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last updated: Sat, 04 Jul 2015 14:55:52 GMT

 Fri, 03 Jul 2015 13:00:00 GMT Gene therapy breakthrough for cystic fibrosis

“Cystic fibrosis hope as new gene therapy improves condition,” The Daily Telegraph reports. Researchers have, for the first time, managed to successfully "smuggle" healthy copies of genes into the lungs of people with cystic fibrosis.

Cystic fibrosis is a genetic condition caused by a mutated gene called CFTR. The mutation causes the lungs and digestive system to become clogged up with sticky mucus.

The goal of gene therapy for cystic fibrosis is to replace the faulty CFTR gene with a working one.

Previous attempts of using a virus to deliver the working gene proved unsuccessful, as the lungs’ defence system against infection stopped the virus from entering.

In this new study, the researchers tried a different approach – the gene was encased in a bubble of fat, which was then delivered to the lungs via a nebuliser.

When compared to placebo, the nebuliser-delivered approach showed a modest, but significant, improvement in lung function (3.7%).

A 3.7% improvement may not sound that impressive, but the exciting news is that the technique actually worked in a few of the study’s participants in the first place. It may be possible to enhance the technique in the future to boost lung function dramatically.

It is likely that larger and longer trials are now being planned. 

Where did the story come from?

The study was carried out by researchers from University of Oxford and Imperial College London, and was jointly funded by the Cystic Fibrosis Trust, National Institute for Health Research (NIHR) Clinical Research Network, and Just Gene Therapy.

A number of the researchers have patents related to the gene therapy reported in the study and also declared links to pharmaceutical companies. The team state that the: “funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.”

The study was published in the peer-reviewed medical journal The Lancet on an open-access basis, so it is free to read online or download as a PDF.

This story was widely covered by UK media. Overall, the media reported the story accurately, but the limitations of the study were not fully explained.

BBC News published an important quote from one of the researchers involved in this study, Prof Eric Alton, of Imperial College London, who said: "The effect is modest and it is variable. It is not ready to go straight into the clinic yet."


What kind of research was this?

This was a randomised controlled trial (RCT) that aimed to assess the effectiveness of non-viral gene therapy compared with inactive placebo in people with cystic fibrosis. It was a phase 2b trial, meaning it was gathering information on effectiveness and safety, which will hopefully pave the way to larger phase 3 trials comparing the technique with existing treatments.

Cystic fibrosis is a genetic condition in which the lungs and digestive system become clogged with thick, sticky mucus. Symptoms of cystic fibrosis usually start in early childhood and include:

  • a persistent cough
  • recurring chest and lung infections
  • poor weight gain

An early sign is that an affected child’s sweat is unusually salty, which can be noticeable when you kiss your child. However, most cases of cystic fibrosis in the UK are now identified through screening tests carried out early in life, before symptoms appear.

There is currently no cure for cystic fibrosis. Treatment options for cystic fibrosis include those that aim to control symptoms, such as physiotherapy (a range of exercises can clear mucus from the lungs) and bronchodilators (a type of medication that expands the airways, making it easier to breathe), and antibiotics to treat lung infections. In some cases, a lung transplant may eventually be required, if the lungs become extensively damaged.

Previous studies have tried to use viruses to deliver a functioning CFTR gene into the lungs, with limited success. This study used a non-virus based method to deliver the CFTR gene – encasing it in a bubble of fat – in the expectation this would be more successful.

RCTs are one of the best types of study design to determine whether a treatment is effective. Potential biases are reduced through randomisation. This study was also double blind, meaning that both patients and those assessing them were unaware of whether the person had received treatment or placebo.


What did the research involve?

A group of 140 people with cystic fibrosis were randomly assigned to either the gene treatment, which was given the name pGM169/GL67A (78 patients), or placebo (62 patients).

Patients received either 5ml of pGM169/GL67A (containing 13.3mg of plasmid DNA and 75mg of the GL67A lipid mixture), or 5ml of inactive saline (salt solution) through a nebuliser (a machine that converts the medicine to a mist, so it can be inhaled into the lungs).

Patients received either treatment or placebo at 28-day intervals (plus or minus 5 days) for 12 months. Patients in both groups also received an average of three courses of oral or intravenous antibiotics during the trial.

