A Motor Neuron Mystery Points to New Potential SMA Treatment Targets

An autopsy of a 17-year-old patient with spinal muscular atrophy (SMA) who had been dependent on life support revealed a curious finding: while most muscles had atrophied from the disease, as expected, the patient’s diaphragm remained strikingly preserved. A new study suggests understanding why this happened could provide new therapeutic targets for patients who don’t respond well to current treatments.

SMA is caused by low levels of the survival motor neuron (SMN) protein, which is essential for maintaining the nerve cells that control muscle movement. When SMN levels drop, motor neurons degenerate, leading to progressive muscle weakness. To address this deficiency, disease-modifying treatments like Spinraza (nusinersen), Zolgensma (onasemnogene abeparvovec) and Evrysdi (risdiplam) aim to increase SMN levels. However, even with these therapies, patients may continue to experience muscle weakness.

To better understand why the disease impacts groups of motor neurons, or motor pools, differently, researchers led by Justin C. Lee of Baylor College of Medicine, examined extensive neuromuscular autopsies from patients with SMA. Their findings, published in Human Molecular Genetics, showed highly divergent degrees of degeneration between neighboring motor pools: while muscles controlling eye movement and certain neck muscles remained largely intact, other nearby muscles showed severe degeneration. Analysis of both human and mouse tissues revealed that resistant motor neurons shared a common trait – high levels of regular activity.

The team also discovered that even in muscles that appeared resistant to SMA, subtle changes had occurred at the cellular level, suggesting that some degree of degeneration happens even in the most SMA-resistant motor pools.

“The prolonged resistance of some motor pools with long survival times demonstrates that SMA-resistance may be nearly absolute,” the study authors wrote. “All current SMA treatments under clinical development focus on increasing levels of SMN. Thus, the characterization of differential motor neuron vulnerability, which may lead to the identification of therapeutic pathways independent of SMN, remains highly relevant.”

The discovery comes at a critical time in SMA treatment. While the approval of three disease-modifying medications since 2016 has transformed the treatment landscape, many treated patients still exhibit neuromuscular weakness. Some patients fail to obtain independent sitting and require ventilators to breath, while some later-onset SMA patients show no motor improvements.

The study also reinforces the critical importance of early treatment. A study earlier this year in JAMA Pediatricsfound that 91% of newborns treated before six weeks of age achieved independent sitting, compared with 74% of infants treated after 10 months. Even more striking, 64% of the early-treated group achieved independent walking, versus just 15% of those treated later – evidence of extensive motor neuron loss that occurs in SMA patients by 4 months to 8 months of age.