Spinal Muscular Atrophy, Questions That Remain Unanswered

Darryl De Vivo, MD, the Sidney Carter Professor of Neurology, Professor Pediatrics and Director Emeritus of the Pediatric Neurology Service at Columbia University Medical Center

Darryl De Vivo, MD

Darryl De Vivo, MD, the Sidney Carter Professor of Neurology, Professor Pediatrics and Director Emeritus (1979—2000) of the Pediatric Neurology Service at Columbia University Medical Center, sat down with NeurologyLive at the 47^th Child Neurology Society Annual Meeting in Chicago, Illinois, to further explore his introduction into the spinal muscular atrophy symposium over the last 127 years.

De Vivo also discussed his hope for the future of spinal muscular atrophy as well as the challenges that remain and questions that need to be addressed. While 127 years after the original description by Werdnig in 1891 proves an exciting time, De Vivo explains that it’s not yet time to walk away. With the antisense oligonucleotide nusinersen available as potential treatment, there’s other options that may soon be emerging as so-called designer drug treatments.

This is the time, De Vivo adds, to really tinker around the margins to try and advance as much possible, continuing to work hard especially since this tremendous advance that has been made over the last several years.

NeurologyLive: What do you hope for the future of spinal muscular atrophy?

Daryll De Vivo, MD: Well I like to liken it to the first man on the moon: One small step for man, one giant leap for mankind. This has been extraordinary, we’ve gone from the truly untreatable, largely fatal disease, at least 60% of the time, to a condition now where if we get in early we can allow these infants to develop fairly normally, possibly entirely normally.

On the other hand, it isn’t time to put your hands in your pocket and walk away with a big smile on your face, this is the time now to really tinker around the margins and to try to make it perfect as possible. We have other treatments in the pipeline, yes, we have other splicing molecules that can be taken by mouth, we have the antisense oligonucleotide nusinersen marketed as Spinraza, which has to be given in the spine intrathecally, and this has to be done repeatedly. Right now, we load these patients with 4 treatments over the first 2 months and then they get 1 treatment every 4 months after. It may be on the basis of Dr. Manneni’s work, for example, that we might not have to continue doing it every 4 months, maybe we can do it every 6 months or maybe even once a year. We don’t know the answer to that, again that’s why we need to continue working hard now that we’ve made this tremendous advance over the last several years.

Also, there is a drug in the pipeline that works like Spinraza, but you can take it by mouth, it’s a small molecule and it distributes not only in the brain but through the body. That’s another question, is treating the nervous system necessary and sufficient, or is it necessary but insufficient? It may be that when these infants and young children we’re now treating with intrathecal Spinraza, as they get to be older, whatever that is—5 years old, 10 years old, 20 years old—maybe they’ll stop developing some muscle weakness because they still have deficiency of SMN in their muscle and the rest of their body, we’re only treating the brain. An oral molecule that might distribute itself throughout the body and the brain might ultimately have an added benefit, if in fact treating the brain is necessary but not sufficient, as such.

Then finally we have the opportunity for gene therapy, so that’s immediately attractive because that’s a treatment where one time and you’re done. It sounds very attractive, but is that going to turn out to be the case? If you treat a newborn infant with gene therapy, and let’s say a newborn infant weighs 3500 grams, at 1 year of age they weigh 10,000 grams, 10 kilograms, and of course ultimately, we end up being 50 or 100 kilograms. Just think of how many times all of the cells in our body have divided, now as it turns out the gene therapy currently being investigated is what we call a non-integrating therapy, so it sets up housekeeping in the nucleus, adjacent to our genome, but it doesn’t get incorporated into our genome. Now that’s a benefit because some of the side effects like the potential to create cancer largely is related to integration into the genome, so this does not integrate, so that’s the good news.

On the other hand, every time the cell divides only 1 of the daughter cells gets the gene transfer and the other cell doesn’t. You’re diluting out the benefits of the treatment by 50% each time the cell divides. Here we have a baby that weighs 3.5 kilograms at birth and may end up weighing 70 kilograms when he or she is fully grown, just think of how much of a dilution we’ve had during that time. Now admittedly Dr. Manneni’s work has showed us that maybe our requirement for SMN will lessen as we get older. Again, it’s a question we can present for which we don’t have any good answers at the moment and that’s why all of this work needs to continue now to make this wonderfully effective treatment that we have in 2018 increasingly more perfect with the passage of time.

What challenges lie ahead?

DD: I think we have other challenges as well. We have the idea that health care is a right, not a privilege, on the other hand we have a drug that is extremely expensive, and it’s only 1 of a lot of drugs that will be emerging now as so called designer drug treatments, as such, so we know exactly what is wrong genetically that causes your disease and increasingly the scientists are going to be clever enough to very quickly design a treatment that will be perfect for you. On the other hand, there’s a built-in cost to that.

Increasingly it’s not really a right, it will be a privilege for those who can afford it, or for societies that can afford it, some societies can’t afford even Spinraza and I think some countries have not approved the use of Spinraza for members of their society, because the cost imposes such a huge burden on their society.

That introduces all sorts of fundamental ethical questions, basic societal issues related to health care delivery, and economic issues, that is, are we at our limit in terms of affording what we are capable of creating scientifically and medically? These are all extraordinarily important questions and they’re kind of the interface I think between medicine and science, ethics, philosophical issues and so forth. It forces us to think about how we are going to use our precious resources as a society. I think every great advance opens up a whole new series of questions, which is the nature of life.

Every time somebody in our past has made a great observation it’s created a new set of opportunities to think beyond what we were able to think in the past. I think we’re here, and this is where we are in this point of time, recognizing yes, we can treat these genetic diseases but when we treat them they introduce a whole new set of issues for which we’re not very well prepared as a society to deal with. I think that is the continuing excitement and challenges we face.