“TO SEE children who would have been dead sitting and standing is something I never thought I would see.”
Professor Francesco Muntoni, University College London, is talking about videos of children given an experimental drug for treating spinal muscular atrophy. This genetic disorder involves the deterioration of nerves connecting the brain and spinal cord to the body’s muscles. Children with the severest form can’t sit upright and seldom survive past the age of 2. Yet a few parents have posted videos online showing children given the drug, called nusinersen, who appear to be sitting and even walking with assistance.
The trial of nusinersen was stopped in August when it became clear it was effective, making it unethical not to give the real drug to those on the placebo.
The full results haven’t yet been published, but what has been revealed so far of this “antisense” therapy suggests we have overcome the biggest obstacle – how to deliver such therapies – at least in disorders that affect the nervous system. The breakthrough could open the floodgates for similar treatments for neurological conditions such as Huntington’s, motor neurone disease and possibly even Alzheimer’s.
Antisense drugs are essentially pieces of DNA that bind to specific RNAs – the recipe that cells use to make proteins. By binding to RNAs, they can block the production of proteins, or alter their form.
These drugs have the potential to prevent or cure many diseases. But there’s been a huge snag: if naked DNA is injected into people, it doesn’t last long, let alone get into cells. So biologists have spent decades trying to create synthetic forms that can survive in the body. They have strengthened the DNA backbone, for example, to help it bind more strongly to RNA. They have also made tweaks that help it enter nerve cells.
Nusinersen is one such modified antisense drug. Reports of its success have created great excitement among parents of children with spinal muscular atrophy, but we need to be cautious about individual reports, says neuroscientist James Sleigh at the University of Oxford.
Even if the final results show nusinersen doesn’t work as well as hoped, there is still cause for optimism. Animal studies, and postmortems of children who died despite being given nusinersen, show widespread distribution of the antisense molecule in the brain and spinal cord, says Muntoni, who has helped develop and test therapies such as nusinersen.
These findings, and others, show it is possible to get antisense molecules into nerve cells, meaning improved versions should soon become available.
“It became clear that the drug was effective, meaning it was unethical to keep giving the placebo, I think it will happen surprisingly quickly,” says Dr Edward Wild at the National Hospital for Neurology and Neurosurgery in London, who is part of a team testing an antisense drug for Huntington’s disease.
This inherited condition remains untreatable despite decades of attempts to develop therapies. With the delivery problem seemingly cracked, Wild thinks that will soon change. The Huntington’s antisense drug that Wild’s team is trialling has passed initial safety tests with flying colours.
Such therapies could be used to treat a range of disorders, possibly including Alzheimer’s. There is no single mutation that causes Alzheimer’s, says Wild, but we know of several gene variations that increase the risk of the disease. In theory, blocking the production of proteins encoded by these genes could delay or prevent people becoming ill.
The downside of antisense treatments is that repeat doses are required at least every few months, and often for life. The drugs have to be injected directly into the cerebrospinal fluid, which flows around the brain and spine. This procedure, called a lumbar puncture, can cause side effects including headaches and back pain.
But Muntoni and colleagues may have found a way to modify the antisense molecules so they can cross the blood-brain barrier, meaning they can be injected into the bloodstream. Animal studies published last month suggest this approach works well, Sleigh says, but it has not yet been tested in people.
The advent of therapies for genetic conditions considered untreatable could change the way we approach them. If treatments become available for childhood disorders such as spinal muscular atrophy, it will mean children should be tested for the condition at birth so they can begin therapy as soon as possible.
It could also change the way adults approach genetic sequencing of their own genes. At present, most people who have their genome sequenced opt not to find out if they have inherited diseases such as Huntington’s, preferring not to know their fate. But if it becomes treatable and perhaps even preventable, they may wish to start therapies early.
“As soon as we have something that works, people will want to get tested,” says Wild.
Source: University College London