There have been few happy endings when it comes to spinal muscular atrophy (SMA), the most common genetic cause of death in childhood. The disease inexorably destroys the motor neurons of the spinal cord and brainstem that control movement, including swallowing and breathing. In its most severe form, SMA kills those afflicted at about age 2, most commonly by suffocating them. There are no Food and Drug Administration (FDA)–approved drugs for the disease. That is almost certainly about to change.
An innovative drug that helps cells bypass the genetic flaw responsible for SMA may be approved as soon as this month, on the heels of strongly positive results from late-stage clinical trials. On 7 November, a trial of the drug, nusinersen, in wheelchair-bound children aged 2 to 12, was stopped on the grounds that it was unethical to deny the drug to children in the control arm, given the positive results in the treated children. In August, a similar trial in infants was stopped for the same reason, allowing the untreated infants in a control arm to begin receiving the drug. And today, a paper appearing in The Lancet provides compelling biological evidence that nusinersen is having its desired effect in the cells of the brain and spinal cord.
“These [infant-onset] SMA kids are going to die. And not only are they now not dying, you are essentially on the path to a true cure of a degenerative [neurological] disease, which is unheard of,” says Jeffrey Rothstein, a neurologist at the Johns Hopkins School of Medicine in Baltimore, Maryland, who was not affiliated with the trials of the drug and is not connected with either of the two companies involved in its development: Ionis of Carlsbad, California, and Biogen of Cambridge, Massachusetts.
Spinal muscular atrophy affects between one in 8000 and one in 12,000 infants, and about one in 50 adults are unaffected carriers. If both parents are carriers, their chance of having an affected infant is 25%. In affected children, the protein produced by the gene SMN1—for “survival of motor neuron-1”—is defective or missing. Although the protein’s functions are not fully understood, what is certain is that motor neurons die in its absence.
Children with milder forms of spinal muscular atrophy can survive longer, and even through adulthood, depending on how many copies they carry of a slightly different gene, SMN2, that produces a modest amount of the same protein, SMN. But the way cells typically translate the SMN2 DNA sequence, most of its protein is truncated and is quickly degraded.
In 2003, Adrian Krainer and his postdoctoral colleague Luca Cartegni, biochemists at the Cold Sping Harbor Laboratory in New York, engineered a synthetic, RNA-like molecule that in the test tube changed how the transcripts from SMN2 are spliced into the mature messenger RNAs that then are translated into protein—in principle, this could boost production of the normal, full-length SMN protein. Three thousand miles away, at Isis—now renamed Ionis—a scientist named Frank Bennett noticed the work, published in Nature Structural Biology, and called Krainer. The Spinal Muscular Atrophy Foundation provided funding for Krainer to hire researcher Yimin Hua. Hua’s extensive work in Krainer’s lab, in collaboration with Ionis, led to the identification and preclinical development of nusinersen, a snippet of modified RNA called an antisense oligonucleotide that intervenes in the splicing process to ensure that SMN2 expresses the full-length SMN protein.
After extensive preclinical development and testing, the drug began trials in SMA patients in late 2011. In a phase II trial described in The Lancet today, Ionis and academic collaborators report that it extended the life spans and improved the motor function of babies with severe SMA, compared with the disease courses in natural history studies of untreated babies. To receive nusinersen, the babies had to have developed SMA symptoms between 3 weeks and 6 months of age; the drug was injected into the cerebrospinal fluid surrounding the spinal cord.
Of the 20 babies that started treatment in the trial during 2014 and 2015, 13 are alive and breathing on their own today, at 2 and 3 years old. even though half of untreated babies with this form of SMA ordinarily die or end up on ventilators before their first birthdays. The treatment didn’t save every child: a 5-month-old and an 11-month-old died of respiratory infections, and a 1-year-old died from asphyxiation; another infant died of the disease at nearly 7 months old.
Still, when the brain cells and spinal cord cells of these babies were examined at autopsy, there was clear evidence that nusinersen had tricked SMN2 into producing a great deal more of the full length, motor neuron-protecting protein: two to six times more copies of SMN’s messenger RNA were found in spinal cord samples from nusinersen-treated babies than in autopsy samples from untreated infants. Tissue studies also showed that the drug had been taken up into motor neurons throughout the spinal cord, and into neurons and other cells in the brain, at levels higher than those thought necessary for the drug to be effective. And there was more full-length SMN protein in the spinal cords of the treated infants than in untreated babies who died of spinal muscular atrophy.
Although just published in The Lancet, those findings have since been overtaken by strikingly positive results from the larger phase III trials. In their November announcement about the second trial’s halt, Ionis and Biogen, which has licensed nusinersen and has dubbed it Spinraza, said the treated children experienced a “highly statistically significant improvement” in motor function compared to untreated children. The companies had used an established, widely used test of motor movements that monitors actions like sitting, standing, putting the hands on the head and taking steps.
Stanley Crooke, the CEO of Ionis, is bluntly enthusiastic. “The babies [with the severest disease] are alive and the longer we treat the better they seem to get,” he says. “It’s a miracle.”
Whether drug regulators agree remains to be seen. But both FDA and the European Medicines Agency have entered nusinersen in their fast track processes for drug approval. The companies say that they are preparing for FDA approval of Spinraza as soon as this month, or in the first quarter of 2017.
*Correction, 24 February 2017, 2:09 p.m.: Because of an editing mistake, the contributions of Yimin Hua to the development of nusinersen were removed from the original version of this story. Hua, now at the Institute of Neuroscience at Soochow University in Jiangsu, China, led the initial work at Cold Spring Harbor Laboratory on developing the drug and is named as co-inventor on nusinersen’s patent.
*Update, 23 December: FDA today approved the use of nusinersen to treat spinal muscular atrophy. This story on the drug was originally published on 6 December.