Early intervention is crucial for the successful management of spinal muscular atrophy (SMA), according to the authors of a review study that discusses the progress made in newborn screening and treatment strategies for this disease.
The review study, “Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy,” was published in World Journal of Pediatrics.
SMA is caused by defects in both copies of the SMN1 gene, leading to a lack of functional survival motor neuron (SMN) protein. The SMN2 gene is almost identical to SMN1, and people can have two or more copies of this gene. However, the slight variations between these genes cause SMN2 to produce differently spliced mRNA, and thus much less functional SMN protein.
Based on this, two broad strategies for treating SMA have been proposed and investigated.
The first strategy is to alter the splicing of SMN2, allowing a full SMN protein to be produced. This is how Biogen’s Spinraza (nusinersen), the first treatment for SMA approved by the U.S. Food and Drug Administration and the European Medicines Agency, works. In the Phase 3 ENDEAR clinical trial (NCT02193074), this treatment improved motor function and increased survival rates.
The Phase 2 NURTURE trial (NCT02386553) was designed to test whether Spinraza would be effective for very young infants (less than 6 weeks of age) who had not yet shown SMA symptoms. The trial is still ongoing, though according to interim results announced by Biogen, all 25 of the included infants were still alive at 14 months old. Furthermore, all of them could sit up unassisted, and most could walk to some degree.
Spinraza can only be administered via an injection into the spinal canal. Other compounds designed to have the same effect but that can be taken orally are currently being tested in other studies, namely the Phase 2/3 FIREFISH trial (NCT02913482) and the Phase 2/3 SUNFISH trial (NCT02908685), both of which are assessing risdiplam in different age groups and SMA types.
The second general strategy for treating SMA is through gene therapy, the goal of which is to add a functional version of the SMN1 gene to cells using a modified virus.
Zolgensma, previously known as AVXS-101, is one such investigational gene therapy. Results of a Phase 1 trial (NCT02122952) were promising; most patients had improvements in motor control and survival that persisted over two years of follow-up, with patients who received higher doses doing particularly well. Additional clinical trials are ongoing, and Zolgensma is currently undergoing priority review by the FDA, with a decision on approval expected in May.
Because the above therapies are thought to be most effective when started even before symptoms develop, early detection is critical. Consequently, it’s no surprise that screening newborns for SMA is becoming more widespread — though the researchers point out that there are still hurdles to overcome both for screening and ensuring access to treatment.
This is a concern particularly in China: “Structurally, the Chinese hospital system relies on patient advocacy for care,” the researchers wrote, adding that gene therapies, which require strict physician oversight, may be difficult to implement in a system where “physician visits are often only minutes long.”
They also note that “making new therapies affordable to the average Chinese family will need to be a priority,” and that other barriers, such as social stigma regarding disability, may cause further complications for patients.
Still, they say, the overall outlook is hopeful. SMA has historically been a fatal disease, but as more new therapies are tested and approved and as more and better screening practices are implemented, patient outcomes are likely to keep improving.