Stories about: spinal muscular atrophy

Antisense drug for spinal muscular atrophy nears the clinic

spinal muscular atrophy Spinraza
Max High of South Carolina was diagnosed with SMA before the age of 1. (Ron Brinson/Flickr)

Update: Nusinersen received FDA approval on December 23, 2016, and will be marketed as Spinraza.

In recent months, two Phase III clinical trials have shown a clear benefit of nusinersen in children with spinal muscular atrophy (SMA), a genetic motor neuron disease that robs children of muscle control and is the leading genetic cause of infant mortality. The ENDEAR trial, involving infants with the more severe SMA Type 1, was first to terminate randomization in August 2016. The CHERISH trial, involving older children with milder Type 2 SMA, was halted on November 8, 2016, because it also met its efficacy target.

Both trials are now open-label, and the FDA has granted nusinersen a priority review. The drug, formerly called SMNRx and now brand-named Spinraza, is an antisense oligonucleotide works by altering gene splicing (see sidebar).

Vector asked Basil Darras, MD, director of the Spinal Muscular Atrophy Program at Boston Children’s Hospital, to put these developments in perspective. Darras is site principal investigator at Boston Children’s for both trials. The hospital was the first in the world to enroll a child with SMA Type 1 in the ENDEAR study, in 2014.

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Rallying a backup gene could boost strength in spinal muscular atrophy

Vivienne-20150819

Ed note: As of November 2016, Vivienne remains stable. On December 23, 2016, her test drug, to be marketed as SPINRAZA (TM), was approved by the Food and Drug Administration for all forms of SMA.

Spinal muscular atrophy (SMA), a condition affecting one in every 6,000 to 10,000 children, is caused by a defect in a gene called SMN1 — which stands for “survival of motor neuron.” The defect leaves children with too little functioning SMN protein to maintain their motor neurons, which begin wasting away. Muscle strength declines and children eventually develop difficulties eating and breathing.

For Vivienne, whose name means “to live,” that meant being slow to reach motor milestones like crawling, cruising and walking as a toddler. For her parents, it meant hearing that her life expectancy would not be normal.

But a new back-door approach seems to be helping Vivienne, now in first grade, at least thus far.

As it happens, most of us carry a backup gene for SMN1 — namely SMN2.

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Spinal muscular atrophy: Helping nerve fibers find their way

Replacing the missing SMN protein seems to strengthen muscles in mice -- but not in human trials. Now, a closer look at SMN's function offers up new leads for drug discovery.

Spinal muscular atrophy is sometimes referred to as a “Lou Gehrig’s disease of babies.” About 1 in 40 people carry the defective gene for this untreatable recessive disease, which causes progressive muscle degeneration and is the leading genetic killer of infants and toddlers. Affected children have weak, floppy legs and arms and must go on ventilators, too weak to breathe on their own.

Researchers have had some success in mouse models of spinal muscular atrophy by adding back SMN, the protein that’s missing or abnormal, or getting the mice to produce more of it. The mice live longer, and do seem to have stronger muscles. But not so in human clinical trials to date.

Looking for another approach, Mustafa Sahin and Judith Steen in Children’s F.M. Kirby Neurobiology Center asked a simple question: What does SMN do?

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