Excitement as trial shows Huntington’s drug could slow progress of disease

Hailed as enormously significant, results in groundbreaking trial are first time a drug has been shown to suppress effects of Huntingtons genetic mutation

A landmark trial for Huntingtons disease has announced positive results, suggesting that an experimental drug could become the first to slow the progression of the devastating genetic illness.

The results have been hailed as enormously significant because it is the first time any drug has been shown to suppress the effects of the Huntingtons mutation that causes irreversible damage to the brain. Current treatments only help with symptoms, rather than slowing the diseases progression.

Q&A

What is Huntington’s disease?

Huntingtons disease is a congenital degenerative condition caused by a single defective gene. Most patients are diagnosed in middle age, with symptoms including mood swings, irritability and depression. As the disease progresses, more serious symptoms can include involuntary jerky movements, cognitive difficulties and issues with speech and swallowing.

Currently there is no cure for Huntington’s, although drugs exist which help manage some of the symptoms. It is thought that about 12 people in 100,000 are affected by Huntington’s, and if a parent carries the faulty gene there is a 50% chance they will pass it on to their offspring.

Prof Sarah Tabrizi, director of University College Londons Huntingtons Disease Centre who led the phase 1 trial, said the results were beyond what Id ever hoped … The results of this trial are of ground-breaking importance for Huntingtons disease patients and families, she said.

The results have also caused ripples of excitement across the scientific world because the drug, which is a synthetic strand of DNA, could potentially be adapted to target other incurable brain disorders such as Alzheimers and Parkinsons. The Swiss pharmaceutical giant Roche has paid a $45m licence fee to take the drug forward to clinical use.

Huntingtons is an incurable degenerative disease caused by a single gene defect that is passed down through families.

The first symptoms, which typically appear in middle age, include mood swings, anger and depression. Later patients develop uncontrolled jerky movements, dementia and ultimately paralysis. Some people die within a decade of diagnosis.

Most of our patients know whats in their future, said Ed Wild, a UCL scientist and consultant neurologist at the National Hospital for Neurology and Neurosurgery in London, who administered the drug in the trial.

The mutant Huntingtons gene contains instructions for cells to make a toxic protein, called huntingtin. This code is copied by a messenger molecule and dispatched to the cells protein-making machinery. The drug, called Ionis-HTTRx, works by intercepting the messenger molecule and destroying it before the harmful protein can be made, effectively silencing the effects of the mutant gene.

How the drug works to slow the progress of Huntington’s disease

To deliver the drug to the brain, it has to be injected into the fluid around the spine using a four-inch needle.

Prof John Hardy, a neuroscientist at UCL who was not involved in the trial, said: If Id have been asked five years ago if this could work, I would have absolutely said no. The fact that it does work is really remarkable.

The trial involved 46 men and women with early stage Huntingtons disease in the UK, Germany and Canada. The patients were given four spinal injections one month apart and the drug dose was increased at each session; roughly a quarter of participants had a placebo injection.

After being given the drug, the concentration of harmful protein in the spinal cord fluid dropped significantly and in proportion with the strength of the dose. This kind of closely matched relationship normally indicates a drug is having a powerful effect.

For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well-tolerated, said Tabrizi. This is probably the most significant moment in the history of Huntingtons since the gene [was isolated].

The trial was too small, and not long enough, to show whether patients clinical symptoms improved, but Roche is now expected to launch a major trial aimed at testing this.

If the future trial is successful, Tabrizi believes the drug could ultimately be used in people with the Huntingtons gene before they become ill, possibly stopping symptoms ever occurring. They may just need a pulse every three to four months, she said. One day we want to prevent the disease.

The drug, developed by the California biotech firm Ionis Pharmaceuticals, is a synthetic single strand of DNA customised to latch onto the huntingtin messenger molecule.

The unexpected success raises the tantalising possibility that a similar approach might work for other degenerative brain disorders. The drugs like Lego, said Wild. You can target [any protein].

