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Two New Ways to Treat A Deadly Disease: Spinal Muscular Atrophy

I don’t think I’ll ever tire of covering new ways to treat genetic diseases that I’d always thought hopeless. Teamed with expanded newborn screening, the brave new treatments may even be able to prevent symptoms.

Recently reports in the medical journals of success seem to be accelerating, despite the long regulatory pipeline. Gene therapy has had promising results for adrenoleukodystrophy, two forms of severe combined immune deficiency, and a form of inherited visual loss (RPE65 mutation–associated retinal dystrophy), while protein-refolding drugs have been working on more of the mutations that cause cystic fibrosis.


Sickle cell disease illustrates the multiple approaches being deployed. It’s already treatable with a stem cell transplant or the drug hydroxyurea that reactivates fetal hemoglobin. Options in clinical trials include a once-daily pill (voxelotor) that prevents sickled cells from glomming together, gene therapy, and even the new-kid-on-the-block gene editing, which can so far correct the mutation in stem cells from patients.

This week I’m happy to welcome spinal muscular atrophy (SMA) into the club of conquerable single-gene diseases, and what’s so exciting is that two different DNA-based strategies seem to work: antisense oligonucleotides and gene therapy. Reports are in this week’s New England Journal of Medicine, which I covered for Medscape Medical News here.

SMA damages the motor neurons in the spinal cord, producing extreme weakness and “floppiness,” eventually impairing breathing. It is the most prevalent genetic cause of infant mortality, affecting 1 in 10,000 newborns in the US. One in 50 people are carriers.

Babies with SMA typically don’t live beyond two years, although I visited a hospice patient who was 7 – she was on a respirator and feeding tube, and couldn’t move or respond. At the other end of the severity spectrum are the fetuses that barely move and, if born, are floppy and blue and only live a few days.

Neurons are small in mice with SMA (Sumner lab, Johns Hopkins Medicine)


A genetic quirk makes an antisense approach possible. The causative gene, “survival motor neuron 1” (SMN1), has an echo, a second gene right near it on chromosome 5 in reverse orientation, SMN2. (It’s a little like the situation with sickle cell disease). Most people’s two copies of SMN2 harbor a glitch that disables it, so it only makes a tiny amount of the SMN protein that motor neurons require. The antisense approach corrects that glitch with a DNA-like fragment of nucleic acid that binds to the echo gene, freeing it to direct synthesis of the vital protein. And it works – to an extent.

FDA approved the antisense drug nusinersen (Spinraza) in late 2016. (DNA Science covered the drug’s development and told one family’s story here.) Yesterday the NEJM updated the findings.

Some children given the antisense drug – a series of spinal cord injections – can begin to do things that would otherwise never happen. Of 73 treated children, 37 showed clear signs of improvement: lifting the head, rolling over, sitting, and one child could stand. Of the 37 children in the control group (given a pinprick and a band-aid on the lower spine), none improved. The treated kids also survived longer and the earlier the treatment, the better the outcome. Once the good results came in, the clinical trial was changed to treat the control group patients too.

Gene therapy to treat SMA introduces working copies of the SMN1 gene aboard viruses (AAV9), given in a single intravenous infusion. Three kids given a low dose improved slightly, but 12 kids receiving a higher dose experienced new skills: 11 sat unassisted, 9 rolled over, 11 ate and spoke, and 2 took a few steps on their own. For SMA, that’s big.

By 20 months after treatment, all 15 children were alive, compared to only 8% survival at that point among untreated individuals. And they’ve continued to do well for two years.


The kids who did the best – taking tentative steps – had been diagnosed the earliest, before symptoms appeared, because they had siblings with SMA. That finding argues for the value of eventually adding SMA to the uniform newborn screening panel.

For a terrific look at the SMA gene therapy and one little girl’s incredible story, see this article by Jocelyn Kaiser in Science.

New treatments for fatal diseases introduce a medical phenomenon for which I don’t have a name, but which I heard Barry Byrne, MD PhD, director of the Powell Gene Therapy Center at the University of Florida College of Medicine, address at a meeting at the New York Academy of Sciences last spring: Does a treatment that allows survival bring new symptoms?

Dr. Byrne was discussing the success of enzyme replacement therapy (ERT) for Pompe disease, which would otherwise clog cells of the heart, muscles, liver, and lungs with glycogen, causing death on average at about 9 months of age. ERT, which became available in 2006, enables patients to survive for years. But after 18 months, some of them require assisted ventilation, from a few hours a day to round-the-clock. Why does this happen?

Researchers were puzzled but had an idea. “We think survival after treatment led to significant improvement in heart function, but also enabled better respiration because lung capacity increased. An associated neurological component emerged that wasn’t known because patients otherwise wouldn’t have survived past 18 months. We wanted to understand more,” said Dr. Byrne.

It turned out that the deficiency of the enzyme alpha-glucosidase in Pompe disease also damages motor neurons, which are beyond the reach of ERT, which can’t cross the blood-brain barrier to enter the spinal cord. The phrenic nerves that control the diaphragm are too weak to move the lungs as a child becomes able to breathe, eventually requiring mechanical ventilation. “In Pompe disease the child has to compensate with chest well movement and not the diaphragm,” explained Dr. Byrne.

Preclinical studies are important throughout research, even after a drug is on the market. (NHGRI)

Once experiments in mice revealed the swollen axons and neuromuscular junctions of the phrenic nerves in Pompe disease, Dr. Byrne and his colleagues had a new target. In 2011 they began developing gene therapy that delivers the instructions for the enzyme in three injections into the diaphragm, reaching where ERT cannot: to the nerve cells. So far 4 of 9 treated children have improved, and they’re the ones not on full-time mechanical ventilation.


The results of gene therapy are going to be wide-ranging, and not always a forever fix. Some, like Luxturna that returns vision, will be life-altering, even if further doses are needed if photoreceptors outside the reach of the introduced genes continue to degenerate. Other gene therapies might halt a disease, preventing worsening of existing symptoms and the appearance of new ones so that a child feels well enough to do the hard work, the physical and occupational therapies, that can built enough strength and flexibility to impact activities of daily living. Yet other gene therapies may dampen the worst symptoms so that a child survives beyond what was normal for the condition, only to face new problems.

We just don’t know, and every disease partially conquered will be different.

That last possibility, survival but with new challenges, might be what awaits the children with SMA who receive either antisense or gene therapy. But for a disease that historically prevents most kids with the infantile form from reaching their first birthdays, either approach is a giant step forward.


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