman, PhD

People living with cystic fibrosis (CF) spend their entire lives battling chronic lung infections that are notoriously resistant to antibiotic therapy. Yet a one-size-fits all approach to wiping out the offending bacterium may not be the best approach for all patients with the disease, according to a new study by researchers at University of California San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences. Continue reading For Cystic Fibrosis Lung Infections, How Well Antibiotics Work May be Affected by pH, Oxygen

The Cystic Fibrosis Reproductive & Sexual Health Collaborative (CFReSHC) Invitation to Participate

The Cystic Fibrosis Reproductive & Sexual Health Collaborative (CFReSHC) is a patient engagement project that provides women with CF the opportunity to be equal partners with healthcare professionals to shape the future of CF research.  CFReSHC offers women with CF the opportunity to participate on the Governance Board, Research Advisory Panel and Patient Task Force as Patient Partners to develop research projects that directly respond to the questions faced by women with CF.  CFReSHC holds monthly virtual meetings on topics that impact the lives of women with CF like contraception, family building, hormone influences on CF, incontinence and menopause.  As we enter our third year, CFReSHC is looking for women with CF who are passionate about sexual and reproductive health research to join our collaborative who can commit 4-6 hours a month and we provide  a small honorarium for your time commitment.

CFReSCH is looking for a:

  Social Media Strategist who has connections in the CF community or who is willing to engage with the CF community on our behalf.  CFReSHC currently has a social media presence on Facebook, Twitter and Instagram and the applicant would need to be able to post 2-3 times per week as well as check the platforms regularly and make responses as needed.  The applicant would need to attend 3 paid monthly meetings often held during work hours.

Grant writer and Coordinator who has connections in the CF community or is willing to connect with the CF community and engage it to seek out funding opportunities for potential grants.  The applicant would need to maintain a database of potential grant opportunities.  An applicant who has experience writing applications is preferred.  The applicant would need to attend 3 paid monthly meetings often held during work hours.

Women with CF are welcome to send a letter of interest to: cfreprohealth@gmail.com.  Together, we will respond to the health needs of the CF community by providing data for healthcare professionals to pave the way for improved sexual and reproductive health resources, healthcare, and knowledge.

I’m Drowning – A researcher-patient’s plea for broader inclusion in cystic fibrosis trials

By: Ella Balasa

I’ve always known cystic fibrosis (CF) is a progressive disease; it destroys lung cells, tightens the small airways in the bottom of my chest, and each day takes me closer to the time when it will have ravaged my lungs. I had never really questioned if there was some way this process could be altered. I accepted that it couldn’t.

Recently, however, this has changed. The epicenter of new CF research is the development of medications that will slow, stop, and hopefully even reverse the effects and damage that CF inflicts on the body. The possibility of the cells in my lungs functioning to their full potential — with CF transmembrane conductance regulator protein function restored and working correctly, expelling chloride out of my cells, hydrating the surface of my lungs, and halting the thick sticky mucus that has caused my airways to be enveloped in a suffocating cloak for all these years — is like a feeling of being rescued when you are drowning.

Unfortunately, I am still drowning.

“I’m very sorry, Ms. Balasa, but you will not be able to be a participant in this clinical trial.” This was the response I received during one of my searches for these drug trials. Excited by the possibility of participating, finding one recruiting at my local adult clinic, I reached out to study coordinators and was informed that I met all but one criterion to participate in the studies. This specific criterion has prevented me from prior trial participation involving other investigational medications treating the symptoms of CF, including anti-infectives and anti-inflammatories.

Most CF studies, including phase I, II, and III trials, require a lung function minimum of at least 40% FEV1 (forced expiratory volume in one second). My FEV1 is 25%, so I am excluded from these trials. Many patients face a similar situation. The 40% threshold biases samples toward a young patient population, as this degenerative condition causes steadily decreasing lung function with time. Furthermore, as CF treatment has rapidly progressed and increased patients’ life expectancies, there are now more adults with CF in the U.S. than children, according to the CF Foundation Patient Registry.

As a patient who works in the science field, I started to ask myself: Where does that number come from? Should this one variable be such a deciding factor? Are we getting comprehensive results from these studies if a subset of patients is omitted? Are investigators using eligibility criteria from a prior study without determining whether the exclusions are scientifically justifiable?

To continue reading, please visit MedPage Today.

Monitoring Pulmonary Exacerbation in Cystic Fibrosis: The Hunt for Urine-based Biomarkers Begins

By Michele Wilson PhD

The buildup of mucus in the lungs is an ongoing challenge faced by people with cystic fibrosis, and knowing whether they should seek medical attention is not always clear.