For instance, a similar synthetic strand of DNA could be made to target the messenger that produces misshapen amyloid or tau proteins in Alzheimers.

Huntingtons alone is exciting enough, said Hardy, who first proposed that amyloid proteins play a central role in Alzheimers. I dont want to overstate this too much, but if it works for one, why cant it work for a lot of them? I am very, very excited.

Prof Giovanna Mallucci, associate director of UK Dementia Research Institute at the University of Cambridge, described the work as a tremendous step forward for individuals with Huntingtons disease and their families.

Clearly, there will be much interest into whether it can be applied to the treatment of other neurodegenerative diseases, like Alzheimers, she added. However, she said that in the case of most other disorders the genetic causes are complex and less well understood, making them potentially harder to target.

About 10,000 people in the UK have the condition and about 25,000 are at risk. Most people with Huntingtons inherited the gene from a parent, but about one in five patients have no known family history of the disease.

The full results of the trial are expected to be published in a scientific journal next year.

Read more: https://www.theguardian.com/science/2017/dec/11/excitement-as-huntingtons-drug-shown-to-slow-progress-of-devastating-disease

The shorter your sleep, the shorter your life: the new sleep science

Leading neuroscientist Matthew Walker on why sleep deprivation is increasing our risk of cancer, heart attack and Alzheimers and what you can do about it

Matthew Walker has learned to dread the question What do you do? At parties, it signals the end of his evening; thereafter, his new acquaintance will inevitably cling to him like ivy. On an aeroplane, it usually means that while everyone else watches movies or reads a thriller, he will find himself running an hours-long salon for the benefit of passengers and crew alike. Ive begun to lie, he says. Seriously. I just tell people Im a dolphin trainer. Its better for everyone.

Walker is a sleep scientist. To be specific, he is the director of the Center for Human Sleep Science at the University of California, Berkeley, a research institute whose goal possibly unachievable is to understand everything about sleeps impact on us, from birth to death, in sickness and health. No wonder, then, that people long for his counsel. As the line between work and leisure grows ever more blurred, rare is the person who doesnt worry about their sleep. But even as we contemplate the shadows beneath our eyes, most of us dont know the half of it and perhaps this is the real reason he has stopped telling strangers how he makes his living. When Walker talks about sleep he cant, in all conscience, limit himself to whispering comforting nothings about camomile tea and warm baths. Its his conviction that we are in the midst of a catastrophic sleep-loss epidemic, the consequences of which are far graver than any of us could imagine. This situation, he believes, is only likely to change if government gets involved.

Walker has spent the last four and a half years writing Why We Sleep, a complex but urgent book that examines the effects of this epidemic close up, the idea being that once people know of the powerful links between sleep loss and, among other things, Alzheimers disease, cancer, diabetes, obesity and poor mental health, they will try harder to get the recommended eight hours a night (sleep deprivation, amazing as this may sound to Donald Trump types, constitutes anything less than seven hours). But, in the end, the individual can achieve only so much. Walker wants major institutions and law-makers to take up his ideas, too. No aspect of our biology is left unscathed by sleep deprivation, he says. It sinks down into every possible nook and cranny. And yet no one is doing anything about it. Things have to change: in the workplace and our communities, our homes and families. But when did you ever see an NHS poster urging sleep on people? When did a doctor prescribe, not sleeping pills, but sleep itself? It needs to be prioritised, even incentivised. Sleep loss costs the UK economy over 30bn a year in lost revenue, or 2% of GDP. I could double the NHS budget if only they would institute policies to mandate or powerfully encourage sleep.

Why, exactly, are we so sleep-deprived? What has happened over the course of the last 75 years? In 1942, less than 8% of the population was trying to survive on six hours or less sleep a night; in 2017, almost one in two people is. The reasons are seemingly obvious. First, we electrified the night, Walker says. Light is a profound degrader of our sleep. Second, there is the issue of work: not only the porous borders between when you start and finish, but longer commuter times, too. No one wants to give up time with their family or entertainment, so they give up sleep instead. And anxiety plays a part. Were a lonelier, more depressed society. Alcohol and caffeine are more widely available. All these are the enemies of sleep.

