SMN Protein Levels in Blood May Mark SMA Severity, Help Guide Treatment

Levels of the survival motor neuron (SMN) protein in the blood of people with spinal muscular atrophy (SMA) shows promise as a biomarker for predicting disease severity, a study reports.

Specifically, SMN levels correlate with the severity of motor-neuron loss — denervation — and with the number of copies of the SMN2 gene that a person has. Fewer copies of this gene tend to correlate with more severe disease.

The study, “Whole Blood SMN Protein Levels Correlate with Severity of Denervation in Spinal Muscular Atrophy,” was published in the journal Muscle & Nerve.

SMA is caused by mutations in the SMN1 gene, which result in no to low levels of SMN, a protein produced by virtually every cell in the body and essential for muscle health. However, some patients have extra — three or four — copies of the SMN2 gene, which also produces this protein but in low amounts.

As more therapies are approved or investigated to treat SMA, the identification of biomarkers that allow clinicians to predict disease progression early in life is seen as a key priority. Some, including light and heavy chain neurofilaments and creatine, are currently under investigation.

Building upon previous work that validated a test for SMN protein levels in whole blood, researchers from Massachusetts General Hospital, in Boston, sought to determine whether their test could also distinguish SMA patients with two or three copies of SMN2 — who usually develop type 1 or type 2 SMA — from others.

These patients typically show symptoms within their first year of life, and the ability to measure their potential risk before that happens is increasingly seen as essential for best possible treatment.

“While experts agree that treatment should be initiated as early as possible in newborns with SMA who have two or three copies to ensure the best outcomes, there are challenges that can delay initiation of treatment … including the local approval of these therapies because of the high costs, the logistics involving insurance approval, and dosing,” the researchers wrote.

Researchers mined patient records from two SMA databases, looking for those with blood sample data and two, three or four SMN2 copies.

This resulted in a first dataset of 209 blood samples from 74 patients, 19 of whom were no older than age 3. Thirty-one patients in this group had been treated with Spinraza (nusinersen, by Biogen).

A second dataset, covering 23 SMA patients, contained 86 observations of SMN levels within the first three years of life. This allowed researchers to “determine whether SMN protein levels were associated with SMN2 copy number early in life,” since data from fetal and infant autopsies suggests that SMN levels peak in tissues during fetal development and rapidly decline after birth.

Among this group, one had four  SMN2 copies, and the other 22 had two or three copies. Eleven of these children had received no therapy, eight were treated Spinraza, three with Zolgensma (by Novartis), and one with both Spinraza and Zolgensma.

Among the 74 patients, SMN blood levels associated significantly with compound muscle action potential (CMAP), a test of motor function that correlates with SMA severity. Both of these measures were low in more severe cases, suggesting that low SMN levels indicated more severe motor nerve cell loss in SMA.

Among the 23 patients, SMN protein levels were higher in the blood of those with three SMN2 copies than of those with two gene copies. Blood SMN levels also dropped after the onset of symptoms in types 1 and 2 patients, with type 1 showing the greatest drop in SMN protein.

Data from all patients treated either with Spinraza, Zolgensma, or both showed no evidence that these treatments raised SMN levels in whole blood.

Despite the study’s small sample size and retrospective nature, SMN protein levels varied with SMN2 gene copy number, and therefore with risk of SMA severity, making SMN blood levels a potentially useful biomarker for guiding treatment urgency in newborns and infants.

Data from two ongoing clinical trials (NURTURE, NCT02386553; and SPRINT, NCT03505099) testing either Spinraza or Zolgensma in newborns, show that the time at which treatment begins affects disease course, depending on whether a patient has two or three copies of SMN2.

“Moving forward,” the researchers concluded, “we propose that whole blood SMN protein measurements should be included as an exploratory biomarker in the prospective assessment of all newborn SMA patients in conjunction with other promising candidate blood biomarkers, such as neurofilament levels.”