Success in trials for Huntington’s and Spinal Muscular Atrophy raises hopes that diseases such as Alzheimer’s and ALS could be tackled using a new class of drugs

They are diseases that threaten more than physical health: memories, personality, and the ability to move and speak are incrementally stolen. And until this year neurodegenerative diseases, from Alzheimer’s to ALS, had been entirely unstoppable.

However, a breakthrough in Huntington’s disease this week suggests this bleak picture could be about to change. The landmark trial was the first to show that the genetic defect that causes Huntington’s could be corrected, raising hopes that the drug will become the first to slow the progress of the disease – or even stop it.

The Huntington’s results alone would have been remarkable enough, but they come just a month after the same experimental class of drugs were revealed to help patients with a different degenerative disease, called Spinal Muscular Atrophy (SMA). Babies with the most severe form of SMA normally never develop the strength to sit up or roll over, but after four years on the drug, some of these children are starting to stand and take their first steps with a walker.

Q&A What is Huntington's disease? Show Hide Huntington’s 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.

The two trials have triggered a wave of optimism that drugs built on similar principles could be used to target a wide range of deadly brain disorders, possibly even Alzheimer’s and Parkinson’s. “I don’t want to overstate this too much, but this could be a turning point,” said Prof John Hardy, a neuroscientist at University College London who was awarded the Breakthrough prize for his work on Alzheimer’s.

Hardy describes the results as potentially the biggest advance for neurodegenerative disease in 50 years. “If it’s worked for one, why can’t it work for a lot of them? I am very, very excited,” he added.

The power of this new class of drugs – called antisense oligonucleotides – comes from their unique ability to home in on genetic flaws and shut down their destructive effects at source. They work by intercepting messenger molecules known as RNA, which are responsible for translating instructions in the genetic code into proteins.

The synthetic DNA used in the treatments can be built in the lab, like Lego, meaning that scientists can now use nature’s own machinery to intervene and switch the production of proteins on and off.

In Huntington’s, the drug called Ionis-HTTRx works by killing off the messenger molecule that is responsible for producing a toxic protein called huntingtin. A larger trial is expected to show whether this also slows or reverses the progression of the disease.



The SMA drug, Nusinersen, has already crossed this milestone. When babies were injected with the medicine in a phase 3 trial, they not only stabilised but began to gain strength. In fact, the success was so striking that the trial was stopped early so the babies who had been placed on a placebo treatment could be immediately switched to the drug.

“It’s a sentinel moment,” said Richard Finkel, the paediatric neurologist at the Nemours Children’s Hospital in Orlando, Florida, who led the trial. “Having spent 30 years telling parents that we had nothing to offer their baby except for comfort care, basically sending them home with a death sentence, having something that can be offered to them is remarkable. It’s not a cure, but it’s a great first step.”

The SMA drug works in the reverse direction – instead of blocking the production of a bad protein, it manages to restore the body’s ability to make a protein that is essential for the survival of neurons in the base of the brain and spinal cord.

Preliminary results from a new trial suggests that when the drug is given before symptoms appear (typically about three months old) its effects can be even more profound. Babies in the latest trial, who were given the drug from shortly after birth, are, incredibly, showing no physical signs of their illness.

They have learned to sit and roll over, and two of the three babies Finkel is treating were walking at their first birthday. “The [third one] is a little hesitant, but she’s healthy as can be,” he said. “These babies are doing remarkably well.”

Finkel said there is now a strong case for adding SMA to the panel of diseases such as cystic fibrosis that are routinely screened for at birth because, for the first time, there is a treatment.

Since bad proteins, or missing proteins, lie at the heart of all neurodegenerative diseases, a race is now underway to find new targets that synthetic DNA drugs could be applied to.

A protein called synuclein is implicated in Parkinson’s and the production of amyloid and tau are known to run out of control in Alzheimer’s and some other dementias. However, it is not yet clear whether blocking these substances in the brain will help – and the many previous drugs aimed at doing so have failed in clinical trials.

Facebook Twitter Pinterest Prof Sarah Tabrizi, director of University College London’s Huntington’s Disease Centre who led the trial. Photograph: David Bishop, UCL Health Creatives

Tim Miller, David Clayson professor of neurology at Washington University in St Louis, led the preclinical testing of a drug aimed at lowering tau in the brain. In mice, it reversed the animals’ brain damage, halted memory loss and extended their lives.

The biotech company Ionis, which was behind the Huntington’s success, is now carrying out a clinical trial of the treatment in early Alzheimer’s patients that is expected to end in 2020.

Miller describes the recent results in SMA and Huntington’s as a “massive deal”, that have added to his confidence in trying the approach for other degenerative diseases. He is also involved in a trial for a genetic form of ALS. “We don’t know whether there will be success yet,” he said. “I want to be a little bit careful, because we just don’t know yet.”

If the drugs were ultimately shown to help treat the kinds of dementias that affect millions of people, it would pose a new problem of economics rather than science.

DNA strands cannot be conveniently packaged into a pill form, and the drugs have to be spinally injected in order to have an impact in the brain. In a recent talk, Hardy estimated the current cost of treating a single patient with this kind of drug at $750,000 per year. Of course, the figure would come down if more patients were treated, he said, but from a high starting point. There would also be the question, ethical and economic, of whether treatments that just slowed the progress of dementia, potentially prolonging the period of decline, could be justified.

“These are very complicated questions,” said Hardy. “It’s going to be a challenge for neurologists and the health service in general.”