Current Series: Understanding Spinal Muscular Atrophy

Nancy L. Kuntz, MD: We’ve talked extensively about the probably 3 most advanced treatment protocols for spinal muscular atrophy [SMA], and there’s so much more to come. There have been trials in the past with other supportive treatments and other things that we’re looking at—neuroprotection, supporting neuromuscular transmission, improving power generation from muscle cells, improving muscle regeneration—and some of these are ongoing, some of these were done. But these are not specific to spinal muscular atrophy. So the whole question is about whether combinations of these gene therapies or combinations of these with other supportive therapies would be optimum for children or adults with spinal muscular atrophy and which ones at which age. These are unanswered questions that we’re all looking forward to discovering together.

I think there are 2 things that I would like to circle back to in our last bit of time that we have here, and 1 of them would be to say that we wanted to touch base on newborn screening, the need for it, and what perspective these current treatments and therapies give us on the effort to promote newborn screening. So maybe you could start, Claudia.

Claudia A. Chiriboga, MD, MPH: Absolutely. I think all the studies that have been discussed show that even if it’s later-onset SMA or infant SMA, early treatment is important, and there’s a differential response to early treatment, with the ASL [amyotrophic lateral sclerosis] treatment showing the best response and possibly normal development. I think it’ll be very exciting to see on an equal playing field these presymptomatic studies that are ongoing that will be comparing the small-molecule risdiplam with the AVXS-101, in the SPR1NT study as well as the NURTURE study, to see if there’s any benefit or advantage to 1 over the other.

I think the issue of whether you have a CNS [central nervous system]–restricted therapy like nusinersen versus something that is more widely disseminated makes a difference. My own approach to that is for the symptomatic child, especially the infant, the FIREFISH data are very exciting in that they can salvage babies who are that much older. Whereas with the AVXS-101, if the older child didn’t seem to respond very well, there was a differential response where if they were under 5 months or later than 5 months, the response would come to flat once they got past a certain age, which may reflect a critical number of neurons that you need. If you’re more advanced, there’s not enough gene to produce it.

But so far we don’t know because a lot of the nusinersen babies are doing very well. So CNS restricted, if you start early enough, may be enough to make a difference. So we’ll have to wait to see if indeed you need combination therapy when you treat presymptomatically. When they’re symptomatic, I think it’s a different story because you want to maximize SMN, and then combination therapy with a gene transfer and an SMN to a slicing modulator—either risdiplam or an ASO [antisense oligonucleotides]—may make sense, if we’re permitted to do so. The studies in the pipeline now that are using ancillary drugs that are not SMN specific but that enhance muscle are another option to use in combination with an SMN-modifying therapy. So I think it will be exciting to see how much benefit is given.

One question that always comes up is if their supraphysiological SMN protein levels are toxic, it doesn’t seem to be the case, and it seems like if you have more SMN and you’re more affected, that might improve function even further than if you use 1, which would be a reason to use combination therapy in children who are a bit more advanced.

Nancy L. Kuntz, MD: Basil, what are you thinking?

Basil Darras, MD: I think Claudia covered the topic very, very nicely. I don’t have a lot to add except to say that in addition to preventing the disease, we have to realize that we may also do something that diminished the cost of the disease. Because it’s not just having a child who has more normal development, but also having a child who does not have to be admitted to the hospital multiple times, and sometimes into the intensive care unit, which is as we all know can be quite expensive.

The other point I would like to make is that we tend to forget the value of the preconception carrier screening, which aims at diminishing the number of babies who are born with SMA. And as I said at the beginning, 1 of 50 people in the general population are carriers of this mutation, which means that it’s quite common. And it will help enormously, and it prevents the disease if prospective parents are screened for carrier status around the world.

Elizabeth Kichula, MD, PhD: And SMA has been on the recommendations for obstetrics and gynecology for testing since 2017, and so certainly it seems like it’s being done a lot more broadly, although I think there are limits to that type of carrier screening. So it’s important to remember that that’s screening and not testing, but I think sometimes not everyone is aware of. So important limitations are that primarily it does testing for the deletion and not for sequence variance, which as we mentioned before, would miss about 5%.

And also, particularly in certain cases, there are a higher percentage of people who may have two copies of the SMN1 gene on 1 chromosome. It’s particularly true in African Americans, and so the sensitivity of carrier testing in them is only between 70% and 80%, while it’s well over 90% in Caucasians. And so really trying to think about those limitations and the interpretation of this, I think, is also important. And newborn screening could help fill in some of those holes, although it will still miss some of them.

Nancy L. Kuntz, MD: I’m aware that some legislation has been passed in Australia to try to do a nationwide preconception counseling as a strategy to minimize the occurrence of spinal muscular atrophy. So I imagine we’ll hear from them, and our colleagues overseas, about their experience.