History – 2020 (Section 1)
SECTION 1 (FIRST AUTHOR A TO J)
Bose SJ, Krainer G, Ng DRS, Schenkel M, Shishido H, Yoon JS, Haggie PM, Schlierf M, Sheppard DN, Skach WR. Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR. J Cyst Fibros. 2020 Jan 2. pii: S1569-1993(19)30989-0. doi: 10.1016/j.jcf.2019.12.009. [Epub ahead of print] [Pubmed]
The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, they review selectively recent advances in CFTR folding, function and pharmacology. They highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. They discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, they illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators.
The first author of this multinational paper is S J Bose from the School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK
Calthorpe RJ, Smith S, Gathercole K, Smyth AR. Using digital technology for home monitoring, adherence and self-management in cystic fibrosis: a state-of-the-art review.
Thorax. 2020 Jan;75(1):72-77. doi: 10.1136/thoraxjnl-2019-213233. Epub 2019 Oct 8.[Pubmed]
Digital healthcare is a rapidly growing healthcare sector. Its importance has been recognised at both national and international level, with the WHO recently publishing its first global strategy for digital health. The use of digital technology within cystic fibrosis (CF) has also increased. CF is a chronic, life-limiting condition, in which the treatment burden is high and treatment regimens are not static. Digital technologies present an opportunity to support the lives of people with CF. We included 59 articles and protocols in this state-of-the-art review, relating to 48 studies from 1999 until 2019. This provides a comprehensive overview of the expansion and evolution of the use of digital technology. Technology has been used with the aim of increasing accessibility to healthcare, earlier detection of pulmonary exacerbations and objective electronic adherence monitoring. It may also be used to promote adherence and self-management through education, treatment management Apps and social media.
-This is a comprehensive review of the use of technology in various aspects of CF care. The fully referenced Thorax draft of the paper is available on the internet (R J Calthorpe) and is an excellent source of information for anyone looking in depth into this area.
Dr Rebecca J Calthorpe Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK.
Danahay HL, Lilley S, Fox R, Charlton H, Sabater J, Button B, McCarthy C, Collingwood SP, Gosling M. TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis.
Am J Respir Crit Care Med. 2020 Jan 3. doi: 10.1164/rccm.201908-1641OC. [Epub ahead of print] [Pubmed]
Rationale: Enhancing non-CFTR mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis and other muco-obstructive diseases. Objectives: To determine the effects of TMEM16A potentiation upon epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low molecular weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Measurements & Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca2+-activated Cl- channel activity and anion secretion in human bronchial epithelial cells from cystic fibrosis patients without impacting on calcium signalling. ETX001 rapidly increased fluid secretion and airway surface liquid height in cystic fibrosis human bronchial epithelial cells under both static and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with cystic fibrosis and non-CF muco-obstructive diseases. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Dr Henry Danahay is co-founder of Enterprise Therapeutics Ltd, Brighton, head of biology and Hon. Senior Research Fellow University of Sussex
Francis J, Cross D, Schultz A, Armstrong D, Nguyen R, Branch-Smith C. Developing a smartphone application to support social connectedness and wellbeing in young people with cystic fibrosis.
J Cyst Fibros. 2020 Jan 6. pii: S1569-1993(19)30991-9. doi: 10.1016/j.jcf.2019.12.011. [Epub ahead of print] [Pubmed]
Young people with cystic fibrosis (CF) may be at increased risk of social isolation and mental illness. This study aimed to design and evaluate the usability and acceptability of a smartphone application (app) to support the social connectedness and wellbeing of young people living with CF.
Young people with CF aged 12-17 years (N = 22) were recruited from two paediatric hospitals in Australia. Study participants tested the CF app for six weeks before responding to an online survey about the app’s usability and acceptability. A subsample of participants (n = 20) discussed the app’s strengths and weaknesses during 11 online group interviews.
During the six-week testing period, 77% of participants used the app at least once a week and 82% accessed the app from a smartphone. Usability of the CF app was rated high. Most participants agreed the app was easy to use (86%) and felt comfortable using it (96%). Acceptability of the app was moderate. 77% of participants agreed they would recommend the app to others. Recommendations to improve the app’s functionality and acceptability included locating the chatroom within the app rather than redirecting users to a web browser and allowing users to personalise images, wellness tips and videos.
The authors concluded this study tested a highly usable, and moderately acceptable, smartphone app to improve the psychosocial health of young people living with CF. Future research will test the efficacy of the CF app on users’ social connectedness and wellbeing.
Dr Jacinta Francis is at Telethon Kids Institute, The University of Western Australia, Perth, Australia.
Hernandez-Nieto C, Alkon-Meadows T, Lee J, Cacchione T, Iyune-Cojab E, Garza-Galvan M, Luna-Rojas M, Copperman AB, Sandler B. Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population. Prenat Diagn. 2020 Jan 31. doi: 10.1002/pd.5656. [Epub ahead of print] [Pubmed]
Genetic carrier screening has the potential to identify couples at risk of having a child affected with an autosomal recessive or X-linked disorder. However, the current prevalence of carrier status for these conditions in developing countries is not well defined. This study assesses the prevalence of carrier status of selected genetic conditions utilizing an expanded, pan-ethnic genetic carrier screening panel (ECS) in a large population of Mexican patients.