Patients recruited for this study were from 18 sites in the UK and were aged 12 years or older. Their lung function was measured using a standard test called forced expiratory volume in 1 second (FEV1). This measures the amount of air that can be forcibly exhaled in the first second after a maximal inspiration. To be included in the study, participants had to have an FEV1 of 50-90% of the normal level.

The main outcome of interest was the change in the percentage of predicted FEV1. Other outcomes examined were CT scans of the lungs, self-reported symptoms ratings and quality of life scores.

The main analysis was per-protocol. Per-protocol means that only people who took the medicine as planned were analysed. This excludes those who had dropped out for any reason. Intention to treat analysis is the more realistic scenario, as people might stop treatment in the real world. Per protocol analysis gives a good idea of whether the medicine works in those who took it as intended.

In this study, the per-protocol analysis included 116 people, 83% of those were randomised.


What were the basic results?

Researchers found that, overall, the treatment (pGM169/GL67A) significantly improved FEV1 by 3.7% compared with placebo at 12 months follow-up. This was described as a “modest” benefit to lung function and a statistically significant one.

The changes within each of the individual groups were an average reduction of 4.0% in the placebo group, compared with a 0.4% reduction in the pGM169/GL67A group. This means that lung function got a little worse in both groups over the year, but those in the placebo group deteriorated more. This led some headlines to report that the new drug was able to “stabilise” symptoms; that is, stopping them getting any worse, which was accurate.

There was no statistically significant difference between groups in adverse effects like fatigue and increased respiratory symptoms and flu-like symptoms. Overall, authors say that some patients responded to the new treatment better than the others.

Six serious adverse events, all in the pGM169/GL67A group, were recorded. But neither the Data Monitoring and Ethics Committee, nor the Trial Steering Committee involved in the research, regarded any serious adverse event as related to the study drug. One event was considered to be possibly related to a trial procedure (bronchoscopy).


How did the researchers interpret the results?

The researchers concluded that: “Although we are encouraged by the first demonstration of a significant beneficial effect in lung function compared with placebo associated with gene therapy in patients with cystic fibrosis, the mean difference was modest, only recorded in some individuals, and at the lower end of the range of results seen in clinical trials which result in changes in patient-related care.”

They added: “Further improvements in efficacy and consistency of response to the current formulation, or its combination with CFTR potentiators, are needed before gene therapy is suitable for clinical practice.”



This RCT showed that a new non-viral-based gene therapy for cystic fibrosis was able to produce “modest” benefits in lung function compared to a placebo. The treatments were given once a month for a year.

The study had many strengths, including its double-blind randomised design, recruiting adequate numbers to demonstrate real differences between groups, and using pre-specified outcomes and sub-analysis. This means we can be confident in the reliability of the findings presented.

Although the findings of this study are encouraging, there are always limitations.

These include:

  • This study was relatively small, recruiting just 140 patients. This is normal for a phase II trial, but large clinical trials are needed to fully assess the effects and safety of this treatment in development.
  • Patients recruited in this trial had to be clinically stable to be included. This means they might be at their optimum respiratory health at this stage. Therefore, we don’t know how the treatment would work in clinically unstable or very severe patient groups.

It is important to realise that both groups’ lung function got worse over the year, so the treatment as it stands is quite limited. The new gene therapy was able to lessen some of the deterioration, but not in all. Nonetheless, this gives the researchers hope and scope to work out how to improve it.

Optimising the dose, working out why it worked in some people and not others, and trialling the therapy in more people are the natural next steps in this treatment development.

This is very much a proof-of-concept study rather than a study that provides a viable treatment in itself. It is a breakthrough in the development of gene therapy treatment for cystic fibrosis, but there is a lot of refinement and experimentation needed before this could be a routinely available treatment.

Links To The Headlines

Cystic fibrosis hope as new gene therapy improves condition. The Daily Telegraph, July 3 2015

Gene therapy stabilises lungs of cystic fibrosis patients. BBC News, July 3 2015

Cystic fibrosis: Gene therapy offers hope to patients after successful trials. The Independent, July 3 2015

Breakthrough for cystic fibrosis sufferers as scientists use gene therapy to significantly improve the function of patients' lungs. Mail Online, July 3 2015

Cystic fibrosis: Gene therapy treatment for cystic fibrosis may be possible by 2020, scientists say. The Guardian, July 3 2015

Links To Science

Alton EWF, Armstrong DK, Ashby D, et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial (PDF, 1.07Mb). The Lancet. Published online July 3 2015

 Thu, 02 Jul 2015 12:00:00 GMT 'Sleeping on it' may not be best after traumatic event

"Staying awake may be the best way to stop disturbing flashbacks," the Daily Mail reports. A small psychological experiment carried out at Oxford University suggests that sleep could possibly help embed traumatic events in the memory, in some cases.

