Certain Protein Levels May Track Effectiveness of Spinraza, Case Report Shows

Measuring the levels of proteins known as neurofilaments, and tau in the cerebrospinal fluid of infantile-onset spinal muscular atrophy (SMA) patients can be used as biomarkers to monitor the effectiveness of Spinraza (nusinersen), a case report shows.

The case study, “Neurofilaments and tau in CSF in an infant with SMA type 1 treated with nusinersen,” was published as a letter in the Journal of Neurology, Neurosurgery & Psychiatry. A letter is a short report of original research that is of interest to investigators in other fields.

Two years ago, the U.S. Food and Drug Administration approved Biogen‘s Spinraza for the treatment of SMA in both infants and adults.

SMA patients are unable to generate adequate amounts of survival motor neuron (SMN) protein, for which the SMN1 and SMN2 genes provide instructions. Spinraza works by increasing the ability of the SMN2 gene to produce a full-length SMN protein, improving motor function and overall survival.

Spinraza is administered via an injection into the spinal canal by lumbar puncture on the first day of treatment, and then on days 14, 28, and 63, followed by maintenance therapy every four months.

Neurofilaments are proteins that are part of the motor nerve cell skeleton, meaning they provide neurons with the necessary structure to hold their components.

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Higher levels of neurofilaments in the cerebrospinal fluid (CSF) — the liquid around the brain and spinal cord — have been found to be useful diagnostic markers in various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). When neurons die, neurofilaments are found “on the loose” in the bloodstream or in the cerebrospinal fluid.

Increased cerebrospinal fluid levels of a protein called tau, which is involved in the transport of essential nutrients and molecules into brain cells, have also been observed in neurological diseases associated with significant neuronal loss, but there’s no consensus on its usefulness in disease diagnosis. Increased tau phosphorylation (a chemical process that adds a phosphate group to proteins) alters the protein’s configuration, changing its function, and leading to toxic buildup within cells.

“Therefore, the question arises, what role [cerebrospinal fluid neurofilaments] and tau play in SMA, and how important the use of these parameters in SMA could be with regard to new therapies,” the study’s authors wrote.

These researchers from Ulm University in Germany treated a female SMA type 1 infant with Spinraza, and evaluated the child’s cerebrospinal fluid levels of neurofilaments and tau.

Three protein subunits of neurofilaments exist: heavy, intermediate, and light, which can differ in their capacity to serve as diagnostic biomarkers. In this analysis, the researchers focused on the heavy and light forms.

Symptoms of low muscle tone (muscular hypotonia) were first recognized by the girl’s parents at 4 months of age. Genetic testing revealed a homozygous deletion in the SMN1 gene — a missing portion of the DNA sequence in both copies of the gene — and two SMN2 copy numbers.

Although it was previously believed that there were almost always only two copies of each gene, evidence suggests there are exceptions to this rule, and changes in the gene copy number have been linked to disease. The SMN2 copy number correlates with disease severity, with multiple copies usually associated with less severe forms that develop later in life.

Spinraza treatment began when the girl was 8 months old. At that time, she had poor head control, was not able to sit unassisted, her mouth and throat muscles were weak, and she could not breathe properly.

Two months after beginning treatment, there was significant improvement in her motor function.

At 14 months, the girl was able to sit unassisted. Six months later, she was able to stand and walk some steps with little help, and her respiratory function was stable.  The issues with her mouth and throat muscles did not improve.

Before Spinraza administration, there were 2,460 pg/mL of neurofilament light chain, and 1,263 pg/mL of phosphorylated neurofilament heavy chain in the CSF. After two months of therapy, there was a decrease in phosphorylated neurofilament heavy chain values to below the lower limit of detection of less than 62.5 pg/mL.  These values stayed low in the next two lumbar punctures.

Likewise, there was also a decrease in neurofilament light chain values two months after treatment from an initial value of 741 pg/mL, which continued to occur in successive measurement periods to 209 pg/mL, and finally below the lower limit of detection of less than 100 pg/mL.

After two months of Spinraza treatment, total tau also decreased from initial values of 549 pg/mL to 465 pg/mL and phosphorylated tau protein concentrations decreased from 66 pg/mL to 63 pg/mL. In the final lumbar puncture, there were 323 pg/mL of total tau and 45 pg/mL of phosphorylated tau.

To draw accurate conclusions, it is necessary to establish appropriate neurofilaments and tau pediatric reference values “as it is also conceivable that these values may be elevated in healthy infants during neuromuscular maturation,” the researchers wrote.

However, these results show, for the first time, elevated neurofilament and tau levels in the CSF of “infantile-onset SMA, that decrease under treatment with [Spinraza].”

“Considering the clinical improvement under treatment of this girl, which would have not been possible in the spontaneous course of SMA type 1, it can be speculated that these parameters, most notably [neurofilaments], may be used as an additional marker for therapy monitoring in infantile-onset SMA,” the researchers concluded.