Newborns are now screened for the crippling disorder

[00:00:00] Host Amber Smith: Upstate Medical University in Syracuse, New York invites you to be "The Informed Patient" with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. Spinal muscular atrophy was added to the recommended uniform screening panel for newborn babies in July, 2018 after new disease modifying therapies became available. With me to discuss the first three years of this new screening in New York State is Dr. Ai Sakonju. Welcome to "The Informed Patient," Dr. Sakonju.

[00:00:35] Ai Sakonju, MD: Thank you very much for having me. I appreciate this.

[00:00:38] Host Amber Smith: Let me ask you first, if you would, please, explain what spinal muscular atrophy is.

[00:00:46] Ai Sakonju, MD: Spinal muscular atrophy is a motor neuron disease. It's one of the most common causes of infant and childhood mortality, from a genetic cause. It's due to a genetic defect in the survival motor neuron gene. Fortunately for us, we have two different versions of the spinal motor neuron gene, SMN1 and SMN2. And if you actually are missing both copies of your SMN1 gene, then you have the disease. But the disease is modified by how many backup copies, if you will, of the imperfect SMN2 gene. So if you have more copies of your SMN2 gene, you have a milder disease and a later onset with a longer life expectancy.

So we can go into a little bit more detail of how severe this disease is. If you have only a knockout or two mutations of your SMN1 gene, which gives you the disease, and you have two copies of your SMN2, your backup that's imperfectly made protein, that gives you the most severe form -- well, nearly -- the most severe form is if you don't have any SMN2, and you can't really survive if you have zero copies. But if you have one copy, even that's really not survivable. Two copies gives you the most common infantile onset spinal muscular atrophy type one. And that is a very severe disorder where you present in early infancy, typically by two to four months of age, with respiratory distress. And it's a progressive disorder where they die early by about two years of age.

[00:02:27] Host Amber Smith: If you have, say, three or more copies of your SMN2 protein, you live a little longer, but you still will have some progressive muscle weakness and later onset. And it's not exactly predictable. So it's a genetic birth defect, right?

[00:02:44] Ai Sakonju, MD: That's correct.

[00:02:45] Host Amber Smith: How many babies are affected?

[00:02:48] Ai Sakonju, MD: We really thought it would be much more common than it actually is, and that's a good thing in the end. The carrier rate used to be predicted as to be one in 40. That means if you had a high school class of 40 members, one in that particular classroom would be carrier of that gene. And if you happen to marry another person with the mutation in the SMN1 gene and you had children, about 25% of those children might be affected.

We thought it would be much more common. And that's what prompted this paper where we did newborn screening. We're one of the very lucky states that started newborn screening early, in 2017. We weren't one of the first, but really early on. And New York State is a huge state. So we did a paper where we looked at screening infants to see how many would come out, and it actually ended up being a lot more rare than we thought. Their carrier rate being closer to one in 60. Still, that's quite frequent, closer to what you see with cystic fibrosis, which is a very common disorder as well, relatively speaking, when you're talking about genetic disorders.

[00:03:52] Host Amber Smith: But people who are carriers, they don't necessarily know that they're a carrier, is that right?

[00:03:58] Ai Sakonju, MD: That's correct, and that's the scary part. Any of us could be a carrier, and you're normal. If you have one survival motor neuron gene that's affected. You only need, really, one to really work really well. And that's what's crucial about the genetic screening because we have now a wonderful therapy that can actually cure the disease if it's given early before they start having the motor neuron disease.

[00:04:23] Host Amber Smith: So what's the difference between spinal muscular atrophy and muscular dystrophy?

[00:04:30] Ai Sakonju, MD: Yeah, so spinal muscular atrophy, the name came about before it was known that it was a nerve disease. So it's not really a muscle disease. Muscular dystrophies are primarily muscle disorders. That's the difference.

[00:04:43] Host Amber Smith: I see.

Now the paper you mentioned, that was published in the journal, Neurology, and it looked at the first three years of newborn screening for spinal muscular atrophy in New York State. How many infants were screened in those first three years?

[00:04:57] Ai Sakonju, MD: Yes, it was an enormous project and there are about 650,000 infants or newborns screened and only about 34 that were discovered to have the two mutations causing SMA, (spinal muscular atrophy.)

[00:05:12] Host Amber Smith: And is the screening through a routine blood test?

[00:05:16] Ai Sakonju, MD: It's part of the newborn screen that you get, so it's not that extra blood test that's necessary. It's just part of the newborn screening now.