But Walker believes, too, that in the developed world sleep is strongly associated with weakness, even shame. We have stigmatised sleep with the label of laziness. We want to seem busy, and one way we express that is by proclaiming how little sleep were getting. Its a badge of honour. When I give lectures, people will wait behind until there is no one around and then tell me quietly: I seem to be one of those people who need eight or nine hours sleep. Its embarrassing to say it in public. They would rather wait 45 minutes for the confessional. Theyre convinced that theyre abnormal, and why wouldnt they be? We chastise people for sleeping what are, after all, only sufficient amounts. We think of them as slothful. No one would look at an infant baby asleep, and say What a lazy baby! We know sleeping is non-negotiable for a baby. But that notion is quickly abandoned [as we grow up]. Humans are the only species that deliberately deprive themselves of sleep for no apparent reason. In case youre wondering, the number of people who can survive on five hours of sleep or less without any impairment, expressed as a percent of the population and rounded to a whole number, is zero.

The world of sleep science is still relatively small. But it is growing exponentially, thanks both to demand (the multifarious and growing pressures caused by the epidemic) and to new technology (such as electrical and magnetic brain stimulators), which enables researchers to have what Walker describes as VIP access to the sleeping brain. Walker, who is 44 and was born in Liverpool, has been in the field for more than 20 years, having published his first research paper at the age of just 21. I would love to tell you that I was fascinated by conscious states from childhood, he says. But in truth, it was accidental. He started out studying for a medical degree in Nottingham. But having discovered that doctoring wasnt for him he was more enthralled by questions than by answers he switched to neuroscience, and after graduation, began a PhD in neurophysiology supported by the Medical Research Council. It was while working on this that he stumbled into the realm of sleep.

Matthew
Matthew Walker photographed in his sleep lab. Photograph: Saroyan Humphrey for the Observer

I was looking at the brainwave patterns of people with different forms of dementia, but I was failing miserably at finding any difference between them, he recalls now. One night, however, he read a scientific paper that changed everything. It described which parts of the brain were being attacked by these different types of dementia: Some were attacking parts of the brain that had to do with controlled sleep, while other types left those sleep centres unaffected. I realised my mistake. I had been measuring the brainwave activity of my patients while they were awake, when I should have been doing so while they were asleep. Over the next six months, Walker taught himself how to set up a sleep laboratory and, sure enough, the recordings he made in it subsequently spoke loudly of a clear difference between patients. Sleep, it seemed, could be a new early diagnostic litmus test for different subtypes of dementia.

After this, sleep became his obsession. Only then did I ask: what is this thing called sleep, and what does it do? I was always curious, annoyingly so, but when I started to read about sleep, I would look up and hours would have gone by. No one could answer the simple question: why do we sleep? That seemed to me to be the greatest scientific mystery. I was going to attack it, and I was going to do that in two years. But I was naive. I didnt realise that some of the greatest scientific minds had been trying to do the same thing for their entire careers. That was two decades ago, and Im still cracking away. After gaining his doctorate, he moved to the US. Formerly a professor of psychiatry at Harvard Medical School, he is now professor of neuroscience and psychology at the University of California.

Does his obsession extend to the bedroom? Does he take his own advice when it comes to sleep? Yes. I give myself a non-negotiable eight-hour sleep opportunity every night, and I keep very regular hours: if there is one thing I tell people, its to go to bed and to wake up at the same time every day, no matter what. I take my sleep incredibly seriously because I have seen the evidence. Once you know that after just one night of only four or five hours sleep, your natural killer cells the ones that attack the cancer cells that appear in your body every day drop by 70%, or that a lack of sleep is linked to cancer of the bowel, prostate and breast, or even just that the World Health Organisation has classed any form of night-time shift work as a probable carcinogen, how could you do anything else?

