Russell Butterfield, MD, PhD Pediatric Neurologist and Neuromuscular Specialist, Associate Professor of Neurology at University of Utah Health & Intermountain Primary Children’s Hospital talks about a new type of gene replacement therapy for children.
What is spinal muscular atrophy, or SMA?
Dr. Butterfield: Spinal muscular atrophy, or SMA, is a disease of motor nerves. We have nerves that originate in the spinal cord and go out to a muscle and tell your muscle when to contract, when to relax and that sort of thing. SMA is a disorder that disrupts the communication of that motor nerve with the muscle and ends up in muscle atrophy and loss of function of those muscles. So, patients with SMA have severe weakness that’s progressive over their whole lifetime.
Was your patient, Cinch, born with normal function and then lost his function in a matter of months?
Dr. Butterfield: Cinch is a special case because he was born with SMA and that was identified through a newborn screening program. We never saw symptoms of SMA in him because of the early screening process. Before we had that newborn screening program, patients would present us with clinical features such as muscle weakness, difficulty swallowing, difficulty breathing. In the most severe cases at just even a few weeks of age, they would show up to our clinic with really profound weakness. In Cinch’s case, he has a slightly milder type of SMA that usually manifests around eight or nine months of age. In that case, those patients never reach walking as a developmental milestone, but really start to regress around that eight or nine month time point, to where they start losing muscle mass and losing muscle strength rapidly.
How would you traditionally treat this?
Dr. Butterfield: Traditionally, we had no treatment. There’s been an evolution over the last 10 or 15 years from a palliative approach to care for these kids with the most severe forms of SMA to a more proactive approach to care that relied on a lot of technology, like breathing support and nutrition support through feeding tubes and that sort of thing. Usually when we would meet a patient for the first time, we often admit them to the hospital right from that first clinic visit, establish care with some of these technologies, and then hope the best for the future and do our best to keep them out of the hospital and safe and healthy as possible. But we really didn’t have a treatment that could stop the progression of the disease.
How recently was SMA added? Was it always in the newborn screening?
Dr. Butterfield: No. We had thought for a long time that SMA should be a part of newborn screening. But until we had a treatment, it didn’t meet the criteria that had set out to get a disorder onto the newborn screening. That first treatment was approved in the end of 2016 as a drug called Nusinersen and plays a little genetic trick in order to increase the expression of a gene called SMN2. That therapy changed the entire landscape for treating SMA. That gave us, for the first time, an opportunity to intervene. What became clear is that the earlier the intervention happened, the better the outcomes. That made newborn screening for SMA a high priority for us here in Utah and others around the country as well. January of 2018, we were the first state to start that screening. So, we’ve had that now for about two and a half years. Every baby born here in Utah is screened for SMA and we find them usually under a week of age before symptoms start.
Have more states adopted SMA screening?
Dr. Butterfield: Yes, slowly that’s rolling out to hopefully every state. I think we’re up to about half of the states now that have implemented newborn screening for SMA, and I think other states are just in various stages of implementation to get it on the panel.
How does the infusion work?
Dr. Butterfield: There are two different drugs available. Nusinersen, the first drug approved for SMA is given directly into the spinal fluid by a series of spinal taps It’s a pretty large molecule and can’t get past the blood-brain barrier, so we deliver that over the course of four loading doses in two months’ time and then every 4 months after that. It’s a fairly intensive loading procedure for these patients to get the drug. They get that drug for the rest of their life, presumably. Cinch was treated with a different drug called Zolgensma that was approved by the FDA just a day before he was born.
But for Cinch, something better came along?
Dr. Butterfield: Yes, for Cinch, something better came along. Instead of playing a little genetic trick on the SMN2 gene to make it produce more normal protein, it actually replaces the missing SMN1 gene. We were pretty excited to get a phone call from the Department of Health and have this baby who we can use this treatment on after its approval. Just like every other newborn screening baby, we saw Cinch a few days after he was born, did the genetic testing to verify that original newborn screening result, and then had him in here for his treatment for SMA with the gene therapy, Zolgensma.
How does the gene therapy work?
Dr. Butterfield: With Nusinersen, it could be considered a gene therapy because we’re manipulating a gene, but kind of a downstream manipulation. For the gene therapy that Cinch received, we used a virus to deliver a new copy of that gene into his motor nerves. A virus is a protein shell with DNA or RNA inside of it. The function of the virus is to deliver that DNA into the cell. So instead of delivering the genes that might make more virus, we design the gene that we want to put into the cell, and use that protein capsid to deliver it. It’s like a delivery truck to deliver genes where you want them to go. Inside that truck, we put a gene that looks just like the human SMN1 gene and deliver that by IV infusion. It’s a one-time thing. That virus then goes to different parts of the body, but precisely into motor neuron cells, and delivers a small package that contains the SMN1 gene where it activates and then makes this normal SMN1 protein.
Would you consider this a cure?
Dr. Butterfield: It’s not exactly a cure. Our goal is to treat kids at the earliest stage possible, and we call that pre-symptomatic or early symptomatic. What that does is it stops the disease right where it is. In some cases, children have a little bit of residual muscle weakness left, but then it unleashes this normal developmental process that can continue as it normally would have. Most kids who get this treatment before symptoms start, they walk and talk and go to school and do normal things. So, it’s not a cure, but it’s probably as close as we can get to a full cure. It’s also not without some risk about causing inflammation in the liver and other areas that we have to really pay close attention to. We don’t know how long it lasts. We think it lasts for many years, but it just hasn’t been around long enough to know the answer to that question.
Will Cinch come in every six months, or yearly?
Dr. Butterfield: At first, we saw Cinch almost once a week just to screen for those problems that can happen when doing an infusion for a gene transfer. Now, it’s probably about every six months or so we’ll see him. We’ll follow-up, see how he’s doing, monitor his progress. The last time we saw him, he was just starting to walk and run around and act like a normal toddler. We want to see that development continue. We expect we’ll have to pay close attention over many years to make sure we don’t see anything fall off.
Is this few and far between for a doctor like you to treat SMA and then see where normal outcomes would go?
Dr. Butterfield: Yes. It’s really remarkable to see. Going back a little further to Nusinersen because that’s when that hit me the hardest. It was a really profound moment holding a baby in one hand and holding that drug in the other and really feeling the weight of that and understanding how different this child’s life will be with this new medicine. Now, with the IV infusion, it’s even simpler. It’s anticlimactic, actually, to be sitting there in the hospital with an IV infusion that runs for an hour, and then we’re done and we just all go away and think… this amazing gene transfer just happened!
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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