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Q&A: Lingering Theories and Questions in SMA Research


Alexander Fay, MD, PhD, joined for a Q&A about the current state of spinal muscular atrophy (SMA) treatment and the unanswered questions in the field.

Alexander Fay, MD, PhD | Image Credit: University of California San Francisco's Benioff Children's Hospital

Alexander Fay, MD, PhD

Image Credit: University of California San Francisco's

Benioff Children's Hospital

Following the publication of his article, “Spinal Muscular Atrophy: A (Now) Treatable Neurodegenerative Disease,” in Pediatric Clinics of North America, Alexander Fay, MD, PhD, pediatric neurologist and assistant professor of neurology at University of California San Francisco's Benioff Children's Hospital, sat with The American Journal of Managed Care® (AJMC®) to discuss the ongoing theories and lingering questions for aspects of spinal muscular atrophy (SMA) that are not yet fully understood.

This transcript has been lightly edited for clarity and length.

AJMC: You note that the susceptibility of motor neurons to the loss of the survival motor neuron (SMN) protein is not fully understood and that there are some indications that SMA is more than just motor neuron disease. Can you explain some of the working theories that research is exploring in this area?

Fay: In some of the animal models, particularly the mouse model, it's clear that there's involvement outside of the motor neuron tissue. Even in patients, we know that other parts of the nervous system may be affected, particularly in the earliest onset. I think there is a threshold amount of this gene and protein—the SMM protein, SMN1 and SMN2 genes—that are needed for healthy neuronal function. The motor neurons are clearly the most susceptible part of the nervous system. But as patients’ motor neurons are more completely treated with time, some of these treatments may not treat the cells beyond the motor neurons. And so, one of the open questions is whether we will start to see a later impact of SMA disease beyond the motor neurons in either the brain or other organs of the body that we just haven't seen before. Because in the past, children with SMA type 1, the most severe form, typically wouldn't live beyond their second birthday. As a result, there hasn’t really been time to even see these later effects in other organs.

Some people have argued that maybe risdiplam (Evrysdi, Genentech) will be a better treatment for those tissues outside the motor neurons because it is taken orally and is delivered throughout the body, whereas nusinersen is delivered to the spinal fluid. Nusinersen (Spinraza, Biogen) is going to reach the motor neurons and may reach some cells in the brain but isn't going to spread throughout the body. Onasemnogene abeparvovec (Zolgensma, Novartis) gene therapy seems to be delivered to many different tissues, particularly the liver. It crosses the blood-brain barrier and may reach some other tissues. But I think the long-term question will be whether we see disease manifestations outside of the motor neurons in patients with the most severe forms of SMA who have been treated for many, many years with these new therapies. This may be something that doesn't become apparent for many years or even decades; it's going to be something that we're all following far into the future.

To answer this question: It's more hypothetical right now based on the animal models, and it remains to be seen what that's going to mean for our patients with SMA.

AJMC: Are there other lingering questions on SMA that we might anticipate guiding future research, and is there research being performed in these areas that you can share?

FAY: One point to remember is that SMA is actually a group of diseases. When people say spinal muscular atrophy, most commonly they mean the most prevalent form of SMA, which is type 1. But there are dozens of other genes that cause motor neuron disease—and SMA is another term for that—that begin very early in life, if not before birth. Each of those different genes is likely to require a unique treatment approach that targets the genetic defect.

In other recessive diseases, for example, there's a gene called IGHMBP2, which is associated with a type of SMA called SMARD1: SMA with respiratory distress type 1. It’s a recessive disease where both copies of the gene are lost. There's a gene therapy currently in trial trying to treat that disease very early and prevent the respiratory failure that happens usually in the first year of life.

There also is ongoing research for some of the dominant SMAs, too. An example of that is the TRPV4 gene, which causes a distal SMA that primarily affects the feet and the lower legs, and sometimes the hands. This is due to an overactive calcium channel in the motor neurons. There's some ongoing work to try to block that excess channel activity and see if the disease manifestations can be improved.

I would say there's still a lot of work to be done in the less-common forms of SMA. And if we come back to the more common SMA, you know, it's great that we have these 3 treatments—nusinersen, risdiplam, and onasemnogene abeparvovec—but there’s still a need for augmenting the effects of patients who are treated after they're symptomatic. I think it's pretty clear that treating some children before they develop any symptoms is pretty close to, if not, curative. But for the rest of the patients who are treated a little bit later than optimally, we still need additional therapies there.

Right now, there's a trial going on with a myostatin inhibitor that promotes muscle growth to see if combining that kind of muscle growth promotion with one of the approved therapies can lead to even greater gains in strength for these patients.

Another lingering question is whether we have a way of generating new motor neurons so that patients who have lost a lot of their motor neurons might be able to regenerate some in the spinal cord and reinnervate their muscles to become stronger that way. I think that is much further off than something like the myostatin inhibitor approach, which is well along in terms of clinical trials.

One other approach is, since we can treat patients in the first weeks of life, and that is a highly effective treatment for most patients, what if we treat before birth with fetal therapies? That's another area of ongoing research, and I wouldn't be surprised if in the next 5 years or so there are patients who are treated before birth with one of the approved therapies to try to boost the effectiveness of these treatments even more by rescuing the motor neurons at the earliest possible developmental time points.


Fay A. Spinal muscular atrophy: a (now) treatable Neurodegenerative disease. Pediatr Clin North Am. 2023;70(5):963-977. doi:10.1016/j.pcl.2023.06.002

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