Recently, Mologic – a developer of personalized diagnostics – have developed a tool which they hope will help guide people with cystic fibrosis so they can avoid unnecessary stays in hospital.

The app-embedded algorithm converts data collected from a urinary test to a traffic light result, which indicates whether a patient is stable or in need of medical intervention.

Recently, Mologic, announced that they are launching a clinical trial to assess the company’s urine-based diagnostic tool, ‘HeadsUp’.

To learn more about how this point-of-care diagnostic tool could help improve healthcare for people with cystic fibrosis, we spoke with Gita Parekh, Head of R&D at Mologic.

How do you define pulmonary exacerbation, and why is it important that it is monitored in people with cystic fibrosis? Continue reading Monitoring Pulmonary Exacerbation in Cystic Fibrosis: The Hunt for Urine-based Biomarkers Begins

The open door policy – An important and under-recognized activity of the adult CF center

By Anna Sze Tai and Sue Morey

Improvement in survival in cystic fibrosis (CF) has led to a substantial increase in numbers of the adults with CF past few decades [12]. In many parts of the world, the number of adults now exceeds the numbers of children with CF [12]. Adults with CF face the daily challenge in balancing education, work and family commitments with their disease management. Patients often need to contact the Adult CF specialist team for advice on disease management and coordination of care around their work and family time-table. Current ECFS guideline recommends patients have ready access to the CF center for telephone advice for emergency management or consultation [34]. The ‘open-door’ policy of adult CF centers is an important component of ambulatory care in adults with CF, ensuring a timely and expert-level response to patient queries. Management of unscheduled patient-initiated contacts is an important and often under-recognized function of the adult CF team. There is a paucity of data on the nature and frequency of these unscheduled contacts and their potential impact (and demands) on the organization of the CF team.

In this issue of the Journal of Cystic Fibrosis, Burnet et al. reported the results of a two-staged prospective study of unplanned patient-initiated contacts in a single adult CF center (n = 410 patients) [5]. During the first stage, all patient-initiated contacts were prospectively recorded over a four-month period. Four physicians and three nurses prospectively documented how and why patients contacted the team and the time spent responding to these requests. During the second stage, contacts generated from a subset of 212 patients were prospectively recorded to explore the association between contact frequency and disease severity.

During the first stage, 259/410 (65%) patients initiated 1067 contacts over 4 months, averaging 13.3 contacts per day. Average time spent addressing patient contacts by all participants combined was 8 h and 7 min per work week. This was likely an underestimate given not all team members (e.g. allied health specialists) who might be contacted by patients participated, and data collection was limited to working hours during weekdays. Nevertheless, the result confirmed that managing unscheduled contacts added a significant workload to the CF team. Factors associated with greater contacts (≥5 contacts/year) included female sex and greater disease severity, reflected in severe airflow obstruction (FEV1 ≤ 30% predicted), ≥ 5 physician visits/year and ≥ 1 hospital admission/year.

The frequency of unscheduled contact in adults with CF was markedly higher than that observed amongst high-risk COPD patients, reflecting the greater healthcare demand of adults with CF [6]. Interestingly, only <20% of requests were related to medical issues (e.g. exacerbations), whereas the bulk of requests were related to daily management issues (e.g. script renewal), intravenous antibiotic requests, administrative queries and non-urgent miscellaneous matters. This perhaps reflects that the adult CF center has generally provided comprehensive, primary up to expert-level tertiary care to their adults with CF. The adult CF center can be viewed by the patient as ‘the one-stop shop’ for both their CF and non-CF related healthcare needs. Patients may not be aware of the need for a family physician for their non-CF related healthcare needs, including travel vaccinations, women health issues, age-specific screening (e.g. mammograms, monitoring for hypertension).

This is the first study which demonstrates the significant burden of unplanned contacts on the organization of the adult CF centre. The strength of the study is the prospective design which enables differentiation between planned and unplanned contacts. There was a comprehensive recording of response time in the clear majority of patient contacts (>95%) by the team members as they carry out their day-to-day services within a large CF centre which is an impressive undertaking. The key limitation is the single centre nature of the study which limits its comparability to other centres in other health settings internationally. Nevertheless, Burnet et al. has clearly revealed the burden of unscheduled contacts and highlighted the need for more efficient management strategies. Firstly, development of an effective centralised triaging system (e.g. collective ‘CF Team’ email inbox and phone line) managed by experienced CF staff who prioritise and streamline all incoming requests to appropriate team members can maximize efficiency of the CF team. Secondly, involvement of administrative staff to assist with relevant non-medical requests (e.g. clinic rescheduling, etc) will lighten the burden on the clinical team. Thirdly, ultilisation of new telecommunication and health informatics technologies can potentially improve communication and data transparency. Telehealth technologies (e.g. Smartphone apps, Skype or WhatsApp) have already shown significant promise in improving patient access to care and early treatment in CF, particularly in setting where distance from centre to the patients is considerable and pop-in clinics are likely to be impractical [[7][8][9]]. Some of these telehealth technologies can potentially serve as communication platforms to provide education resources on commonly-asked questions.