The study involved 42 students, half of whom were randomly assigned to sleep deprivation and the other to sleep at home as usual. They all watched a 15-minute film compilation of distressing clips of simulated events such as suicides and injuries. Both groups had a drop in mood after watching the clips. Over the next six days, those who were not allowed to sleep had on average 2.3 "flashbacks" while the sleep group had 3.8 flashbacks.

The small amount of study participants and the experimental study design mean that the results would (or should) not lead to changes in current clinical advice for people affected by trauma. But if the results are replicated in larger populations, then it could mean that the common practice of giving sedatives to people affected by trauma to help them sleep, could be doing more harm than good.

It you are troubled by intrusive thoughts or images following a traumatic event, for four weeks or more, then you may be at risk for post-traumatic stress disorder (PTSD). We recommend you contact your GP for an assessment.

If symptoms persist, treatments such as cognitive behavioural therapy can often help.


Where did the story come from?

The study was carried out by researchers from the University of Oxford, the MRC Cognition and Brain Sciences Unit in Cambridge and the Karolinska Institute in Sweden. It was funded by the Wellcome Trust and the National Institute for Health Research.

The study was published in the peer-reviewed medical journal Sleep.

The study was widely covered in the UK media but none of the reporting explained any of the limitations of this study.

Also The Daily Telegraph did not provide details of the actual number of flashbacks experienced, but instead reported that the sleep-deprived group had around 40% fewer flashbacks. This sounds like a much more dramatic difference than the actual figures reported in the study (3.8 compared with 2.3).

Finally, the Daily Mirror’s headline that sleeping "could actually cause flashbacks" is unsupported by the results provided by the study.


What kind of research was this?

This was a small, non-blinded randomised controlled trial that aimed to see if sleep deprivation could reduce intrusive images (flashbacks) and memories following a traumatic event.


What did the research involve?

Forty-two healthy students aged 18 to 25 were paid to participate in the research. They completed questionnaires before the study commenced to ensure that they had regular sleeping patterns and no personal or family history of mental health problems. None smoked and none were taking any medication other than the contraceptive pill. They were randomly split into two groups, 20 in a "sleep deprived" group (14 females) and 22 in the "sleep" group (15 females).

On the first day of the study the volunteers completed assessments to measure their mood (visual analogue mood scale (VAS)) and a level of detachment from their surroundings (dissociative state scale (DSS)) before and after watching a "trauma film" in the evening. The trauma film was a 15-minute compilation of distressing clips from films and TV adverts including a suicide, bullying, injury and cutting of the face. The students had consented to watch distressing images and were instructed to imagine that they were at the scene, watching it happen. They were told they could stop the film at any time but none of the students chose to do so.

The sleep group went home and were allowed to sleep as usual but were asked not to watch TV or listen to music. The sleep deprived group were kept awake until 7pm the following day in a sleep laboratory with researchers keeping them awake. They were allowed to play board games, read, talk to researchers and walk about. They were not allowed to use computers, TV, DVDs, music or to leave the laboratory. They had access to a sandwich or fruit every two hours and could have a shower in the morning.

In the morning, both groups were assessed for the impact of the film using the well-validated Impact of Event Scale – Revised (IES-R). This is a 22-item assessment for post-traumatic symptoms such as intrusive memories, avoidance of distressing stimuli and increased alertness. It gives a range in score from 0 (no symptoms) to 88 (disabling symptoms). They were then asked to keep a diary of any intrusive memories over the next six days and rate their distress from the memory.


What were the basic results?

Both groups experienced the same level of negative mood and feeling of detachment immediately after watching the film.

On day one, the sleep deprived group had a lower score on the IES-R than the sleep group (8.47 versus 11.52).

Over the next six days, the sleep deprived group reported fewer intrusive memories or disturbing images than the sleep group (mean 2.28 intrusive memories per person versus 3.76).


How did the researchers interpret the results?