[00:05:25] Host Amber Smith: Now, let me go back to before 2018. If you found that a baby had spinal muscular atrophy, what was the outlook for them before 2018?

[00:05:36] Ai Sakonju, MD: Well, actually, the therapies that came about that were really phenomenal started coming out in 2017. So there was at least therapy back then, in 2018. But it still is very difficult. The main option was something called nusinersen, the generic name, and the brand name is Spinraza. This is a very difficult, but very effective therapy.

It was given intra -- it is still given, actually -- it's given intrathecally. And what that means is it's given into the spinal cord region, so you have to do a needle poke into the back of a baby. And that has to happen quite frequently at the very beginning, every two weeks. And then it goes to every couple months. So you get it several times a year.

And it worked great because it's going directly to the motor neurons. And if you gave it to babies before they started showing signs of neuropathy, or muscle weakness, then you could actually cure them. But you would continue to need therapies. And so then there were a lot of problems with giving it through the spinal cord every time. So they did find an oral version, which is pretty good. But you have to still take it for the rest of your life.

So then, after all those therapies were being worked out, they finally came through with gene transfer therapy. And that is amazing. It's worked great on these children when, especially, you give it before they start showing symptoms. And even if you give it when they have symptoms, you stop the progression, and you hold them where they are, and you allow them to grow, and they get stronger. So it's actually miraculous, if you ask me. This is one of the best diseases to work with.

[00:07:11] Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith. I'm talking with pediatric neurologist Dr. Ai Sakonju about spinal muscular atrophy. Now, in the paper, there were 34 babies that tested positive over the three years, and they received, did you call it gene replacement, or gene transfer?

[00:07:32] Ai Sakonju, MD: Yes. So it's called gene transfer therapy because we're not really replacing your gene. The gene is actually given in a little virus. It's a virus that doesn't cause human disease, and it's called an adenovirus. You might have heard an adenovirus as a viral illness, like a runny nose or ear infection, but this one doesn't cause human disease. And so it's given, hidden in this little virus. The SMN protein is just about eight exons. It's a very tiny gene that holds a very small protein and that's put inside the virus with a promoter, which is basically turning it on all the time. That is given through the IV (intravenous line) into your bloodstream. And it's just a one-time IV injection into the bloodstream.

And, that viral vector goes into the bloodstream and goes into your cells, all of your cells. So you have to be very careful when you're giving it because all of your cells are saying, "whoa, I'm getting this virus. I better go and attack it." So we have to put them on some prednisone so they don't go crazy attacking the virus. It doesn't cause any harm. And then the virus goes into your cells. That DNA then hangs out next to your own DNA and replicates itself. So it's not incorporating into the DNA itself at all. It's staying right in the cells.

Now, there is a question of how long it'll stay replicating as your cells reproduce. And it's, so far, showed really great, robust endurance. In other words, we've seen kids up to about seven years of age now. That's the oldest child, and he's walking -- and this is a child who would never be able to roll or sit -- walking and carrying a backpack and going to school. So it does seem to last years and years.

It's not incorporated into your own DNA. It's actually hanging out and making its own protein like it should. This is important because this SMN protein is actually found in all of your cells. So even though it's causing motor neuron disease, it is being somehow, very specific for your motor neuron. It's expressed in all of your cells. So, I think the IV is working really great when you give that injection of adenovirus that's carrying the gene.

So that's why we call it gene transfer therapy. It's not a gene replacement, but this is effectively a cure when you give it early on, and that's really crucial. That's why we have the newborn screen.

[00:09:57] Host Amber Smith: Yes. So when you say early on, that's soon after birth?

[00:10:03] Ai Sakonju, MD: That depends on how many SMN2 genes you have and how severe your disease is predicted to be. But most of us do want to treat you within the first year of life. If you have only two copies of SMN2, and you're affected with SMN1 being both affected, that gives you SMA type one. That means you're going to have infantile onset. And that varies with every child.

Sometimes you have in utero start of your disease, and so you're born very weak. By then, it's really difficult to treat, but we still try to treat within weeks of life. And that's a race against time, because as time goes on your nerves are degrading, and they're not going to regenerate. We don't have a nerve regenerating therapy at this point. We only have a way to preventdegeneration.

So, yes, if you have SMA type one, we try to inject within the first month of life, ideally. Ideally, we would give it even sooner if we could. But I think we have a lot of things we need to work out with insurance. And then telling the families that they have this deadly disease. It's quite devastating to families, and some are not quite ready for it unless they've had other family members born with the disease. Then they want the disease treated very rapidly. And we do have siblings of families that get treated much quicker because they are on the lookout for it, and we can treat them very quickly in that way.

