Michael Muhonen, MD, Neurosurgeon and Head of neurosurgery at Children’s Hospital of Orange County at St. Joseph Hospital, talks about an easier way for patients suffering from spinal muscular atrophy to get the lifesaving drug, Spinraza, into the spinal cord.
Interview conducted by Ivanhoe Broadcast News in May 2019.
Tell us what SMA is.
MUHONEN: SMA refers to a very rare disease called spinal muscular atrophy. It’s a disease that has various subtypes. You can get type 1, type 2, type 3, for example. But basically, the disease is a disease of the spinal cord. A certain part of the spinal cord no longer functions well. And specific it’s in your horn cells. It’s a very complicated disease biochemically when you look at why it happens and how it happens. But scientists have been able to break that down. And as they figured out why this disease happens that’s how we approached a cure for this disease.
What are some of the symptoms of the disease?
MUHONEN: Most patients with spinal muscular atrophy present early on in life. It might be difficulty breathing in a baby, in children that have started to walk by the age of 1 then they may quit walking, they get weakness of the top of the legs, they get weakness of the back muscles, and very poor swallowing reflex in some of them. So, the generalized decline in the motor function at the same time they have good sensation, so they can feel sharp touch, light touch, they know where their feet are in space. But it’s a decline in the motor function. And most patients but not all of them that have SMA are confined to a wheelchair at an early age.
Is it life shortening as well?
MUHONEN: When I first started medical school, I had my first encounter with a type 1 SMA and that child lived to the age of 4 which everybody thought this was remarkable that anybody could live that long. As time has gone on with treatments and better pulmonary treatments these children can live much longer than that. And can now with a type 2 and type 3 even live to be elderly.
How was SMA treated?
MUHONEN: Typically, SMA was treated by treating the symptoms of the disease. For example, these patients would have no back muscles to support their body. So, they would get a curvature of the back. You would treat that with a spinal fusion and put metallic rods in to hold the spine in an upright position. You would lose your diaphragm and breathing muscles. So, you would put these patients on ventilators so they could have automatic breathing done for them. But there wasn’t a medical cure per say where you could put a medication in there and treat the disease itself. You were treating the symptoms of the disease and prolonging life by treating the symptoms of the disease.
So Spinraza comes along and what does it do?
MUHONEN: So Spinraza is a very unique drug for a rare disease that is used very infrequently. Spinraza was developed to counter act the enzyme that is actually causing spinal muscular atrophy. Basically, when you have type 1 spinal muscular atrophy, you’re missing a part of the gene that codes for the protein that should be made by SMN 1. They don’t all die suddenly because the SMN 2 makes enough copies of the SMN 1 so those patients can still have function. So, they don’t die immediately because you still have other copies of the gene that’s trying to make up for the deficit of the SMN 1 which is the primary defect with spinal muscular atrophy. It’s a very complicated pathway. But basically, it’s affecting the growth and the development of the motor horn cells. And the motor horn cells are the motor part in the spinal cord that runs down the front of the spinal cord that generates the signal to tell us to move our arms and legs.
And Spinraza does what?
MUHONEN: Spinraza basically goes in there and it supplements that SMN 2 to make SMN work. It’s almost magical. If you can get enough of the drug to latch on to stop cleaving these enzymes, it essentially can reverse that cleaving process. So, it produces more copies and you have more of the regular gene that you need in there to prevent this destruction of the motor horn cells.
So can it reverse symptoms or does it just hold them steady?
MUHONEN: Clinically we know it can reverse symptoms. I have had patients that had no arm function and can now move their arms. I have had patients that were ventilated who couldn’t breathe on their own, they can now breathe. So, we know that it can reverse function. The earlier on in life you get the drug, the more effective it’s going to be. The later on in life you get the drug, the less effective it is going to be. I would say primarily we want to hit the children as early as we can. We want to hit them in infancy with the drug to stop the effects of the spinal muscular atrophy from causing severe changes in the peripheral motor functions that we have. Elderly patients, elderly, in this case is patients even over the age of 30 and 40 which is elderly for this disorder, our goal is to maintain. If we get more function wonderful. And I have seen more function in patients over the age of 30. But a good outcome is maintaining so they don’t go downhill and ultimately end up being on a ventilator or a life support machine.