There is, however, a sting in the tale. Should his eyelids fail to close, Walker admits that he can be a touch Woody Allen-neurotic. When, for instance, he came to London over the summer, he found himself jet-lagged and wide awake in his hotel room at two oclock in the morning. His problem then, as always in these situations, was that he knew too much. His brain began to race. I thought: my orexin isnt being turned off, the sensory gate of my thalamus is wedged open, my dorsolateral prefrontal cortex wont shut down, and my melatonin surge wont happen for another seven hours. What did he do? In the end, it seems, even world experts in sleep act just like the rest of us when struck by the curse of insomnia. He turned on a light and read for a while.

Will Why We Sleep have the impact its author hopes? Im not sure: the science bits, it must be said, require some concentration. But what I can tell you is that it had a powerful effect on me. After reading it, I was absolutely determined to go to bed earlier a regime to which I am sticking determinedly. In a way, I was prepared for this. I first encountered Walker some months ago, when he spoke at an event at Somerset House in London, and he struck me then as both passionate and convincing (our later interview takes place via Skype from the basement of his sleep centre, a spot which, with its bedrooms off a long corridor, apparently resembles the ward of a private hospital). But in another way, it was unexpected. I am mostly immune to health advice. Inside my head, there is always a voice that says just enjoy life while it lasts.

The evidence Walker presents, however, is enough to send anyone early to bed. Its no kind of choice at all. Without sleep, there is low energy and disease. With sleep, there is vitality and health. More than 20 large scale epidemiological studies all report the same clear relationship: the shorter your sleep, the shorter your life. To take just one example, adults aged 45 years or older who sleep less than six hours a night are 200% more likely to have a heart attack or stroke in their lifetime, as compared with those sleeping seven or eight hours a night (part of the reason for this has to do with blood pressure: even just one night of modest sleep reduction will speed the rate of a persons heart, hour upon hour, and significantly increase their blood pressure).

A lack of sleep also appears to hijack the bodys effective control of blood sugar, the cells of the sleep-deprived appearing, in experiments, to become less responsive to insulin, and thus to cause a prediabetic state of hyperglycaemia. When your sleep becomes short, moreover, you are susceptible to weight gain. Among the reasons for this are the fact that inadequate sleep decreases levels of the satiety-signalling hormone, leptin, and increases levels of the hunger-signalling hormone, ghrelin. Im not going to say that the obesity crisis is caused by the sleep-loss epidemic alone, says Walker. Its not. However, processed food and sedentary lifestyles do not adequately explain its rise. Something is missing. Its now clear that sleep is that third ingredient. Tiredness, of course, also affects motivation.

Sleep has a powerful effect on the immune system, which is why, when we have flu, our first instinct is to go to bed: our body is trying to sleep itself well. Reduce sleep even for a single night, and your resilience is drastically reduced. If you are tired, you are more likely to catch a cold. The well-rested also respond better to the flu vaccine. As Walker has already said, more gravely, studies show that short sleep can affect our cancer-fighting immune cells. A number of epidemiological studies have reported that night-time shift work and the disruption to circadian sleep and rhythms that it causes increase the odds of developing cancers including breast, prostate, endometrium and colon.

Getting too little sleep across the adult lifespan will significantly raise your risk of developing Alzheimers disease. The reasons for this are difficult to summarise, but in essence it has to do with the amyloid deposits (a toxin protein) that accumulate in the brains of those suffering from the disease, killing the surrounding cells. During deep sleep, such deposits are effectively cleaned from the brain. What occurs in an Alzheimers patient is a kind of vicious circle. Without sufficient sleep, these plaques build up, especially in the brains deep-sleep-generating regions, attacking and degrading them. The loss of deep sleep caused by this assault therefore lessens our ability to remove them from the brain at night. More amyloid, less deep sleep; less deep sleep, more amyloid, and so on. (In his book, Walker notes unscientifically that he has always found it curious that Margaret Thatcher and Ronald Reagan, both of whom were vocal about how little sleep they needed, both went on to develop the disease; it is, moreover, a myth that older adults need less sleep.) Away from dementia, sleep aids our ability to make new memories, and restores our capacity for learning.

