Until three years ago, when Children’s Hospital of Philadelphia (CHOP) neurologists John Brandsema, MD, and Elizabeth Kichula, MD, PhD, had to tell parents their child had spinal muscular atrophy (SMA), “it was one of the worst diagnoses we had to make because at that time there was nothing for these children,” Kichula says.
In SMA, motor neurons, the cells that signal muscles to move, are missing an essential protein and die. Without the signal, muscles waste away. In the past, children with type 1 SMA never sat independently and eventually lost the ability to breathe or swallow on their own. They rarely survived past their second birthday. Those with type 2 regressed as infants and toddlers, losing skills when they should be gaining them. They would never walk, would need help eating, dressing and with other routine activities of living, and would need mechanical assistance to breathe. While it’s a rare disease, with about 1 in every 10,000 babies born with SMA, it is the leading genetic cause of death in infants.
“It was a progressive, irreversible disease,” Brandsema says. “Heartbreaking.”
Notice the past tense. Was.
“Now when we see a child with SMA, we’re kind of glad because we know we can do something,” Kichula says.
Two miracle treatments
The “something” is two treatments that halt the destructive disease, allowing children to continue normal development. As one of the largest neurology practices in the country, CHOP was a pivotal clinical trial site as the treatments were tested prior to their eventual Food and Drug Administration (FDA) approvals. Both work with the genes that effect motor neurons.
When the survival motor neuron gene 1 (SMN1) is faulty, it doesn’t make SMN protein, which motor neurons need to function and send signals to muscles. Another gene, SMN2, is a “back-up” gene and also produces SMN protein, but at about one-tenth the amount as SMN1. The severity of a child’s SMA is linked to how much SMN protein they have.
First came nusinersen (brand name Spinraza®), which was FDA approved in December 2016. It works by boosting the efforts of SMN2 so it makes more SMN protein. It is given as an injection in the spinal cord for patients of all ages. After four initial loading doses over two months, patients must continue receiving a dose every four months for life.
Then a gene therapy for SMA, onasemnogene abeparvovec-xioi (brand name Zolgensma®), was approved by the FDA in May 2019, limited to patients under the age of 2. Corrected copies of the SMN gene are delivered by a one-time intravenous infusion. These modified genes live in the cell nucleus and make SMN protein, so motor neurons keep firing.
In both treatments, SMA’s unrelenting march of degenerative nerve damage is stopped or at least slowed. Muscle function is restored.
“It’s very exciting to see the impact in patients,” Brandsema says. “We’re changing lives.”
The sooner the better
Research so far shows that the earlier children received treatment, the better their outcomes. Once a motor neuron dies, it’s gone forever. “The speed to treatment is big,” Kichula says. “Every week, every month ... they lose motor neurons they’re not able to get back.”
For the Figueroa family, it was a matter of only 19 days between when their daughter, Millie, was born and when she received SMA gene therapy. She is the youngest patient to be treated with Zolgensma at CHOP.
Lizmara and Angel Figueroa knew there was a 25% chance their baby would have SMA because late in the pregnancy both found out they were carriers of the defective SMN1 gene. “I did the worst thing; I Googled SMA,” Lizmara says. “I saw how their muscles stop functioning and they can’t breathe or feed. It was so scary. We wanted to be prepared, but were hoping for the best.”
Millie’s blood was drawn for the newborn screening test while she was still in the hospital. She had been home four days when Angel got the call from their pediatrician: The test was positive for SMA, and she was genetically highly likely to have the most severe type 1 form.
“They referred us to CHOP right away,” Angel says. “We had an appointment with Dr. Brandsema the very next day.”
Choosing between two good options
After describing SMA, Dr. Brandsema first told the family about nusinersen. “I was thinking to myself, ‘Yes, we can do this. It will slow down the progression of SMA,’” Lizmara remembers.
