NeuroVoices: Crystal Proud, MD, on High-Dose Nusinersen and the Next Era of Spinal Muscular Atrophy Care

Spinal muscular atrophy (SMA) has undergone a profound transformation over the past decade, shifting from a largely untreatable neuromuscular disorder to one with multiple disease-modifying therapies. With the advent of SMN-targeted treatments—including antisense oligonucleotides, gene therapy, and small molecule approaches—clinicians are now increasingly focused on optimizing outcomes beyond initial treatment, particularly in patients with residual disease burden.

Among these evolving strategies is the development and recent approval of higher-dose nusinersen (Spinraza), which aims to build upon the established safety and efficacy profile of the standard 12 mg regimen. Nearly 10 years after its original approval, the FDA gave greenlight to this new dosing regimen, which is designed to deliver a higher concentration of the drug and deliver potentially greater efficacious, functional outcomes for patients with SMA.

In parallel, the field is also exploring combination and sequential treatment approaches, particularly in patients previously treated with gene therapy. As part of a new iteration of NeuroVoices, Crystal Proud, MD, chief of neurology and director of Neuromuscular Medicine at Children’s Hospital of The King’s Daughters, shared insights on the clinical considerations around high-dose nusinersen, as well as findings from the phase 4 RESPOND study, a trial that examined whether use of nusinersen after gene therapy could unlock further benefits for individuals with SMA. Furthermore, she spoke on the broader direction of SMA care and future of SMA research as clinicians aim to further optimize long-term outcomes for patients.

NeurologyLive: What should clinicians understand about high-dose nusinersen and its potential clinical impact?

Crystal Proud, MD: I think it’s incredibly exciting. When we look back at our experience with the current dose of Spinraza, what really stands out, in addition to the efficacy and the impact that it’s had on patients’ lives, is truly the safety. And so, when you have a product that has demonstrated such significant safety, you have to ask yourself, have we really optimized that particular therapeutic? There was every reason to pursue a higher dosing of nusinersen.

I think we can be really encouraged as we look at the data package that comes along with higher-dose Spinraza, because we’re seeing a very similar safety profile, but we’re also seeing additional efficacy, which is really encouraging. We’re nearing 10 years of approval of Spinraza later this year, and our patients have had incredible success over that time period in changing what their future held. It’s natural to then ask, what’s next, and can I do better?

When we look at the data from (the phase 3) DEVOTE (study), we can see that patients who had previously been treated with 12 mg Spinraza had, on average, been treated for almost four years and still were able to demonstrate improvements in some of their motor functional scores. So, there is more potential while maintaining that safety profile, and I’m incredibly encouraged by that.

Are there any practical differences clinicians should expect with the higher dose?

Essentially, no. It doesn’t necessarily change the flow of how we administer Spinraza. It’s still going to be the same cadence of maintenance dosing. Now, if we have a patient, for example, who is not currently on Spinraza and they wish to transition to this higher dose, there is a less burdensome loading dose phase, which is also really exciting.

But the maintenance cadence of three times per year stays the same. The actual procedure itself is no different. It’s still lumbar puncture administration, which traditionally is quite brief, and I find that it’s very well tolerated by my patients, both young and adult. Nothing is different, including the number of milliliters—nothing is different except for the milligrams. So, this makes that transition, hopefully, a smoother one for our patients who are on the current dosing.

What was the rationale behind the phase 4 RESPOND study, and what were the key findings?

This trial was near and dear to my heart because we are in an incredible period of time where we have the opportunity for gene transfer therapy for our patients with SMA. But we know that even when we treat patients very early, even pre-symptomatically, there is still symptomatology of their SMA that persists. The highest-risk group are the two-copy patients, but we’ve also seen patients with three copies continue to have progression of their disease even after an initial therapy.

The thought of trying to help optimize long-term outcomes by additional nusinersen really grew to support this RESPOND study. We also know that only a certain portion of motor neurons are transduced with the AAV vector that is being utilized for gene transfer. While it is a successful and efficacious therapy, it is not delivered to every single motor neuron, and that means there are motor neurons that are untransduced and at risk for progressive degeneration. From a biological perspective, once you lose a motor neuron, you can’t get that back.

Our hope with additional nusinersen was to treat those untransduced motor neurons and thereby improve clinical outcomes. What was observed was exactly that. We saw improvements in clinician-reported outcomes, parent and caregiver-reported outcomes, motor function scales, and electrophysiologic markers like CMAP measurements. What was incredibly impactful to me was that many patients entering the study had elevated neurofilament levels, which indicate active neurodegeneration, and after additional Spinraza, that biomarker dramatically reduced and sustained at a low value. So, there was a measurable biological impact of that additional therapy.

How close are we to combination or layered treatment strategies in SMA?

It’s been really interesting to see this combination approach evolve. To be honest, I had pursued additional Spinraza for some of my patients commercially even prior to the initiation of the RESPOND study, recognizing that there could be this potential benefit given that there were untransduced motor neurons.

Recognizing that we don’t have a cure and that our goal is optimizing therapy, it makes sense to take a look collectively at the therapeutic landscape and try to see what could work collaboratively. The question we still have left unanswered is whether we would see a different outcome with a singular therapy, because we don’t yet have comparative trials.

There are studies underway that may help answer this question. It may be that we need combination therapy, but I’m also open to the possibility that we may not, and that early administration of a single therapy could optimize outcomes. We’re also looking beyond the motor neuron, including the neuromuscular junction and muscle, and ultimately toward motor neuron regeneration. There are so many places for us to explore because our job is not done yet.

Where should future SMA research efforts be focused?

Any time we can utilize an opportunity to reduce burden on patients and families is incredibly worthwhile. Right now, our patients are seeing us on a standard cadence of every six months, and then on top of that they have therapy visits, equipment needs, and additional subspecialty care. There is a tremendous demand on families.

Even when therapies like Spinraza have become more efficient over time, there is still a procedural burden. So, looking toward options that reduce treatment frequency, such as once-yearly dosing approaches, is incredibly exciting. I think the future is really bright as we look at reducing both the burden of disease and the burden of therapy.

What have we learned over the past decade of SMA treatment evolution?

It’s been an incredible journey over the past 10 years. I’m very thankful to have the perspective of joining this community at a time when we didn’t have treatment, having those incredibly difficult conversations with families and saying that I don’t have the ability to stop this disease. That is a humbling experience, and it makes you incredibly grateful for where we’ve come.

Spinraza really laid the foundation for this space to grow, and I’m so grateful for that, as well as for our patients. It didn’t stop there—it evolved. Now we are looking at different therapies, combination approaches, and ways to optimize outcomes by intervening early.

We’re also focusing on biomarkers like neurofilament, trying to understand disease activity before clinical symptoms appear and to track treatment impact over time. What we don’t yet know is whether early intervention today will ensure long-term outcomes decades later.

We still have a lot more to do, but it has been an incredibly transformative 10 years, and it’s a really exciting space to be in.

Transcript edited for clarity.

REFERENCES
1. FDA Approves New High Dose Regimen of SPINRAZA® (nusinersen) for Spinal Muscular Atrophy. News release. Biogen. March 30, 2026. Accessed March 31, 2026. https://investors.biogen.com/news-releases/news-release-details/fda-approves-new-high-dose-regimen-spinrazar-nusinersen-spinal
2. Proud CM, Finkel RS, Parsons JA, et al. Open-label phase IV trial evaluating nusinersen after onasemnogene abeparvovec in children with spinal muscular atrophy. J Clin Invest. 2025;135(22):e193956. doi:10.1172/JCI193956