And then there is sleeps effect on mental health. When your mother told you that everything would look better in the morning, she was wise. Walkers book includes a long section on dreams (which, says Walker, contrary to Dr Freud, cannot be analysed). Here he details the various ways in which the dream state connects to creativity. He also suggests that dreaming is a soothing balm. If we sleep to remember (see above), then we also sleep to forget. Deep sleep the part when we begin to dream is a therapeutic state during which we cast off the emotional charge of our experiences, making them easier to bear. Sleep, or a lack of it, also affects our mood more generally. Brain scans carried out by Walker revealed a 60% amplification in the reactivity of the amygdala a key spot for triggering anger and rage in those who were sleep-deprived. In children, sleeplessness has been linked to aggression and bullying; in adolescents, to suicidal thoughts. Insufficient sleep is also associated with relapse in addiction disorders. A prevailing view in psychiatry is that mental disorders cause sleep disruption. But Walker believes it is, in fact, a two-way street. Regulated sleep can improve the health of, for instance, those with bipolar disorder.

Ive mentioned deep sleep in this (too brief) summary several times. What is it, exactly? We sleep in 90-minute cycles, and its only towards the end of each one of these that we go into deep sleep. Each cycle comprises two kinds of sleep. First, there is NREM sleep (non-rapid eye movement sleep); this is then followed by REM (rapid eye movement) sleep. When Walker talks about these cycles, which still have their mysteries, his voice changes. He sounds bewitched, almost dazed.

During NREM sleep, your brain goes into this incredible synchronised pattern of rhythmic chanting, he says. Theres a remarkable unity across the surface of the brain, like a deep, slow mantra. Researchers were once fooled that this state was similar to a coma. But nothing could be further from the truth. Vast amounts of memory processing is going on. To produce these brainwaves, hundreds of thousands of cells all sing together, and then go silent, and on and on. Meanwhile, your body settles into this lovely low state of energy, the best blood-pressure medicine you could ever hope for. REM sleep, on the other hand, is sometimes known as paradoxical sleep, because the brain patterns are identical to when youre awake. Its an incredibly active brain state. Your heart and nervous system go through spurts of activity: were still not exactly sure why.

Does the 90-minute cycle mean that so-called power naps are worthless? They can take the edge off basic sleepiness. But you need 90 minutes to get to deep sleep, and one cycle isnt enough to do all the work. You need four or five cycles to get all the benefit. Is it possible to have too much sleep? This is unclear. There is no good evidence at the moment. But I do think 14 hours is too much. Too much water can kill you, and too much food, and I think ultimately the same will prove to be true for sleep. How is it possible to tell if a person is sleep-deprived? Walker thinks we should trust our instincts. Those who would sleep on if their alarm clock was turned off are simply not getting enough. Ditto those who need caffeine in the afternoon to stay awake. I see it all the time, he says. I get on a flight at 10am when people should be at peak alert, and I look around, and half of the plane has immediately fallen asleep.

So what can the individual do? First, they should avoid pulling all-nighters, at their desks or on the dancefloor. After being awake for 19 hours, youre as cognitively impaired as someone who is drunk. Second, they should start thinking about sleep as a kind of work, like going to the gym (with the key difference that it is both free and, if youre me, enjoyable). People use alarms to wake up, Walker says. So why dont we have a bedtime alarm to tell us weve got half an hour, that we should start cycling down? We should start thinking of midnight more in terms of its original meaning: as the middle of the night. Schools should consider later starts for students; such delays correlate with improved IQs. Companies should think about rewarding sleep. Productivity will rise, and motivation, creativity and even levels of honesty will be improved. Sleep can be measured using tracking devices, and some far-sighted companies in the US already give employees time off if they clock enough of it. Sleeping pills, by the way, are to be avoided. Among other things, they can have a deleterious effect on memory.

