Targeted therapy improvements cap a decade of innovation in spinal muscular atrophy care

Ten years ago, spinal muscular atrophy (SMA) was uniformly fatal because no effective therapies existed. But innovation has been the hallmark of the last decade of SMA treatment — setting the stage for today, where therapy options are now helping children thrive. A faulty SMN1 gene causes the inherited disease and results in the breakdown of specialized nerve cells in the brain and spinal cord, with gradual loss of motor function and, in more severe Type 1 cases, death by age 2, if untreated.

The first effective treatments for SMA, which affects 1 in 15,000 births in the U.S., became available in 2016. These treatments were a revelation, but it was clear that the treatment effect relied on treating early through a swift response before the disease progressed beyond rescue. To help facilitate this, SMA was added to the U.S. Recommended Uniform Screening Panel (RUSP) in 2018. This meant the disease, which has varying levels of severity and can remain undetected without proper screening, could be detected by population-based newborn screening and treated as early as possible, even presymptomatically.

As screening and treatment availability improved, the average time between diagnosis and first SMA treatment fell from 195 days in 2017 to just 18 days in 2024. Because of the impact of these advances, the mortality rate of SMA has dropped nearly 80% in this relatively short timeframe.

Incremental but consistent improvement has become the key to providing better care for more people with SMA. At St. Jude Children’s Research Hospital, Richard Finkel, MD, Center for Experimental Neurotherapeutics director, continues to play a critical role in these advances. In 2022, he led the first prenatal treatment for a child diagnosed with SMA Type 1, which was published in the New England Journal of Medicine. Finkel and his colleagues worldwide are continuing the work of developing and testing treatments to refine and enhance SMA care through clinical trials.

SMA treatments ready for a tune-up

Therapies for SMA do not necessarily cure the disease; they tame it. Nusinersen, the first approved therapy for SMA, modifies the SMN1 backup gene, SMN2, promoting it to full-time production of SMN protein and mitigating the faulty gene. However, the unpredictable nature of when and how SMA symptoms can manifest means it can be difficult to fine-tune treatment regimens to maximize effect. People with SMA who start treatment shortly after birth, when there are minimal or no manifestations of the disease, can still experience delayed milestones and emerging weakness later in life.

“When nusinersen was approved, it was essential to get it to people who needed it as quickly as possible, at a dose that was safe and showed benefit,” Finkel said. “We are now at a state where we can aim to optimize the dose for efficacy while maintaining a strong safety profile.” In response to this need, Finkel and colleagues launched the DEVOTE clinical trial in 2020, a three-part sponsored study to examine the safety and efficacy of higher doses of nusinersen.

Part A of the DEVOTE trial, published in 2023 in the Journal of Neuromuscular Diseases, with Finkel as first author, focused on the primary safety assessment of a higher dose. Standard nusinersen treatments involve four 12 milligram (mg) loading (start-up) doses followed by ongoing maintenance doses every four months. The DEVOTE trial tested the effects of a higher 50 mg loading dose and boosting the maintenance schedule to 28 mg doses, and found no safety concerns in participants receiving this higher dose.

Increased dosage demonstrates increased efficacy

This result gave Finkel and the team the green light to assess the efficacy of higher loading doses and maintenance doses. This stage of the study had two arms: children who had never received treatment for SMA (Part B), and a group with a wide range of ages and disease progression who had been receiving nusinersen for at least a year (Part C). Results from both parts were published together in 2026 in Nature Medicine, with Finkel as senior author.

The researchers found that the 50/28 mg regimen had the same safety profile as the default 12/12 mg regimen but with notably improved clinical outcomes. Neurological development and movement quality are measured using multiple assessment tools. Based on these assessments, children in Part B showed significantly improved function and milestone attainment compared to a control group and exceeded expectations in the group treated with nusinersen for several years.

The higher dose also slowed neurodegeneration more rapidly and generally trended towards greater improvement across all measures taken. “The pharmaceutical company is to be applauded for evaluating a higher, optimal dose for a drug that has already shown good safety and clinical benefit and has treated thousands of patients with SMA,” Finkel said. “Now we can treat these patients knowing that we are giving them the best chance for a maximal response to the drug.”

Combating SMA by expanding access to treatments

Optimizing dosage is just one way to maximize the impact of available treatments. Researchers are also making therapies accessible to older children with milder, but still life-threatening forms of SMA. This was the rationale behind the pharmaceutical-sponsored STEER research study to expand access to OAV101, a one-time gene replacement therapy aimed at the nonworking SMN1.

The study aimed to examine the safety and efficacy of intrathecal (into spinal fluid) administration to children and teens between 2 and 18 years of age with SMA Type 2, who can sit, but not walk. While SMA Type 2 is less severe than Type 1, with life expectancy stretching into adulthood, longevity is still reduced if untreated, highlighting the immediate impact within this age group.

The particular branch of this study for children who had not been treated before was co-designed by Finkel and published in 2025 in Nature Medicine. Participants demonstrated a statistically significant improvement in motor function. The findings supported the safe expansion of OAV101 to older children through intrathecal administration, a hugely impactful conclusion.

“The results of this study were persuasive to the FDA to approve this intrathecal administration of the gene therapy in 2025 for all patients over 2 years of age, with no age limit or degree of disease severity,” Finkel said. “This approval, in addition to the previously approved intravenous administration, provides potential access to this gene therapy throughout a person’s lifespan.”

Beginning a new frontier for SMA

Further expansion of therapeutic options for SMA has given researchers, clinicians and patient families with varying age and disease severity a chance to stop this debilitating and life-threatening disease in its tracks.

Ongoing improvements to therapy reflect the efforts of researchers such as Finkel to continue to move the needle in treatment efficacy and expand the patient population that can readily access therapies. Even after a decade of consistent improvement, the work will not be done until SMA no longer poses a barrier to health, mobility or quality of life.