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Boston Children’s Hospital is known for pioneering treatments and has the world’s largest research program at a pediatric institution. We have been active in both clinical and laboratory research on spinal muscular atrophy (SMA) since 2004 under the leadership of our director, Basil Darras, MD.

Nusinersen (Spinraza) clinical trials

Nusinersen is a drug that has been shown to increase the survival of motor neurons that die off in SMA, robbing children of muscle control. The drug compensates for the effects of the SMN1 mutation by rallying a “backup” gene, known as SMN2. SMN2, like SMN1, also makes the SMN protein needed to keep motor neurons healthy, but most of it is truncated and nonfunctional. Nusinersen uses a genetically based technology called antisense oligonucleotide to shore up this backup gene. This enables people to make more of the full-length, functional SMN protein.

Boston Children’s has been involved in clinical trials of nusinersen, sponsored by Ionis Pharmaceuticals and Biogen, since it was first initiated in 2011. We were the first in the world to enroll an infant with type 1 SMA in the Phase 3 ENDEAR trial, in 2014. This trial enrolled infants under 7 months of age and randomly assigned them to receive nusinersen, given by injection into the spinal canal through a lumbar puncture, or a placebo (a “fake” lumbar puncture). In the final analysis, 51 percent of babies given nusinersen — versus none of the babies given placebo — achieved some improvement in motor milestones (head control, rolling over, sitting, standing, and, in a few cases, walking with support). The trial was stopped in August 2016 because of positive findings in an interim analysis.

A second trial, called CHERISH, evaluated nusinersen in children with later-onset SMA ages 2 to 12 who had the ability to sit independently but not walk independently. Children receiving nusinersen showed improved motor function, and this trial was also stopped due to positive findings, in November 2016.

Because of these positive results, the FDA gave nusinersen priority review status and approved the drug in December 2016 for all forms of SMA. The drug has been marketed by Biogen under the brand name Spinraza™.

Risdiplam (Evrysdi) clinical trials

Risdiplam is an oral drug taken daily that also appears to boost the production of the SMN protein through the SMN2 gene. Our researchers are an essential part of the clinical testing of risdiplam in the FIREFISH and JEWELFISH studies, which both continue to look at the drug’s efficacy and side effects in infants through adults.

The FIREFISH study involves infants age 1 month to 7 months with infantile-onset SMA, the most severe type. The babies receive risdiplam given as an oral drug daily. The drug increases SMN protein in the infants and improves their ability to sit without support. After two years of treatment, the FIREFISH study shows that 59 percent of treated babies were able to sit without support for five seconds, 65 percent maintained upright head control, 29 percent were able to turn over, and 30 percent were able to stand with support or supporting weight.

One-year results from the JEWELFISH study of risdiplam in children with all types of SMA aged 6 months to 60 years and previously treated with other SMA therapies, showed that risdiplam increases SMN protein levels. The drug appears to double SMN levels among patients who were previously treated with nusinerson or Zolgensma, highlighting its potential as an alternative or add-on therapy to those drugs.

Gene therapy trials

To learn more about the potential for gene replacement in children with SMA, we have been involved in several clinical studies. The first, the STR1VE trial, studied intravenous administration of the therapy in infants less than 7 months of age with type 1 SMA. This trial, which followed infants until they were 18 months old, provided the data used by the FDA to approve Zolgensma for the treatment of babies under 2 years.

The STRONG study involves intrathecal (inside the spinal canal) administration of the gene therapy for children between the ages of 6 months to 5 years with SMA type 2. STRONG is on an FDA-hold pending evaluation of pre-clinical information.

SMA Natural History Study

To help families plan for their children’s future and provide a benchmark for evaluating new treatments, Boston Children’s has been involved in long-term studies since 2005 to track the progression, or “natural history,” of SMA over time. The SMA Natural History Study, supported by the SMA Foundation, evaluated children with SMA types 1, 2, and 3 every two to six months, testing muscle strength, motor function, muscle mass, respiratory function, and quality of life. This study was conducted through the Pediatric Neuromuscular Clinical Research (PNCR) Network, together with Columbia University Medical Center, Children’s Hospital of Philadelphia, and the University of Rochester Medical Center.

Newborn screening

Boston Children’s has been at the forefront of advocating for newborn SMA screening that led to Massachusetts becoming one of the first two states to offer this service. Results of a recent study of almost 180,000 newborns in Massachusetts identified nine SMA-affected infants, all of whom were referred to a specialist by their sixth day of life. All of these infants entered into treatment programs. The early data shows that some SMA-affected children have remained asymptomatic and are meeting developmental milestones, and some have mild to moderate delays. Our experience in Massachusetts demonstrates that SMA newborn screening is feasible, can be implemented on a population basis, and helps engage infants for early treatment to maximize benefit.

Visit PubMed to view abstracts about our clinical SMA research.