Day 1, Session 1 - Replace instead of repair – novel therapeutics for all CF patients
Professor Martin Gosling PhD, Chief Scientific Officer, Enterprise Therapeutics
Q. If these TMEM16a channels are also available in other organs such as the pancreas would you predict a possible improvement in pancreatic function too?
Martin: As TMEM16A allows the flow of anions such as bicarbonate, which are very important for pancreatic function, it is feasible (although far from proven) that TMEM16A potentiation could improve pancreatic function - the function of TMEM16A in a number of organs is not yet clear. Enterprise’s lead TMEM16A potentiator is designed for inhalation delivery so unfortunately will not provide an answer in the short term as it has very low systemic exposure (low levels in the blood).
Q. What is the level of activation of TMEM16A in people with CF? If it’s maximally activated already, how will your drugs help?
Martin: Great question and one which we don’t yet know the exact answer. Airway electrophysiology studies in people with CF have shown a potential difference change in response to a calcium elevating agent (ATP/UTP) suggesting the channel is not maximally activated. The ion transport (Using chamber data) we have generated with cells from people with CF in vitro suggest that:
- even when the channel is activated by a maximal concentration of UTP we can increase that maximum current level (and hence amount of chloride transported) with a potentiator.
- the effects of UTP are transient – our potentiators not only sensitise the channel to activation at lower concentrations of UTP they also keep the channel open longer.
Q. TMEM16 activation has also been shown to induce mucus secretion and bronchoconstriction. Wouldn’t this be prejudicial for people with Cystic Fibrosis?
Martin: If TMEM16A activation does induce mucus secretion and bronchoconstriction it would indeed be prejudicial for people with CF. However, the data supporting this premise has been generated with studies using either genetic knockdown strategies in rodents or low potency, poorly selective inhibitors and then making the leap that activation will deliver the opposing phenotype. We have performed multiple in vitro and in vivo studies and do not see evidence of our TMEM16A potentiators inducing either mucus secretion or bronchoconstriction.
Q. Could your drug work in theory for any lung disease with ‘thicky’ sputum?
Martin: As TMEM16A potentiation is a CFTR mutation agnostic approach it should work for all with CF and in other non-CF muco-obstructive diseases.
Q. Why did you choose to use F508del/class1 instead of all the classes of CF mutation?
Martin: Although we believe that TMEM16A potentiation has the potential to deliver clinical benefit for all with CF our early clinical emphasis is on individuals that do not have any effective treatment at present ie. those with class I CFTR mutations. Once we can demonstrate clinical benefit in these individuals we aim to expand our studies to assess the effects of TMEM16A potentiation in all with CF as both a mono-therapy and in combination with CFTR repair.
Q. What does shear stress mean?
Martin: Shear stress in this context is the frictional force experienced by the lung epithelium as fluid passes over it. Our lungs experience stretching and compressive forces, in addition to shear stress, with every breathing cycle. Shear stress causes the epithelial cells lining the airways to release nucleotides such as ATP and UTP which via receptors on the surface of the epithelium stimulate the activity of both TMEM16A and CFTR.
Day 1, Session 3, Talk 1 - Advances in video imaging of cilia motility with applications in CF
Professor Pietro Cicuta, University of Cambridge
Q. What is the stimulus for the ciliary wave? Is it the weight of the mucus or thickness? What's the neuro-physiological pathway for it?
Professor Cicuta: A ciliated cell in the airways can have up to hundreds of cilia, and perhaps half the cells in the epithelium of the airways are ciliated. From our work, and others, it seems that (1) each cilium has the property of beating, at approximately 15 times a second; (2) cilia push the fluid surrounding them, and this acts as a force on the other cilia. In the right conditions (a good cilia beating, cilia not too sparse, and viscosity of the liquid in the right range) the cilia will beat cooperatively forming the traveling wave, which is essential for mucociliary clearance.
Day 1, Session 3, Talk 3 - Why does Pseudomonas like the CF lung?
Dr Martin Welch, University of Cambridge
Q. With new CFTR modulators is it possible that Pseudomonas will not love the new modulator treated CF lung so much?
Dr Welch: Current evidence suggests that although P. aeruginosa titres decline in the first few months after treatment with modulators begins, they bounce back after a year or so. One of the many reasons that this SRC was funded is that P. aeruginosa infections are unfortunately a problem that is likely to be with us for some time to come.
Q. When looking at Pseudomonas how will you account for the poly-microbial nature of infections within the lung and the role these organisms may play.
