CSF Protein Profile May Help Predict Spinraza Responses in Late-onset SMA Patients, Study Shows

Analysis of the protein levels in the cerebrospinal fluid (CSF) of people with late-onset spinal muscular atrophy (SMA) may help to identify biomarkers that not only monitor but also predict Spinraza responses, a study suggests.

The results of the study, “Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy,” were published in the Journal of Neurochemistry.

Developed by Biogen, Spinraza is an approved therapy for all types of SMA that restores the levels of the survival motor neuron (SMN) protein — essential for motor neuron health — that is largely absent or insufficient in people with the neurodegenerative disease.

The medication is injected directly into the CSF — the liquid that surrounds the brain and spinal cord — within the spinal canal, called intrathecal delivery. The recommended treatment schedule is four doses in the first two months followed by a maintenance treatment every four months.

Spinraza’s therapeutic effects have been widely demonstrated in young patients with infantile-onset (type 1) and later-onset (types 2 and 3) SMA. However, there is limited data on its effectiveness in adults with later-onset disease, due in part to the lack of reliable biomarkers for treatment response in older patients.

The CSF may be a source of potential diagnostic and predictive biomarkers, since it is in direct contact with the spinal cord and lower brain — which are affected in SMA — and it is where Spinraza is administered. However, to date, no studies have evaluated the CSF’s protein profile in pediatric or adult SMA patients.

Now, a team of German researchers compared the clinical and CSF data of the first 10 eligible adults with later-onset SMA treated with Spinraza at the Heidelberg University Hospital, in Germany.

Among these patients — five women and five men — nine were classified as type 3 SMA, and one as type 2 SMA. Their mean age was 36.8, with a range of 18 to 50 years, and they were living with the disease for a mean of 28.3 years.

CSF samples were taken immediately before (baseline) and after 10 months of Spinraza treatment, and were compared with a single CSF sample from 10 age- and gender-matched healthy individuals (controls). The motor function of the adults with SMA was assessed using the Hammersmith Functional Motor Scale-Expanded.

Before treatment, there were no significant differences between the SMA patients and healthy people in CSF basic parameters. These included white blood cell count, total protein, lactate — a marker of nerve cell damage — and CSF/serum quotients of albumin (Qalb), which are used to evaluate CSF flow, the results showed.

After 10 months of treatment, the CSF of the group with SMA showed a significant increase in total protein levels, a trend of increasing Qalb values, and a higher number of reactive immune cells, compared with both baseline and the group of healthy people.

These data indicated that there was a slight CSF flow dysfunction, which was consistent with previously reported increases in total protein and Qalb levels with Spinraza.

An analysis of the participants’ CSF protein profiles resulted in the identification of a total of 822 distinct proteins, with a clear distinction between the profiles of SMA patients and healthy individuals. At baseline, the levels of PARK7 — a protein involved in neuroprotection upon cellular damage —  were those most significantly increased in SMA patients, compared with healthy individuals.

While Spinraza treatment reduced, to some extent, some of these profile differences, the SMA patients’ profile remained distinct from those of healthy controls.

Notably, “not a single CSF protein was consistently found to be differentially expressed in response to nusinersen treatment,” the researchers said. They speculated that this could be due to the slow disease progression of these later-onset SMA patients, the specific protein and treatment response signatures of each individual, and the reduced number of participants.

The slow disease progression of those with later-onset SMA may have hindered the detection of considerable changes during the relatively short evaluation period, the investigators said.

Based on their CSF protein profiles, those with SMA could be divided into two groups, which were subsequently found to be significantly associated with age and distinct molecular pathways.

One group had a younger mean age — 28.2 years — and increased levels of proteins associated with nerve cell development. Meanwhile, the other group included older patients — mean age of 43.6 years — with higher levels of proteins related to neurodegeneration and immune responses. Interestingly, there were no differences in motor function between the two groups at baseline.

The team also was able to divide the SMA patients into two further groups — distinct from the previous ones — based on intra-individual changes in CSF proteins upon Spinraza treatment.

One group of three patients showed significantly different levels of five proteins associated with nerve cell and muscle development: neuronal pentraxin-1, semaphorin 7A, carboxypeptidase E, cadherin 18, and collagen type VI alpha 1. This group showed no improvements in motor function compared with the other one, in which five out of seven patients responded to treatment.

“Intraindividual CSF differences in response to [Spinraza] treatment varied between patients who clinically improved and those who did not,” the researchers said.

“It still needs to be validated to what extent [these candidate proteins] are relevant in SMA patients and their individual response to [Spinraza] treatment, and might then be developed as potential biomarkers,” they said.

The team said the study helped provide new information on grouping patients.

“Comparative CSF proteomic analysis in adult SMA patients before and after treatment with [Spinraza] identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analyses,” the researchers concluded.

Future studies involving more patients and several clinical centers are required to confirm these findings, the team noted.