To continue reading please visit: https://www.sciencedirect.com/science/article/pii/S1569199318306982

Patient-reported outcomes: Time for a new approach?

By Janice Abbott

Patient-reported outcome (PRO) measurement (e.g. health-related quality of life questionnaires, symptom diaries) can provide a standardized, valid and reliable way of gaining the patients’ perspective on ‘how they are’ or the benefits and limitations of a specific intervention. The insights that patients have concerning their health are important given that aspects of patient-reported quality of life are independent predictors of survival in cystic fibrosis (CF) [1]. Regulatory authorities require the inclusion of PROs in clinical trials as an additional outcome parameter and PRO information is becoming important in labelling claims. It is noteworthy that the top 10 research questions, reached by global consensus of patient and healthcare providers, all require the inclusion of CF-specific PROs to achieve meaningful answers [2]. This represents a significant paradigm shift but capturing data that matters to patients, families and clinicians is challenging. Two of the persistent challenges in CF PRO measurement are a) the development and use of technologies to enable efficient administration, accurate scoring, and the correct interpretation of data and b) being able to accurately measure PROs (or parental proxy assessment) across the entire CF lifespan. These important issues are considered by two papers in this issue of the Journal of Cystic Fibrosis [34].

PRO measurement largely remains a research endeavour with little uptake in clinical practice. Administering, scoring and interpreting PROs in a busy clinic is difficult. It requires staff time and expertise and the results are not instantly accessible to steer a discussion with the patient or to aid clinical decision making. Paper-based data collection suffers from missing, unreadable data that is prone to scoring/mathematical error. The development of electronic PRO (ePRO) technologies is immensely important in clinical practice and for endpoint assessment in clinical trials. It is a cost-saving, patient-friendly approach to PRO assessment: data collection can occur in clinic, the patient’s home, workplace or school. Results can be added to a patient’s electronic medical file, alerts triggered by problematic scores and clinicians can track patient/parent-reported symptom/event data over time. Importantly, electronic data capture enhances the integrity and accuracy of the data, makes it logistically easier to collect repeated assessments (daily or at several points over a trial), and is preferred over paper-based data collection by the US Food and Drug Administration (FDA).

There is growing evidence that paper and electronic versions of PROs typically provide comparable data but this requires psychometric evaluation if transferring an original paper-based questionnaire to an electronic mode of administration. Solé and colleagues have demonstrated measurement equivalence with paper and electronic administrations of the Cystic Fibrosis Questionnaire-Revised (CFQ-R teen/adult version) [3]. The e-CFQ-R web version is linked to an online database that can be adapted for any electronic devise (smartphone, tablet, computer). Immediately the patient completes the questionnaire, results are sent to the healthcare team and the data are saved in a centralized, protected database. Real-time patient-reported data are available to the clinician as an adjunct to clinical data. Access to the English and Spanish versions are by independent web addresses provided in the paper. Ultimately, the integration of PRO data within electronic care records as developed by Peckham et al. [5], or in CF patient registries would enable efficient patient care and longitudinal research endeavours.

There is a lack of PROs that can be used as endpoints in early intervention studies in CF. Such instruments are time-consuming and painstakingly difficult to develop so the research of Edwards et al. reporting on the initial development of a CF-specific, parent-reported instrument for children 0–11 years is welcome [4]. The need for an effective way of data collection is also considered. The instrument takes the form of an electronic (web-based data capture), observational sign/symptom diary containing 17 respiratory and activity signs that parents report the presence or absence of. Results suggest that children aged 7 to 11 years are best reporting for themselves, therefore observational reporting by parents should focus on young children aged 0 to 6 years. Considerable evaluation has yet to determine the final instrument but the development of the scale follows FDA guidance enabling its acceptance as a clinical trial endpoint in infants and young children with CF.