Dr Welch: With the support of the CF Trust (via a “VIA” award) and the British Lung Foundation, we are working with the National Centre for Refinement, Reduction and Replacement of animals in research (the “NC3Rs”) to introduce a system that allows us to cultivate most (if not all, with luck) of the polymicrobial “zoo” found in the airways of many pwCF. Current data indicate that the system works well (using sputum as an input and 16S rDNA analysis to monitor the bacterial species – and their titres - present). This system offers us the possibility of recapitulating in vitro, in an experimentally-perturbable system, the CF airway microbiome. I won’t go into details of how we do this (a paper has been submitted on the model and will hopefully be out soon, as long as the referees don’t reject it, which is unlikely) but just to give you a taster of what we’ve found, we know that numerically minor species (present at just 0.1% of the numbers of the P. aeruginosa present) have a major impact on the behaviour of the latter. More on this as the project develops……
Q. Does Pseudomonas behaviour change from life in the airway to life in sputum samples and to life in the lab? If so, is what you’re studying relevant?
Dr Welch: Yes, we use a variant of artificial sputum medium developed over many years by the Whiteley lab. It’s hard to make and expensive, but it has been demonstrated to almost exactly reproduce the transcriptional profile of P. aeruginosa in situ in the CF airways. Most of the consortium members are also focusing on the growth of CF-derived isolates in this medium. The question of whether CF sputum is a suitable reflection (per se) of the physiological environment in the airways themselves has been a long-running issue in the field. As outlined in a response to another question (which I assume will appear near this response on the posting-board), with the assistance of the Trust, we now know that we can stably cultivate most of the species present in the CF airway microbiome in vitro, so our view is that the current experimental setup, while not a perfect mimic of the airway environment, is close enough to begin addressing some key questions.
Q. What about other possible external factors beyond its intake, metabolism and behaviour, for example the scarring in the airways of a CF sufferer?
Dr Welch: Yes, this is a good question which, due to time issues, I was not really able to adequately address in the meeting the other week. The exposure of basement collagen during scarring, and the altered surfaces of CF airway epithelia, are, among other issues, known to promote colonisation of the airways. However, this initial colonisation is separate from the longer-term engagement of the organism with the airways (i.e., going from colonisation to “infection”). I didn’t have time to go into the details in the talk, but there are now several lines of evidence which show that CF isolates undergo genetic and phenotypic adaptation to “focus” their metabolism in the airways. Although there are without doubt other contributory factors as to why P. aeruginosa likes the airways, the balance of evidence *to date* indicates that metabolism and nutrition are key issues to address.
Day 2, Session 1 - UKCFC day one recap
Cystic Fibrosis Trust research team
Q. Do you have any plans in place in the event of a no deal brexit to ensure research and medical developments are not interrupted?
The Trust is in contact with MPs and other stakeholders to ensure we stay abreast of any potential risks that a no deal Brexit could present. We are also a member of multiple groups who monitor the political climate and report any potential affects to us directly.
We fund multiple research centres that form international collaborations and attract the best and brightest wherever they live in the world, and we will continue to collaborate internationally, including with the European Cystic Fibrosis Society and its CF registry regardless of a no deal Brexit.
Q. How does your approach evolve with medical advances? In the 80s people were preparing for a more limited life than now. What if the next generation are living a life unlimited?
The Trust maintains close contact with CF clinicians across the UK, and we also have close ties with the UK CF Medical Association. This allows us to develop standards of care that evolve with healthcare advances and to continue to produce guidelines and information packs for the public that cover a broad range of topics.
The UK CF Registry helps us to keep track of changes in the condition and to anticipate new ones so that we can ensure provision of care is as agile as it needs to be.
The Trust’s research strategy 2018 – 2023 is a forward-looking strategy that aims to address the challenges that remain in CF, including growing older with CF.
Q. When the Trust supports the development of treatments do you make affordable availability a condition of funding?
Till now, the Trust has only supported basic research, ie research that builds the background for developing treatments. Although we would love to be able to fund clinical trials and dictate terms of funding, it costs about $3 billion to bring a drug to market, and we are only a small medical research charity and our contributions are to fund the background work and help to keep researchers interested in CF.
Day 1, Session 2 - The challenges and opportunities of getting older with CF
A virtual conversation between two people with CF
Q. Do you have moments of feeling isolated due to not being able to meet with others with CF and friends perhaps not understanding the challenges of life with CF?
Lauren: I don’t feel that way too often as this is the way it has always been for me growing up. However when I am ill or feeling frustrated, I can feel a little isolated. When I speak to friends about my experiences and some thoughts and feelings, they often don’t know what to say because it is quite a unique experience and many of them cannot relate to it.
Day 2, Session 4 - Packing a punch, the importance of impact
Cystic Fibrosis Trust
Q. What other videos/resources are you planning?
These are planned or in progress:
- Resources for young people and parents on transitioning to adult care
- A resource on clinical trials aimed at children and teens
- A suite of resources looking at emotional wellbeing and mental health
- A new leaflet showing all of the information resources we have available for people affected by cystic fibrosis
- An updated clinical guidelines on management of diabetes and a new guideline on psychosocial care of people with CF
These will likely be a mix of print and online/videos.