‘Garbage Disposal’ Protein May Help in Predicting Response to Spinraza

Marisa Wexler MS avatar

by Marisa Wexler MS |

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In children with spinal muscular atrophy (SMA) who begin treatment with Spinraza (nusinersen) after they are 2 months old, levels of a protein called cathepsin D in the fluid around the brain decline over time.

This decline tends to be more pronounced in those who respond better to Spinraza, according to a new study. Its researchers proposed that cathepsin D could serve as a biomarker to predict patient response to this therapy.

The study, “Cathepsin D as biomarker in CSF of nusinersen-treated patients with spinal muscular atrophy,” was published in the European Journal of Neurology.

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Spinraza is the first disease-modifying treatment to become widely available. It works to increase levels of the SMN protein by modulating the SMN2 gene, which acts as a “backup” for the SMN1 gene that is mutated in SMA.

Treatment with Spinraza has led to once impossible attainments for some with SMA. But every individual is unique, and emerging research has shown that some patients derive more of a benefit from the therapy than others. Figuring out which individuals are more or less likely to benefit is important for guiding decisions about future care.

A team led by scientists in Germany set out to identify biomarkers that could help predict the response to Spinraza. Researchers first analyzed the cerebrospinal fluid (CSF) — the liquid around the brain and spinal cord — of three children with SMA type 1. CSF samples were taken on the day the children started Spinraza treatment, and again two weeks and six months later.

Analyses identified cathepsin D as a potential biomarker. This protein is involved in the molecular “garbage disposal” system that brain cells use to get rid of unwanted debris.

Researchers then conducted a larger study in 31 children with SMA, where CSF was sampled on the first day of treatment, and again after 60 days and 300 days (nearly 10 months). This group included 12 children with SMA type 1, nine with type 2, and six with type 3, as well as four infants under 2 months of age, who were treated with Spinraza presymptomatically or before showing any signs of SMA. 

In these four presymptomatic babies, levels of cathepsin D in the CSF rose over time. This also was seen in CSF of individuals without SMA. By contrast, among the 27 patients who started treatment after showing disease symptoms, cathepsin D levels were high in initial readings, and then gradually declined.

Among the 27 children who started on Spinraza at ages older than 2 months, 14 were determined to be “responders” to the treatment, as evidenced by increased in standardized motor scores. The researchers noted that “non-responders” tended to be older when they started treatment.

“At start of [Spinraza] treatment, a subsequent and highly significant decline of Cathepsin D levels over the course of 300 days of [Spinraza] treatment was identified. This decrease was evident in all SMA subtypes and in all age categories above 2 months of age,” the researchers wrote.

Further analyses showed that the decline in CSF cathepsin D levels was more pronounced among responders than non-responders.

“Of major interest, we identified a significant decline of Cathepsin D values in patients that were categorized to have a positive ‘general treatment response’, while ‘non-responders’ had a less pronounced, non-significant decline,” the scientists wrote.

Based on these findings, as well as cathepsin D’s known role in brain cells’ “garbage disposal” system, the researchers proposed that, under normal circumstances, CSF levels of this protein slowly rise as the nervous system continues to develop.

In children with SMA, however, cathepsin D levels spike soon after birth because of disease-related neuronal damage. The damage causes an accumulation of cellular debris and, consequently, the “garbage disposal” system is “switched on” to try to clear the debris. In this view, levels of the protein could be used as a surrogate to assess the amount of damage in the nervous system.

“We hypothesize, that Cathepsin D serves as a biomarker of neurodegeneration and disease activity, which decreases slowly in natural history,” the scientists concluded. They stressed that this was a relatively small, early study, and further research is needed to validate the results.

Spinraza is marketed by Biogen, which was not directly involved in this study.