Over the last twenty years we have learned a great deal about measuring patient-reported outcomes in CF, and there are many pitfalls when employing PROs in CF trials [6]. They are typically secondary endpoints and the trial is not powered on them, often making it difficult to draw valid inferences about treatments. However, there are trials that have collected patient-reported respiratory symptom data as the primary endpoint [78], employing the only CFQ-R subscale that has been approved by the FDA for use as an endpoint. Scientific, regulatory and pragmatic factors are driving the shift towards ePRO data collection. The development of ePROs is not trivial, yet they are fast becoming the ‘gold standard’ for PRO data capture in clinical trials. The challenge now is to develop CF-specific, lifespan PROs, utilising new technologies that can deliver real-time, high-quality PRO information. They also need to be acceptable to the regulatory bodies to aid their decisions on cost-effectiveness and ensure the appropriate commissioning of new medicines to improve the lives of people with CF and their families.

Original article with references here.

Newfound airway cells may breathe life into tackling cystic fibrosis

By Aimee Cunningham

Meet the ionocyte. This newly discovered cell may be the star of future cystic fibrosis therapies. Researchers have found that the gene tied to the disease is very active in the cells, which line the air passages of the lungs.

While the cells are rare, making up only 1 to 2 percent of cells that line the airways, they seem to play an outsized role in keeping lungs clear. The identification of the ionocyte “provides key information for targeting treatments,” says medical geneticist Garry Cutting of Johns Hopkins School of Medicine in Baltimore, who was not involved in the research. Two teams, working independently, each describe the new cell online August 1 in Nature.

The ionocyte shares its name with similar cells found in fish gills and frog skin. This type of cell regulates fluid movement at surfaces — skin, gills, airways — where air and water meet. In people, special proteins that tunnel across cell membranes lining the airways allow chloride ions (half of what makes salt) to move into the airway. This causes water to move into the airway through a different channel to moisten mucus along the lining, which helps it remove bacteria and inhaled particles from the body.

The tunnel protein that allows chloride ions through is made by a gene called CFTR. In cystic fibrosis patients, that gene is flawed. Airways can’t regulate water movement properly and get clogged with thick mucus that traps bacteria and leads to persistent infections and lung damage. The genetic disease affects at least 70,000 people worldwide, according to the Cystic Fibrosis Foundation in Bethesda, Md.

Researchers had suspected CFTR was most active in ciliated cells — cells with brushlike projections that work along with the mucus in airways to move invaders out. But the new work found very little gene activity in those cells, compared with the ionocytes.

In experiments with laboratory samples of mouse cells from the airway lining, cell biologist Jayaraj Rajagopal of Massachusetts General Hospital in Boston and his colleagues found that the gene was very active in ionocytes: out of all the instructions for building the tunnels detected in the cells, 54 percent came from ionocytes. Aron Jaffe, a respiratory disease researcher at Novartis Institutes for Biomedical Research in Cambridge, Mass., and his colleagues reported that, in laboratory samples of human airways cells, ionocytes were the source of 60 percent of the activity of the tunnels.

The discovery of the new cells raises a lot of questions. Jaffe wonders where ionocytes are positioned in the lining of the airways, and how that placement supports the coordination of water movement and mucus secretion by other cells. “You can imagine the distribution [of ionocytes] is really important,” he says.

A question Rajagopal has: “How does a rare cell type do all of this work?” In fish and frogs, ionocytes are loaded with mitochondria, the so-called cellular energy factories, he notes. Maybe that will be true for human ionocytes, too, giving them lots of energy to do the lion’s share of regulating the movement of water.

Both researchers say the ionocyte’s discovery should lead to a better understanding of cystic fibrosis. “It will let us think about creative new ways to approach the disease,” Rajagopal says.

Original article here.

AIT’s Inhaled Nitric Oxide Shows Potential in Fighting Bacterial Infection Prevalent in CF Patients

By Alice Melao

Inhaled nitric oxide (NO) was shown to be an effective antibacterial agent against Mycobacterium abscessus infection in preclinical studies, as well as in a pilot clinical trial, according to AIT Therapeutics.

The company discussed the latest data on its NO product in two poster presentations during the 3rd Annual World Bronchiectasis Conference held recently at Georgetown University in Washington, D.C.

NO is a small molecule that is an important mediator of immune defense mechanisms against infections. The compound has been shown to have broad-spectrum antibacterial activity against several strains of bacteria that often infect patients with underlying lung diseases, including cystic fibrosis (CF).

Continue reading AIT’s Inhaled Nitric Oxide Shows Potential in Fighting Bacterial Infection Prevalent in CF Patients