Already FDA approved not that long ago, right?
MUHONEN: Yes. Spinraza is FDA approved. And it’s been implanted across the entire world. It’s a very expensive drug for obvious reasons. There aren’t that many patients that will use the drug. And it’s really been controversial in some regards because some countries that are under nationalized health care system like Norway and England have an extremely difficult time approving that for the public use because of the costs of it.
Delivery was a problem of the drug and you have figured out a way to get around the problem. Can you talk a little bit about that?
MUHONEN: If you look at the methods for installation of Spinraza it’s all over the board. There are about 48 different described methods of putting the Spinraza in the spinal fluid. Now it’s not as simple as just put a needle in the back and let’s put this in rather than that’s what it was designed to do. The problem is as I told you many of these patients have a spinal fusion. You have a spinal fusion because their whole body is collapsing. Well, you can no longer put a needle right through that fusion mass. You can’t put a needle through the metal rods or the bony mass that’s been created by the fusion. So, the first patient that I encountered with spinal muscular atrophy an orthopedic surgeon Dr. Rosenfeld called me and said could we drill a hole through the middle of the fusion mass and make a window that he could put a needle in through that hole? And we put metal markers around it so he could identify the hole on x ray. And then every time he gave this spinraza he would just go right through those metallic markers on x ray. Well, the problem with that is you’re exposed to radiation, the fluoroscopy time, the nuisance of having a spinal tap every time you have this done. Not only is it painful but potentially dangerous. And many other complications can arise from a spinal tap. So, we did the first one. And we drilled a hole down the fusion, and it was about two inches deep in her spine that we drilled this hole. And it worked very well. But I was discussing the case with him and I said there has to be a better way. I said, “if this were my child, I would be very upset if I had to get a spinal tap knowing I have to get one three times a year for the rest of my life and more than that during the first year of treatment, knowing the agony and maybe sedating them.” So there has to be a better way. And if you look at the pharmacokinetics in the mechanics of how the drug works, we wanted to attack the region of the spinal cord which is in the anterior part of the spinal cord. When you give the drug in the lower back region you’re flooding the drug in the system or all the nerve roots hang down off the spinal cord. And you hope that the drug circulates uphill and attacks these areas or latches onto these areas where it will be more effective. So that got me thinking why don’t we do something that will get the drug closer in proximity to these anterior horn cells. And perhaps it will be more efficacious. So, I came up with multiple ideas. And I took all the parts I could in the operating room for devices that I can inject spine – into – I took many tubes and pieces and ports from the operating room. Laid them all out trying to come up with a system that I thought would be efficacious. That I could put in the neck and drip the spinal fluid down the spinal cord yet make it very easy access to get into. When you have to do a spinal tap, you have to put the patient on their side typically, curl them up in a ball. There are case reports of patients having broken femurs and dislocated hips merely from trying to do this procedure which is very difficult in a very fragile patient. So, I came up with the system when I was tinkering. And I took a catheter that was designed to be put in the lumbar spine to drain spinal fluid out of a patient and a vascular port that we would use for somebody that you would put under the skin and inject something in the vein. The goal with this was to get something small like this and the tube is very small such that I could put that in the spinal column and there’s 20 holes on the end of this and let the fluid drip out of this down the spinal cord. And at the same time making it so I didn’t have to move the patient outside of their wheelchair. I could just have a port that’s like this that I could have under the skin, have the patient in the wheelchair, put a little tiny needle into the port. I wanted to put something like that through the skin and then inject the spinraza in.
Explain the first patient this was done on.
