Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral ...CFTR gene therapy in patients with cystic fibrosis.
We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867.
Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.
Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.
Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
Background
Cystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (
CFTR
) gene leading to abnormal airway surface ion transport, ...chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco
®
, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediated
CFTR
gene therapy formulation through preclinical and clinical development.
Objective
To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.
Design
This was a randomised, double-blind, placebo-controlled Phase IIb trial of the
CFTR
gene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers.
Settings
Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.
Participants
Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV
1
) between 50% and 90% predicted and any combination of
CFTR
mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).
Interventions
Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.
Main outcome measures
The primary end point was the relative change in percentage predicted FEV
1
over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference.
Results
There was a significant (
p
= 0.046) treatment effect (TE) of 3.7% 95% confidence interval (CI) 0.1% to 7.3% in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (
p
= 0.031) and CT gas trapping (
p
= 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age or
CFTR
mutation class. Subjects with a more severe baseline FEV
1
had a FEV
1
TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (
p
= 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups.
Conclusions
Monthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo.
Limitations
Although encouraging, the improvement in FEV
1
was modest and was not accompanied by detectable improvement in patients’ quality of life.
Future work
Future work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration.
Trial registration
ClinicalTrials.gov NCT01621867.
Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.
To establish benchmarks of significant change for aphasia rehabilitation outcome measures (ie, Western Aphasia Battery-Aphasia Quotient WAB-AQ, Communicative Effectiveness Index CETI, Boston Naming ...Test BNT) and assess if those benchmarks significantly differ across subgroups (ie, time post onset, dose frequency, treatment type).
A comprehensive literature search of 12 databases, reference lists of previous reviews, and evidence-based practice materials was conducted.
Randomized controlled trials, quasi-experimental studies, single-subject design, and case studies that used a standardized outcome measure to assess change were included. Titles and full-text articles were screened using a dual review process. Seventy-eight studies met criteria for inclusion.
Data were extracted independently, and 25% of extractions were checked for reliability. All included studies were assigned quality indicator ratings and an evidence level.
Random-effects meta-analyses were conducted separately for each study design group (ie, within-/between-group comparisons). For within-group designs, the summary effect size after aphasia rehabilitation was 5.03 points (95% confidence interval, 3.95-6.10, P<.001) on the WAB-AQ, 10.37 points (6.08-14.66, P<.001) on the CETI, and 3.30 points (2.43-4.18, P<.001) on the BNT. For between-group designs, the summary effect size was 5.05 points (1.64-8.46, P=.004) on the WAB-AQ and 0.55 points (-1.33 to 2.43, P=.564) on the BNT, the latter of which was not significant. Subgroup analyses for the within-group designs showed no significant differences in the summary effect size as a function of dose frequency or treatment type.
This study established benchmarks of significant change on 3 standardized outcome measures used in aphasia rehabilitation.
Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.
To define the cytokine profile of COVID-19 and to identify evidence of ...immunometabolic alterations in those with severe illness.
Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVID
patients), patients with COVID-19 requiring ICU admission (COVID
patients), and patients with severe community-acquired pneumonia requiring ICU support (CAP
patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.
IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVID
patients could be clearly differentiated from COVID
patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAP
patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (
< 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (
< 0.0001).
The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.
Metal–organic frameworks (MOFs) are a new and growing area of materials with high porosity and customizability. UiO-66, a zirconium-based MOF, has shown much interest to the military because of the ...ability of the MOF to catalytically decontaminate chemical warfare agents (CWAs). Unfortunately, the applications for MOFs are limited because of their powder form, which is difficult to incorporate into protective clothing. As a result, a new area of research has developed to functionalize fabrics with MOFs to make a wearable multifunctional fabric that retains the desired properties of the MOF. In this work, UiO-66 was incorporated into poly(vinylidene) fluoride/Ti(OH)4 composite fabric using electrospinning and evaluated for its use in chemical protective clothing. The base triethanolamine (TEA) was added to the composite fabric to create a self-buffering system that would allow for catalytic decontamination of CWAs without the need for a buffer solution. The fabrics were tested against the simulants methyl-paraoxon (dimethyl (4-nitrophenyl) phosphate, DMNP), diisopropyl fluorophosphate (DFP), and the nerve agent soman (GD). The results show that all of the samples have high moisture vapor transport and filtration efficiency, which are desirable for protective clothing. The incorporation of TEA decreased air permeation of the fabric, but increased the catalytic activity of the composite fabric against DMNP and DFP. Samples with and without TEA have rapid half-lives (t 1/2) as short as 35 min against GD agent. These new catalytically active self-buffering multifunctional fabrics have great potential for application in chemical protective clothings.