The authors concluded that their "findings suggest that sleep deprivation on one night, rather than sleeping, reduces emotional effect and intrusive memories following exposure to experimental trauma".



As the researchers acknowledge, the results of this study are interesting, but it is important to stress that the study was based on a small experimental model of trauma through watching a film with "traumatic content". This is quite different to many real-life experiences that cause PTSD. The participants will have known that the film was not real, which is different to experiences of violence or perceived threat in reality. The number of flashbacks was also very low – on average two to four per person during the whole six days after the film – compared with that which would be experienced by people with PTSD.

Strengths of the study include the use of watches to ensure that naps were not taken during the day by either group and they did not use alcohol or caffeine during the study.

However, there are several limitations including:

  • Staying in the laboratory with other participants and the researchers may have had a confounding effect on the results as participants could have talked through the films and images, which might have helped.
  • The study only looked at short-term effects over a period of six days.
  • None of the sleep group reported any problem in sleeping, whereas in real-life situations following a traumatic event, people are often unable to sleep or have disturbed sleep.
  • The study is based on small numbers of participants, which reduces the reliability of the results.
  • The results may not be generalisable to the wider population as the study participants were all students and were happy to be included in the study with the knowledge that they would be exposed to distressing images.
  • The study is reliant on self-report of intrusive memories.

The results of the study are not conclusive enough to advise that staying awake after trauma will reduce the chance of PTSD, whether with people or alone. Further studies along this line would be required before official advice could be changed.

It is normal to experience upsetting and confusing thoughts after a traumatic event, but in most people these will improve naturally over a few weeks.

You should visit your GP if you or your child are still having problems about four weeks after a traumatic experience, or if the symptoms are particularly troublesome. Read more about post-traumatic stress disorder.

Links To The Headlines

Why sleeping on it WON'T help you forget a trauma: Staying awake may be the best way to stop disturbing flashbacks. Daily Mail, July 1 2015

Sleeping is not the best remedy for psychological trauma - and could actually cause flashbacks. Daily Mirror, July 1 2015

Sleep deprivation could prevent traumatic memories and flashbacks. The Daily Telegraph, July 1 2015

Links To Science

Porcheret K, Holmes EA, Goodwin GM, et al. Psychological Effect of an Analogue Traumatic Event Reduced by Sleep Deprivation. Sleep. Published online July 1 2015

 Wed, 01 Jul 2015 14:30:00 GMT Orange juice and grapefruit linked to melanoma skin cancer

"Drinking a glass of orange juice or eating a fresh grapefruit for breakfast may increase the risk of skin cancer," the Mail Online reports.

A US study did find a small increase in the risk of melanoma, but the benefits of unsweetened fruit juice shouldn't be overlooked.

A glass (150ml) of fruit juice counts as one of your recommended five daily portions of fruit and vegetables, which in turn can protect against a range of chronic diseases.

The US study involved more than 60,000 female and 40,000 male health professionals. Participants were asked to fill out a questionnaire every two to four years about their diet, lifestyle and incidence of skin cancers.

An increased risk of melanoma was found for those who drank more than a glass of orange juice a day, as well as for people who ate fresh grapefruit more than three times a week.

These findings do appear to find a link between citrus fruit and skin cancer risk. But this type of study cannot prove cause and effect.

While researchers attempted to adjust their results for potential underlying factors, such as age, other factors could also have influenced the results. For example, people who live in sunnier parts of the US, such as Florida or California, may also consume more citrus fruits.

By taking a number of commonsense sun-safe precautions, you can have the best of both worlds – enjoying citrus fruit while not significantly raising your skin cancer risk.

These include making sure you wear sunscreen and appropriate clothing, and staying indoors during periods of intense sunlight.   

Where did the story come from?

The study was carried out by researchers from Brigham and Women's Hospital, Harvard Medical School and Brown University, and was funded by a grant from the National Cancer Institute.

It was published in the peer-reviewed Journal of Clinical Oncology.

These findings have been reported reasonably accurately by the Mail Online. But some caution should be taken when reading the Mail's article, as this study cannot prove causation and there are other health benefits associated with eating fruit. It does, however, provide advice on how to detect skin cancer, which is very useful.  

What kind of research was this?

These were two prospective cohort studies with a long follow-up. The studies aimed to investigate whether citrus products may be associated with an increased risk of melanoma. Melanoma is an aggressive type of skin cancer that can spread to other parts of the body.

