More than a decade ago, the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) launched a special project to accelerate the translation of basic scientific discoveries into new treatments for a rare and often fatal disease. Five-year-old Faith Fortenberry whom you see above is among the kids who may benefit from the success of this pioneering endeavor.
Faith was born with spinal muscular atrophy (SMA), a hereditary neurodegenerative disease that can affect movement, breathing, and swallowing. When the NIH project began, there was no treatment for SMA, but researchers had discovered that mutations in the SMN1 gene were responsible for the disorder. Such mutations cause a deficiency of SMN protein, leading to degeneration of neurons in the brain and spinal cord, and progressive muscle weakness throughout the body. The NIH effort supported research to discover ways of raising SMN levels in cells grown in lab dishes, and then worked closely with patient advocates and pharmaceutical companies to move the most promising leads into drug development and clinical testing.
Given the desperate need for SMA treatments and all of the scientific energy that’s been devoted to pursuing them, I’ve been following this field closely. So, I was very encouraged to learn recently about the promising results of human tests of not just one—but two—new treatments for SMA [1, 2].
One of the studies highlights nusinersen (Spinraza). This became the first FDA-approved drug for kids and adults with SMA almost a year ago . Nusinersen capitalizes on a redundancy in the human genome; it contains a second copy of the SMN gene, called SMN2. In fact, that second copy encodes the very same SMN protein. The trouble is that, the vast majority of the time, cells edit RNA transcribed from the SMN2 gene in such a way that a key segment gets left out. As a result, SMN2 fails to produce a protein that might rescue an individual whose SMN1 gene is not working.
That’s where nusinersen enters the picture. Nusinersen isn’t a typical drug. Rather, it’s made up of small single-stranded snippets of DNA, or oligonucleotides. Each is 18 nucleotides long and specially designed to bind to the SMN2 transcript in just the right spot. That “tricks” cells into producing the complete, functional SMN protein from the backup gene. In fact, this strategy arose directly from that earlier NIH push for targeted SMA research!
The strategy caught the attention of Ionis Pharmaceuticals and later Biogen, and a clinical study of nusinersen was launched in older children with a less severe form of SMA. The drug had to be administered through a spinal tap, because the blood-brain barrier would otherwise prevent the drug from reaching the brain and spinal cord. The initial results looked encouraging.
Last year, a team led by Richard Finkel at Nemours Children’s Hospital in Orlando, FL, published the results of another nusinersen study involving 20 infants with the most severe form of SMA . It brought more good news. Babies receiving the highest dose of nusinersen lived longer and showed signs of improvement in grasping ability, sitting, and other developmental milestones. Without the treatment, those youngsters would have been expected to show a progressive decline. An analysis of tissue from some of the children who died despite treatment also confirmed the drug made its way through the spinal fluid into neurons, where it increased levels of SMN protein.
The next step for Finkel’s team was to test the drug in a larger Phase III randomized study in which parents and most of the caregivers wouldn’t know which children received the drug. In that international study, just reported in The New England Journal of Medicine, 81 infants received nusinersen via an injection into their spinal canal up to six times over almost a year. Another 41 received a sham procedure, consisting of small pricks to the base of their spines that were then bandaged to make it appear they had been treated.
An interim six-month analysis showed that 41 percent of babies receiving the drug had improvements in physical abilities, including head control and sitting. None of the untreated babies showed any improvement. In fact, the results were so clear, the researchers halted the trial to allow all the children to begin receiving nusinersen.
In the final analysis, children in the nusinersen group were living longer. Some of them also showed remarkable improvements in meeting developmental milestones: 22 percent had full head control, 10 percent could roll over, 8 percent could sit independently, and 1 percent could even stand by themselves. In the untreated group, none reached any of those milestones. This evidence, together with earlier results and those of another clinical trial not yet reported testing nusinersen in older children, represents very encouraging news for families affected by SMA.
But, what if, rather than tricking cells into producing SMN protein, it were possible to simply correct the genetic defect that’s responsible for SMA in the first place, by supplying a functioning copy of the responsible gene? It might sound too good to be true, but the second paper in The New England Journal of Medicine reports results from this exact strategy. And, while longer-term study is needed, the results are again extremely encouraging.
In the study led by Jerry Mendell at Nationwide Children’s Hospital, Columbus, OH, 15 infants with the most severe form of SMA received a one-time intravenous infusion of a modified virus carrying a good copy of the SMN1 gene. Three of the babies received a lower dose, while another 12 received a higher dose.
At the end of the study, all indications were that the treatment was safe and well tolerated by the babies. The babies that received the higher dose of gene therapy also showed remarkable improvements, with most of them gaining head control. Most could also roll over and sit without any assistance.
By one year, babies with the most severe form of SMA typically need help to breathe and eat. They usually can’t speak or swallow. And yet, of the 12 infants who received the highest dose of gene therapy, 11 could speak and eat when the study ended. All infants in the study were also alive at 20 months. That’s compared to a typical survival rate of just 8 percent at 20 months for babies with severe SMA.
Both studies suggest that early treatment, ideally before symptoms start, will be key in giving children with SMA their best chance. Infants treated earlier generally fared better, both for survival and physical abilities. A clinical trial of nusinersen begun in infants who don’t yet show symptoms is already under way. To help make early treatment possible, there’s now a push to add SMA to the list of diseases included in newborn screening .
The SMA gene therapy has been licensed to a drug company called AveXis. This past summer, the FDA designated it as a breakthrough therapy based on the strength of the early trial results. Mendell reports that infants are already being recruited for a Phase III clinical trial. As we await those results, nusinersen is already FDA-approved, giving new hope to the Fortenberry family and offering me another reason to be grateful this Thanksgiving.
 Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. N Engl J Med. 2017 Nov 2;377(18):1723-1732.
 Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. N Engl J Med. 2017 Nov 2;377(18):1713-1722.
 FDA approves first drug for spinal muscular atrophy. FDA. 2016 Dec 23.
 Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Lancet. 2016 Dec 17;388(10063):3017-3026.
 SMA Could Soon Be on Newborn Screening List in the U.S. SMA News Today. 2017 May 18.
Spinal Muscular Atrophy (National Institute of Neurological Disorders and Stroke/NIH)
Richard Finkel (Nemours Children’s Hospital, Orlando, FL)
Jerry Mendell (Nationwide Children’s Hospital, Columbus, OH)
Faith Fortenberry, Who Lives With SMA, is Seeing Positive Results Thanks to Spinraza. Hlywak S. Strongly, MDA. 2017 November 9.
NIH Support: National Institute of Neurological Disorders and Stroke