Those who are focused on so-called clean sleep are determined to outlaw mobiles and computers from the bedroom and quite right, too, given the effect of LED-emitting devices on melatonin, the sleep-inducing hormone. Ultimately, though, Walker believes that technology will be sleeps saviour. There is going to be a revolution in the quantified self in industrial nations, he says. We will know everything about our bodies from one day to the next in high fidelity. That will be a seismic shift, and we will then start to develop methods by which we can amplify different components of human sleep, and do that from the bedside. Sleep will come to be seen as a preventive medicine.

What questions does Walker still most want to answer? For a while, he is quiet. Its so difficult, he says, with a sigh. There are so many. I would still like to know where we go, psychologically and physiologically, when we dream. Dreaming is the second state of human consciousness, and we have only scratched the surface so far. But I would also like to find out when sleep emerged. I like to posit a ridiculous theory, which is: perhaps sleep did not evolve. Perhaps it was the thing from which wakefulness emerged. He laughs. If I could have some kind of medical Tardis and go back in time to look at that, well, I would sleep better at night.

Why We Sleep: The New Science of Sleep and Dreamsby Matthew Walker is published by Allen Lane (20). To order a copy for 17 go toguardianbookshop.com or call 0330 333 6846. Free UK p&p over 10, online orders only. Phone orders min p&p of 1.99

Sleep in numbers

Two-thirds of adults in developed nations fail to obtain the nightly eight hours of sleep recommended by the World Health Organisation.

An adult sleeping only 6.75 hours a night would be predicted to live only to their early 60s without medical intervention.

A 2013 study reported that men who slept too little had a sperm count 29% lower than those who regularly get a full and restful nights sleep.

If you drive a car when you have had less than five hours sleep, you are 4.3 times more likely to be involved in a crash. If you drive having had four hours, you are 11.5 times more likely to be involved in an accident.

A hot bath aids sleep not because it makes you warm, but because your dilated blood vessels radiate inner heat, and your core body temperature drops. To successfully initiate sleep, your core temperature needs to drop about 1C.

The time taken to reach physical exhaustion by athletes who obtain anything less than eight hours of sleep, and especially less than six hours, drops by 10-30%.

There are now more than 100 diagnosed sleep disorders, of which insomnia is the mostcommon.

Morning types, who prefer to awake at or around dawn, make up about 40% of the population. Evening types, who prefer to go to bed late and wake up late, account for about 30%. The remaining 30% lie somewhere in between.

Read more: https://www.theguardian.com/lifeandstyle/2017/sep/24/why-lack-of-sleep-health-worst-enemy-matthew-walker-why-we-sleep

Brain game: how quitting routine tasks can help you learn new tricks

Daniel Glaser explains the benefits of taking on new challenges in middle age

Although his previous attempt at a career break, by becoming an apprentice shoemaker in Florence, didnt last long, it seems Daniel Day-Lewis is serious about retiring this time.

Maybe hes looking for a newchallenge. As we get older, work can feel more routine andeasy, which is born out in terms of brain activity.

Scans show tasks we are practised at often use less energy than novel activities we tend to do them more efficiently, and the mental energy required decreases. Were all familiar with this as our careers advance.

We also get more skilled at spotting our mistakes and rectifying them; as an old hand, you can notice when the edge has gone but you have enough tricks in the bag to make amends. This neuroprotective effect may be behind some of the results that show an apparent delay in symptoms of age-related cognitive decline for those more active in middle age. In this light a preemptive move, like Day-Lewiss, may be more sensible as we become over familiar with what we do.

It is perhaps typical of this most uncompromising of actors that hes quitting while ahead.

Dr Daniel Glaser is director of Science Gallery at Kings College London

Read more: https://www.theguardian.com/lifeandstyle/2017/jul/02/brain-game-quitting-routine-tasks-to-learn-new-tricks