MUHONEN: I decided to use this port called an AngioDynamics port attached to this catheter. So, for the first patient we made an incision in the neck, drilled a tiny little hole in the bone and put this in the spinal fluid space around the spinal cord. Tunneled out and put this port right under the skin under the neck. The first one wasn’t perfect, but it was good. Afterwards, I was able to pass a needle directly in the port, through the skin, aspirate spinal fluid and inject the spineraza. The next patient was much better. I learned I needed to put the port in an easier access area. I needed to tunnel the catheter and made a few minor modifications. We’ve now done this on 10 patients. And the port sits in this region right here and not a single one of these patients has to be taken out of their wheelchair to do the injections. Now what we don’t know is that a better way to put spinraza in. Is more efficacious to directly have it dripping down the spinal column than to put it in the lumbar cistern and have it migrate uphill. My answer would be yes because I think the results that I’m seeing are better than what I’m seeing in patients that get it in the lumbar cistern. We don’t have enough patients to confirm it’s a better route. But I know it’s very effective. And I know it’s very simple. And I know the patients love it. And that’s what you want in a procedure. You want it to be relatively painless. You want it to be very simple when the patient has to have a refill. I can do an injection of spinraza in a patient in under 10 minutes. Somebody that does it by way of the lumbar puncture. It’s a two-hour process. Sedating the patient during the whole procedure, let alone getting them out of the chair and positioning them. So, the patients have really loved the injection process as compared to what they went through especially the ones that were getting the spinal taps.
Will there be a trial for delivery method or no?
MUHONEN: So, there is a company in Massachusetts named Alcyone, and they are going to be trialing a catheter that is even better than the catheter I’m using. They have a catheter that’s even smaller than the catheter that I was using and a port that can be anchored in the same region here where I have it. And this catheter I love because the ease of it is very simple, I can get it in and out much easier. This one is not designed for what we’re using it for. We’re using it by way of physician discretion in a way that I think works best. So, they have come up with a very ingenious idea to make my procedure much easier and I think much safer because a catheter is smaller. It’s not going to disconnect. This one might. It’s through technology like this it’s going to make this conceptual procedure better. A procedure that most patients with spinal muscular atrophy will have someday because I think the results are going to be better by opening in the spine – I think the results are going to be superior if we drip the Spinraza down the spinal cord rather than putting in the lumbar canal and hoping it goes upward.
What about Shawn’s case? What kind of the difference does it make for him?
MUHONEN: Sean has Type 3 spinal muscular atrophy and his spinal muscular atrophy was not evident until he was three, four or five years of age. He was young. He walked up until he was about 12, then he broke a leg and he’s been wheelchair bound ever since. He has four copies of what we call the SMN 2 and that’s what I talked about earlier that the more copies of this SMN 2 you have the better your outcome. Well, that’s why he’s alive. And he’s in his 40s. Because he has more copies of the SMN 2 to make the good gene that they need. So, Sean has what we would call adult spinal muscular atrophy or type 3 spinal muscular atrophy. Sean started receiving spinraza last year. And his disease which was on a downward course he was losing hand function, losing breathing function, stopped it absolutely dead in its tracks. He’s had no progression of a disease. He’s breathing better. He has better pulmonary function and he feels like there are some aspects of his life that are getting better. He unequivocally feels like his disease has stopped its progression.
What haven’t I asked you about Spinraza that you think we should include in the story?
MUHONEN: My desire is that Spinraza would be made available to every patient in the world that has spinal muscular atrophy. When you have a disease that’s rare like this the drugs are going to be expensive. But the drugs while they’re expensive can save many people’s lives and it can reverse the devastating aspects of spinal muscular atrophy.
MUHONEN: When an infant is born with spinal muscular atrophy, they might look perfectly normal. The first manifestation might be difficulty in breathing. They might notice that child’s not moving their arms and legs as much as a normal child would. They might not be latching on to the mother when they’re breastfeeding. So, this can be determined by a test. It’s a simple blood test to look at essentially the genetic makeup of that patient. It can be termed by a simple blood test it looks at the DNA of that patient, looking at the gene sequencing to see if they’re missing the SMN – the spinal muscular atrophy gene. So, the diagnosis is clinical, and these patients might look normal right after birth. Some of the SMN 1 might not even show you symptoms for a few months but typically it’s early on in the first week or two of life.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
James Chisum
562-493-6023
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