A retrospective chart review of all patients tested with a single ECS panel at an international infertility centre from 2012-2018 were included, the prevalence of positive carrier status in a Mexican population was evaluated.
805 individuals were analysed with ECS testing for 283 genetic conditions. 352 carriers (43.7%) were identified with 503 pathogenic variants in 145 different genes. Seventeen of the 391 participating couples (4.34%) were identified as being at-risk couples. The most prevalent alleles found were associated with alpha-thalassemia, cystic fibrosis, GJB2 non-syndromic hearing loss, biotinidase deficiency, and familial Mediterranean fever.
Based on the prevalence and severity of Mendelian disorders, the authors recommend that couples, who wish to conceive regardless of their ethnicity background, explore carrier screening and genetic counselling prior to reproductive medical treatment.
Dr Carlos Alberto Hernández Nieto is Reproductive Endocrinologist at Reproductive Medicine Associates of New York, New York, United States and Mexico, Mexico City, Mexico
Mithal A, Capilla A, Heinze D, Berical A, Villacorta-Martin C, Vedaie M, Jacob A, Abo K, Szymaniak A, Peasley M, Stuffer A, Mahoney J, Kotton DN, Hawkins F, Mostoslavsky G. Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells.
Nat Commun. 2020 Jan 10;11(1):215. doi: 10.1038/s41467-019-13916-6. [Pubmed]
Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, we report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, we follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or colonic epithelium. We employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modeling and therapeutic screening applications.
Dr A Mithal is at the Center for Regenerative Medicine of Boston University and Boston Medical Center, 670 Albany Street, Boston, MA, 02118, USA.
Munck A, Bourmaud A, Bellon G, Picq P, Farrell PM; DPAM Study Group. Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening.
Pediatr Pulmonol. 2020 Jan 9. doi: 10.1002/ppul.24634. [Epub ahead of print] [Pubmed]
To characterize the phenotypic expression of children with conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labelling if applicable and better define these children’s prognosis.
A multicentre cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)-diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment.
Results – Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow-up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P < .0001, respectively), Wisconsin and Brasfield chest radiograph scores, pulmonary function tests, and improved nutritional status. Among the inconclusive CF diagnosis cohort, 28 cases (44%) converted to CF diagnosis based on genotype (44%), SC (28%) or both (28%); yet, comparing those with or without final CF diagnosis, we found no differences, possibly related to their young age and mild degree of lung disease. In the total cohort, we found significant associations between Brody scores and IRT, SC values, genotype, Wisconsin and Brasfield score and spirometry.
The authors concluded the matched CRMS/CFSPID and CF cohorts showed differences in outcomes. By a mean age of 7.6 years, a high proportion of the CRMS/CFSPID cohort converted to CF. Our results highlight that monitoring at CF clinics until at least 6 years is needed as well as further studies.
Dr Anne Munck is at the Service des maladies digestives et respiratoires de l’enfant, CRCM, Hôpital Robert Debré, Paris, France.
-The final practical message of this useful paper is important – these infants should be followed up by experts in CF for a long time.
Järvholm S, Ericson P, Gilljam M. Patient acceptance and outcome of mental health screening in Swedish adults with cystic fibrosis. Qual Life Res. 2020 Jan 9. doi: 10.1007/s11136-020-02417-5. [Epub ahead of print] [Pubmed]
Anxiety and depression are common among adults with cystic fibrosis (CF), and the International Committee on Mental Health in CF (ICMH) recommends annual screening for mental health problems. We implemented screening according to the recently published guidelines and assessed the results from the first year, as well as the patients’ attitude to annual screening METHODS: Adult patients attending Gothenburg CF-center from Feb 2015 to Dec 2016 completed the GAD-7 (anxiety) and PHQ-9 (depression) forms at the time of their annual review. In addition, questions regarding the screening process and instruments used were asked.
All invited patients (n = 100, 52% males, 2% lung transplanted), with a median age of 28 years (range 18-65), agreed to participate. In general (83%), the patients were positive to screening on an annual basis. No significant differences in total GAD-7 and PHQ-9 scores were found when comparing men and women. Patients younger than 30 years of age reported more symptoms of anxiety compared to older patients (p = 0.02). There were 21 (21%) patients with scores > 10 for GAD-7 and/or PHQ-9 indicating at least moderate anxiety or depression. Scores > 10 were reported by 15 patients on GAD-7, 15 patients on PHQ-9, and 9 patients reported scores above 10 on both measures.
The authors concluded the patients considered annual check-ups for mental health issues important. Although the screening results are reassuring, the group is heterogenic and the suggest younger individuals should be given extra attention. They suggest follow-up over longer time should provide more robust data.
Dr Stina Jarvholm is a psychologist in the Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gröna stråket 9, 413 45, Gothenburg