Citrus products are known to contain high levels of a chemical compound called psoralen, which absorbs ultraviolet light.

Psoralen drugs are used for the treatment of skin conditions such as psoriasis, but animal studies and long-term use of the drugs in people have shown it may increase the risk of melanoma.

This type of study is unable to prove citrus products cause melanoma, but it could find possible links for future investigation. 

What did the research involve?

The study included 63,810 women in the Nurses' Health Study and 41,622 men in the Health Professionals Follow-Up Study, both of which ran from the mid-1980s to 2010.

Every two to four years, people answered detailed questionnaires on their diet, lifestyle and levels of sun exposure. Data on melanoma diagnosis was collected and confirmed with medical records – this included tumour stage and location.

The participants answered questions about how frequently they consumed grapefruits, oranges, grapefruit juice or orange juice.

The total of these four categories was considered an estimate of overall citrus consumption, although it did not include other citruses such as lemons and limes.

Melanomas were classified into two subgroups according to location:

  • high continuous sun exposure – head, neck, extremities
  • low continuous sun exposure – shoulders, back, hips

Various analyses were performed and adjusted for known melanoma risk factors and potential confounders. Subgroup analyses were performed to assess the influence of common medications, healthy diet and sunscreen use. 

What were the basic results?

Over an average of 24 to 26 years of follow-up, there were 1,840 cases of melanoma. Participants with higher citrus intake were less likely to smoke cigarettes and drink coffee, were more likely to exercise, and had a higher intake of individual citrus products and vitamin C.

After adjustments were made for potential risk factors and confounders, there was an increased risk of 36% observed for overall citrus consumption of more than 1.6 times a day, compared with less than twice a week in the reference group (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.14 to 1.63).

Fresh grapefruit showed the strongest link, with a 41% increased risk for those who eat fresh grapefruit more than three times a week compared with those who never ate grapefruit (HR 1.41, 95% CI 1.10 to 1.82). This association was not seen for consumption of grapefruit juice.

statistically significant association was found between grapefruit consumption and melanomas on sites with higher continuous sun exposure.

Consuming orange juice more than once a day had a 25% increased risk of melanoma compared with less than once a week (HR 1.25, 95% CI 1.07 to 1.47). Eating oranges alone did not have a significant effect on melanoma risk.

No associations were found for other fruits and vegetables and the risk of melanoma.  

How did the researchers interpret the results?

The researchers concluded that, "Citrus consumption was associated with an increased risk of malignant melanoma in two cohorts of women and men.

"Nevertheless, further investigation is needed to confirm our findings and explore health-related implications." 


This study aimed to assess the association between psoralens found in citrus fruit and melanoma risk.

A link was observed between orange juice, fresh grapefruit and overall citrus consumption, with grapefruit causing the highest level of increased risk. The researchers say this is because there are higher levels of psoralens in grapefruits than other citrus fruits.

The strengths of this study are its prospective design, large sample size and long-term follow-up.

However, the sample was composed of US health professionals, who may have very different diet and lifestyle habits from most US citizens, which limits the generalisability of the findings.

As participants were required to fill out a questionnaire, this may be subject to recall bias. There were also wide confidence intervals, which reduces the certainty of the results, especially given the large number of participants.

These findings should be taken with caution as they are unable to prove citrus consumption is the cause of melanoma. Fruit intake is known to have beneficial effects on the prevention of chronic diseases. Further investigation is required to confirm this risk.

A positive association was seen for those who had higher sunburn susceptibility as a child, more blistering sunburn episodes, spent more time in direct sunlight, and those with a higher annual UV flux at their home. This may have been the cause of the increased melanoma risk rather than the effect of citrus fruit. 

These findings really stress the importance of taking care in the sun by wearing sunscreen and appropriate clothing, and staying indoors during periods of intense sunlight.

Read more about how to prevent melanoma, a particularly aggressive type of skin cancer that kills more than 2,000 people every year in the UK. 

Links To The Headlines

Is there a link between orange juice and SKIN CANCER? 'Citrus fruits may increase the risk of melanoma', study declares. Mail Online, June 30 2015

Links To Science

Wu S, Han J, Feskanich D, et al. Citrus Consumption and Risk of Cutaneous Malignant Melanoma. Journal of Clinical Oncology. Published online June 29 2015


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