The effect of clinic-based intensive hypertension treatment on ambulatory blood pressure (BP) is unknown. The goal of the SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP ancillary ...study was to evaluate the effect of intensive versus standard clinic-based BP targets on ambulatory BP. Ambulatory BP was obtained within 3 weeks of the 27-month study visit in 897 SPRINT participants. Intensive treatment resulted in lower clinic systolic BP (mean difference between groups=16.0 mm Hg; 95% confidence interval, 14.1-17.8 mm Hg), nighttime systolic BP (mean difference=9.6 mm Hg; 95% confidence interval, 7.7-11.5 mm Hg), daytime systolic BP (mean difference=12.3 mm Hg; 95% confidence interval, 10.6-13.9 mm Hg), and 24-hour systolic BP (mean difference=11.2 mm Hg; 95% confidence interval, 9.7-12.8 mm Hg). The night/day systolic BP ratio was similar between the intensive (0.92±0.09) and standard-treatment groups (0.91±0.09). There was considerable lack of agreement within participants between clinic systolic BP and daytime ambulatory systolic BP with wide limits of agreement on Bland-Altman plots. In conclusion, targeting a systolic BP of <120 mm Hg, when compared with <140 mm Hg, resulted in lower nighttime, daytime, and 24-hour systolic BP, but did not change the night/day systolic BP ratio. Ambulatory BP monitoring may be required to assess the effect of targeted hypertension therapy on out of office BP. Further studies are needed to assess whether targeting hypertension therapy based on ambulatory BP improves clinical outcomes.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835249.
Cardiovascular (CV) risk factors have been associated with changes in clinical outcomes in patients with multiple sclerosis (MS).
To investigate the frequency of CV risks in patients with MS and ...their association with MRI outcomes.
In a prospective study, 326 patients with relapsing-remitting MS and 163 patients with progressive MS, 61 patients with clinically isolated syndrome (CIS) and 175 healthy controls (HCs) were screened for CV risks and scanned on a 3T MRI scanner. Examined CV risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. MRI measures assessed lesion volumes (LVs) and brain atrophy. Association between individual or multiple CV risks and MRI outcomes was examined adjusting for age, sex, race, disease duration and treatment status.
Patients with MS showed increased frequency of smoking (51.7% vs 36.5%, p = 0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared with HCs. In total, 49.9% of patients with MS and 36% of HCs showed ≥ 2 CV risks (p = 0.003), while the frequency of ≥ 3 CV risks was 18.8% in the MS group and 8.6% in the HCs group (p = 0.002). In patients with MS, hypertension and heart disease were associated with decreased grey matter (GM) and cortical volumes (p < 0.05), while overweight/obesity was associated with increased T1-LV (p < 0.39) and smoking with decreased whole brain volume (p = 0.049). Increased lateral ventricle volume was associated with heart disease (p = 0.029) in CIS.
Patients with MS with one or more CV risks showed increased lesion burden and more advanced brain atrophy.
As COVID-19 continues, an increasing number of patients develop long COVID symptoms varying in severity that last for weeks, months, or longer. Symptoms commonly include lingering loss of smell and ...taste, hearing loss, extreme fatigue, and "brain fog." Still, persistent cardiovascular and respiratory problems, muscle weakness, and neurologic issues have also been documented. A major problem is the lack of clear guidelines for diagnosing long COVID. Although some studies suggest that long COVID is due to prolonged inflammation after SARS-CoV-2 infection, the underlying mechanisms remain unclear. The broad range of COVID-19's bodily effects and responses after initial viral infection are also poorly understood. This workshop brought together multidisciplinary experts to showcase and discuss the latest research on long COVID and chronic inflammation that might be associated with the persistent sequelae following COVID-19 infection.
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