Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

In 2020, Cure SMA brought together 11 scientists and healthcare professionals who specialize in SMA research and care to form the SMA Biomarkers Multidisciplinary Working Group. Over the past two decades, researchers have performed many studies on molecules and measurements that may be good biomarkers for SMA. However, before a biomarker is widely accepted for use, scientists must validate it by performing rigorous tests to make sure it meets certain standards.

Therefore, the goals of the SMA Biomarkers Multidisciplinary Working Group were:

• To review what was known so far about potential SMA biomarkers.
• To determine which biomarker is likely to prove the most valuable in ongoing SMA research and care.
• To outline a plan for future research that will support the validation of the selected biomarker.

First, we provided the working group members with a reading list of articles describing research studies on the most promising SMA biomarkers. These “candidate” biomarkers included genetic factors, proteins, imaging techniques, and methods that measure electrical activity in muscles and nerves. Working group members were also invited to add articles to the reading list for the group to review.

After the working group members had time to review the reading list, we collected their input through a series of surveys and phone calls. In the first three surveys, working group members were asked to rank candidate SMA biomarkers in terms of which were likely to be most useful. The second three surveys asked more detailed questions about the biomarkers the group had ranked highest. In the last three surveys, working group members were asked for input on the most important gaps in knowledge about these biomarkers, and how those gaps could be filled. They also weighed in on which SMA biomarkers might be most appropriate for persons of certain ages.

The working group determined that a protein called “neurofilament (NF)” has the most potential for widespread use as a biomarker in SMA research and clinical care. NF is found in the axons of healthy neurons, where it plays an important role in maintaining axon structure. In many diseases that affect neurons, the NF protein is released from axons as neurons start to die. Therefore, changes in NF levels can help track not only disease progression but also responses to treatments that slow or halt disease.

NF can be detected in both blood and cerebral spinal fluid (CSF). In addition, a lot is already known about NF because it has been studied as a biomarker for several neurological diseases, including SMA. For these and other reasons, the working group chose NF as the most promising biomarker to develop for SMA research and clinical care. They also decided which research questions about NF still need to be answered. Finally, the working group outlined which types of experiments would be helpful in answering these questions and validating NF as an SMA biomarker.

The U.S. Food and Drug Administration (FDA) has approved three drugs for the treatment of spinal muscular atrophy (SMA). About 70% of people living in the U.S. with SMA have received one or more of these treatments.² In addition, researchers continue to study many more drugs that may be useful in treating SMA. Some of the new drugs being researched may be used in combination with currently approved treatments to give people with SMA the best possible quality of life. As the number of approved SMA drugs increases, and more people are treated with different combinations of SMA drugs, developing biomarkers that inform research and healthcare decisions is more important than ever.