<p>While recent advances in spinal muscular atrophy (SMA) treatment have significantly improved patient survival and functional outcomes, unmet clinical needs persist. Ongoing research is exploring novel therapeutic targets, including those aimed at enhancing muscle function, and the potential for combining or sequencing US Food and Drug Administration (FDA)–approved disease-modifying therapies (DMTs) with adjunctive agents to further improve the functional outcomes of patients with SMA.</p>

We now have 3 different treatment options for giving the SMN protein back to people with SMA: nusinersen, risdiplam, and onasemnogene abeparvovec. In that context, living with SMA is very different now than it was 10 years ago, although a few challenges remain. For example, even with newborn screening in place and the early identification of symptomatic individuals, there is a subpopulation that still does not thrive as well (ie, usually people with a lower SMN2 copy number), even if we intervene early with SMN-repleting therapy. Also, patients who had been living with SMA for a long time before these treatments were available may now be stabilized with medication but are still quite symptomatic.

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So, the question becomes: How can we further augment the experience of living with SMA for people who are symptomatic? We need additional options to improve their quality of life and their function. I am excited about exploring options such as intrathecal gene therapy as a way to reintroduce SMN to patients with SMA, particularly older individuals, as well as other strategies focusing on the health of the lower motor neuron. The goal is to make the whole unit—from the nerve root through the neuromuscular junction into the muscle—more functional. In this area, myostatin inhibitors are the agents that are furthest along in development. We have to determine as a community how best to define who will benefit the most from which of these interventions at which time.

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We also do not want to be myopic in terms of only looking at the American experience. Some of these newer approaches, if they are looking for treatment-naive populations, are being studied in other countries that may have differences in their approaches to some aspects of standard of care. So, it is really important to be not only inclusive but also sensitive to the treatment differences that sometimes happen relative to where the person with SMA actually is when you are having these conversations.

We are starting to recognize SMA as being not just a disease of the motor neuron and that perhaps repleting SMN expression alone is not sufficient for managing all aspects of the disease. This is where investigational agents such as myostatin inhibitors and the small molecule inhibitor, NMD670, which partially inhibits one of the skeletal muscle–specific chloride channels to help facilitate neuromuscular junction transmission, may come into play by helping to address some of the non–motor neuron aspects of SMA.

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There are other aspects of improving SMA management that I am also looking forward to learning more about. For example, nusinersen is very effective, but one drawback is the need for frequent lumbar punctures with its administration. For children, that often means a lot of sedation or having a more complex neurointerventional radiology–assisted delivery of the medication. I am also looking forward to hearing more about the PIERRE trial, which is investigating a port catheter system that might allow for an easier delivery of the medication. Further, longer-acting ASOs such as salanersen are under development to help allow for less frequent dosing.

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It is important to consider that sometimes the scales that we have to measure treatment effect do not adequately capture the full treatment effect or benefit, particularly for patients with treated phenotypes or more advanced stages of SMA. For example, bulbar symptoms such as decreased voice volume, or, sometimes, fatigability are things that patients might report but are not always adequately captured on some of our scales. This can limit our interpretation of treatment effect in clinical trials.

I think that this is an incredible time of optimism. When we had the results with the first DMTs, which, in many cases, were so dramatic, there was this feeling that our work was done. However, it is very clear now that our work is not yet done. Even with the early treatment of SMA with DMTs, we are seeing new emerging phenotypes that we need to consider and deal with, and we need to understand a little bit more about what those mean, why they are occurring, and how we can best treat them.

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The idea of just “throwing” additional medications at patients with SMA is not really practical. Thus, as a community, we do need to develop very rational, data-driven, evidence-based treatment regimens and plans to be able to effectively treat patients with SMA. We are working on that, but we are not exactly there yet. It is harder to get the data and information that are needed with only real-world evidence, so it is important to have well-designed strategies and multicenter trials that are focused on specific outcomes. Without that, we end up with scattered anecdotal evidence and experience that are not truly evidence based as the basis for understanding what we are doing with these therapies.

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Gene therapy is certainly a popular topic, but we still have a lot of questions about it in terms of its durability and long-term safety, as well as whether the risk-benefit relationship is adequate. There is still a lot that we have to discover before we can come up with a concrete care guideline for patients. What can we do better, and how can we manage things better? How do we really advance therapy for patients with SMA to make certain that they can live their best lives?