Spinal muscular atrophy type 1 is a hereditary disease that causes severe muscle weakness in infants and children. Until now, there was no known cure or disease-modifying treatment for the condition. Clinical trials of a new drug called nusinersen, however, show significant promise.
Spinal muscular atrophy type 1 (SMA-1) – also known as Werdnig-Hoffmann disease – affects around 250 newborn children every year in the United States.
The disease develops when the infant inherits a mutated gene – SMN1 – from both parents. One in 40 people carry the gene mutation responsible for SMA-1.
SMA-1 is the most common genetic cause of death among infants, and the prognosis for those affected is very poor.
The disease kills most infants within 2 years of the diagnosis and, until recently, pediatricians could only recommend that parents make their offspring as comfortable as possible as their health inevitably deteriorated.
A new drug – currently being reviewed for approval by the U.S. Food and Drug Administration (FDA) – has the potential to change that.
In healthy individuals, the SMN1 gene normally encodes a protein called a survival motor neuron (SMN).
This protein protects the nerves that carry signals from the spinal cord to the muscles. Without this protein, the nerves degenerate, causing irreversible muscular atrophy.
Carriers of the faulty gene also have a backup, or a normal copy of the SMN1 gene. This enables carriers to go about their lives without any symptoms.
However, infants with SMA-1 inherit not one but two malfunctioning copies of the SMN1 gene, leading to muscular atrophy.
Ultimately, this makes the patients unable to swallow or even breathe.
According to researchers, there is one section of genetic code that makes the SMN1 gene able to produce the survival motor neuron protein.
The new drug – nusinersen – is able to attach itself to the faulty RNA sequence and “reconstruct” the gene in a way that enables it to produce functional SMN protein.
The drug is still being reviewed for approval by the FDA, and the results of the second phase of its clinical trial have recently been published in theThe Lancet.
Trials for the drug were led by pediatric neurologist Richard Finkel, of Nemours Children’s Hospital in Orlando, FL, and the study was supported by the Department of Pediatrics at Stanford University Medical Center in Stanford, CA.
According to the phase II study, nusinersen is safe and well-tolerated.
The first trial for the drug included 20 children. Although it was initially meant as just a safety test, researchers report that the drug improved patients’ motor function, enabled them to achieve motor milestones, and improved the functioning of the nerves that are normally attacked by the disease.
The FDA have a complex review process in place every time a new drug is proposed. Overall, the review has 12 steps, of which four are clinical trial phases, but the new drug for SMA-1 is moving quickly through the approval process.
Nusinersen has been further evaluated in a phase III study. The trial was stopped early in August, however, because the infants receiving the drug achieved significantly more motor milestones than those in the control group.
The phase III trial is now a so-called open-label study, which means that all the participants can receive nusinersen knowingly, and no placebo is used.
The drug is predicted to be approved by the FDA within the next 2 months, and it is already available as part of an expanded access program at a few hospitals in the U.S., including at Lucile Packard Children’s Hospital Stanford.
Nusinersen is an antisense oligonucleotide.
Antisense oligonucleotides are synthetic single strings of nucleic acids that stick to specific parts of the RNA and can change or inhibit the expression of targeted genes.
There are several trials going on at the moment that aim to treat, prevent, or stop neurodegenerative disorders with antisense oligonucleotides that have shown promise.
Stanford pediatric neurologist Dr. John Day explains that not only does nusinersen change things radically for children with SMA, but it sets a precedent for drugs employing a similar mechanism to treat other genetic diseases. For instance, muscular dystrophy, Huntington’s disease, and amyotrophic lateral sclerosis (ALS) could all benefit from drugs falling in the antisense oligonucleotide category.
Dr. Day directs the Neuromuscular Disorders Clinic at Lucile Packard Children’s Hospital Stanford and is a professor of neurology and of pediatrics at the Stanford University School of Medicine. He also facilitated the access of a baby girl named Zoe Hartings to the nusinersen trial.
When Zoe was first diagnosed with SMA-1 in 2012, nusinersen had already been tested for safety in children with a less severe form of SMA. However, researchers had to further test the drug in children with SMA-1 to see if it actually improved the symptoms.
Dr. Day reached out to the child’s parents and asked them to let Zoe be the first child in the trial. Having looked into the scientific research explaining how nusinersen was expected to work, the parents decided the risk was worth taking.
Zoe started receiving doses of the drug in June 2013, in the form of injections into the spinal fluid. This was done every few months for 4 years.
In the first year, improvements were difficult to notice, as the infant’s nerves had already been significantly damaged before the trial. However, by the patient’s second birthday, it had become apparent that the drug was working.
Improvements in motor skills and muscle strength were deemed “remarkable” by Dr. Day. Zoe started picking up milestones and playing with her toes as she was lying on the back, legs lifted. Soon after, Zoe started speaking, and later on she got strong enough to sit and keep control of her head.
Zoe is still reported to be making gradual progress, going to preschool, playing catch, and using a motorized wheelchair. In the near future, she will be able to use a recumbent bicycle, which will strengthen her legs.
Dr. Day stresses the importance of getting the drug as soon as possible for maximum benefit. Nusinersen will be even more effective than it was for Zoe in patients who get it immediately after the diagnosis, he adds. Families, he advises, should not waste valuable time, even if the doctor diagnosing their child says there is nothing they can do.
“If we identify children early on, before they become symptomatic, we can be optimistic that it will effectively cure them. My goal is to get the word out so that no patient experiences that delay. [Time] is critical.”
Dr. John Day