[00:11:33] Host Amber Smith: But it sounds like the outlook today is a lot more positive for a baby that's born today than five years ago.

[00:11:41] Ai Sakonju, MD: Absolutely. Because like I said, we have other therapies that will slow the progression, like the oral medication called risdiplam, and the intrathecal, which is through the spinal cord versions, that can act really rapidly. So you can save time while you're waiting to get the authorization for the gene transfer therapy, which is quite costly. It's over several millions of dollars. Ugh. But it's not yet the most expensive therapy, believe it or not.

[00:12:07] Host Amber Smith: Do most insurances come through and cover it?

[00:12:11] Ai Sakonju, MD: Oh, I would say that I do meet about twice a year with our group of neuromuscular specialists across the state of New York, and I've heard horror stories from some of my colleagues who've tried to get insurance approval for this.

Most insurances will cover it without hesitation, and we can get approval within three days, rapid, rapidly. But there have been some issues with some insurances. And sometimes parents don't have insurance, and they have to get insurance, and that makes it very tricky. As you know, insurance is not a guarantee in the United States. It depends on your job, which makes it even harder.

[00:12:51] Host Amber Smith: Do you know if all states are screening newborns for this or, I mean, I know New York is, but are other states doing the same?

[00:13:01] Ai Sakonju, MD: Not yet. And that's the unfortunate problem. As of, hmm, I'm not exactly sure of the exact date. But from the last meeting I met with several of my neuromuscular colleagues, and there were about 11 states of the 50 that are not doing newborn screenings.

So if you're born in one of those states, you may have a child with SMA that proceeds to have muscle weakness and severe consequences. And even though the therapies are available and FDA approved, we're already treating at a very late stage. And that's not a good thing, to say the least.

[00:13:41] Host Amber Smith: When you first began your medical career, did you envision a treatment like this becoming available and having the ability to have a substantial impact like this?

[00:13:52] Ai Sakonju, MD: In my residency, I met my very first child that we diagnosed with SMA type one. And after that, it made me really excited to go into the neuromuscular field. I cannot tell you how much it impacted me. I immediately started working with one of my favorite mentors of all time, Kathryn Swoboda, MD. And she is a neurogeneticist, a wonderful teacher and compassionate physician.

She had very strong interest in SMA at that time. We were already doing drug therapies for SMA way back when I was a med student, and then going into residency, using medications that I would not even consider using today, right? Phenylbutyrate, which is a medication that tastes terrible, you had to hide in butter, slip it down the throats of these little babies with SMA. And what it did was, it would allow increased gene transcription, supposedly, of SMN protein. And it didn't work great.

And then we tried Depakote, which is a seizure medicine, and what that does is it unwinds the DNA to allow more gene transcription, but it's sort of a general gene transcription. You're not being very specific to the SMN gene. And then we had this intrathecal medication that started coming about -- and I was in the first drug trials with that -- giving it to these babies very early. We had a huge registry of over 300 SMA patients that we were seeing, and I saw these on a weekly basis, multiple times in the week, twice a week. And I would do their nerve conduction studies. So I knew these patients, and I worked with Dr. Swoboda, who was a very strong research advocate for this particular disorder. And I knew that we were going to come up with a treatment that would work. I was very confident of it because it was so driven by compassionate people.

And I happened to work in the lab of one of the people who came up with the intrathecal version, which is basically a very simple mechanism that most labs can generate. And his name is Doug Kerr, MD, PhD. I was working with him at Johns Hopkins Hospital where I trained. And they came up with the theory that it would work because it had been tried in other disorders. So I was confident. I was confident we would have a cure. This was going to be the best disease to work in, and we were going to be able to make a difference in lives of children.

[00:16:13] Host Amber Smith: Well, this is so encouraging, and Dr. Sakonju, I really appreciate you making time for this interview.

[00:16:19] Ai Sakonju, MD: Thank you so much for having me. I am so excited to be helping kids in this world that we live in, and I think that there's great things coming out.

[00:16:29] Host Amber Smith: My guest has been Dr. Ai Sakonju. She's the medical director of child neurology at Upstate, where she's an associate professor of both neurology and pediatrics. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe. Find our archive of previous episodes at upstate.edu/informed. If you enjoyed this episode, please tell a friend to listen too. And you can rate and review "The Informed Patient" podcast on Spotify, Apple Podcasts, YouTube, or wherever you tune in. This is your host, Amber Smith, thanking you for listening.