Then he described gene therapy. “To learn that it will basically replace the gene mutation and freeze the SMA, we were super excited,” Lizmara says. “We quickly jumped to that option and then hoped our insurance would cover it.”
It was approved. “When we heard, we literally jumped up and down,” Lizmara says. Millie had her infusion on Aug. 14. The IV drip took one hour. She stayed for two more hours for observation, then her parents took her home.
“In one hour, her life was changed completely,” Lizmara says. Chances are good that Millie will be able to do all the things her parents always pictured her doing: playing with her brother, riding a bike. “We call her our miracle baby.”
Millie is being closely monitored for potential liver issues, a side effect of gene therapy, but so far tests have come back normal. “She’s doing amazing,” Lizmara says.
As of March 2019, babies born in Pennsylvania, like Millie, find out within days if they have SMA because it was added to the state’s newborn screening test panel. Both Kichula and Brandsema were on the committee that pushed Pennsylvania through the complicated process to get on board after the U.S. Health and Human Services approved SMA as an addition to the Recommended Uniform Screening Panel in July 2018. CHOP is one of six hospitals in Pennsylvania where babies who test positive are referred. New Jersey has yet to add SMA to its newborn screening.
Amazing impact, uncertain future
The first trials of Zolgensma were started five years ago, and so far the genetically modified genes have continued to be effective; improvements have lasted. It’s just too soon to know if they’ll last a lifetime. Hopes are high, “but we don’t yet understand the long-term durability,” Dr. Brandsema says.
Because Spinraza has been around longer, CHOP has treated more children with it. Some children already taking the medication also received gene therapy for SMA, so it’s difficult to tease out which treatment led to a child’s improvement.
“Gene therapy is not a cure, but it’s such a good treatment,” Kichula says. “We see dramatic changes. It improves their whole life.
“I had a little boy in clinic a week ago,” she adds. “For the first time in his life, he was able to raise both arms over his head. It’s a small thing for most people, but it’s huge for his future. He may not walk or run, but every little bit of improvement gives him more independence for his future. If he can get from a wheelchair to the toilet by himself, from an independence standpoint, that’s huge.”
A current trial of Zolgensma is enrolling children up to age 5 to see if it can help children with milder types of SMA who don’t show symptoms until they are older.
“It’s still so new, and we have limited experience with older patients,” says Brandsema. “We have to be honest with families. There are some unknowns. But there is an incredible opportunity.”
For those with SMA, that opportunity means everything.
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Until three years ago, when Children’s Hospital of Philadelphia (CHOP) neurologists John Brandsema, MD, and Elizabeth Kichula, MD, PhD, had to tell parents their child had spinal muscular atrophy (SMA), “it was one of the worst diagnoses we had to make because at that time there was nothing for these children,” Kichula says.
In SMA, motor neurons, the cells that signal muscles to move, are missing an essential protein and die. Without the signal, muscles waste away. In the past, children with type 1 SMA never sat independently and eventually lost the ability to breathe or swallow on their own. They rarely survived past their second birthday. Those with type 2 regressed as infants and toddlers, losing skills when they should be gaining them. They would never walk, would need help eating, dressing and with other routine activities of living, and would need mechanical assistance to breathe. While it’s a rare disease, with about 1 in every 10,000 babies born with SMA, it is the leading genetic cause of death in infants.
“It was a progressive, irreversible disease,” Brandsema says. “Heartbreaking.”
Notice the past tense. Was.
“Now when we see a child with SMA, we’re kind of glad because we know we can do something,” Kichula says.
Two miracle treatments
The “something” is two treatments that halt the destructive disease, allowing children to continue normal development. As one of the largest neurology practices in the country, CHOP was a pivotal clinical trial site as the treatments were tested prior to their eventual Food and Drug Administration (FDA) approvals. Both work with the genes that effect motor neurons.
When the survival motor neuron gene 1 (SMN1) is faulty, it doesn’t make SMN protein, which motor neurons need to function and send signals to muscles. Another gene, SMN2, is a “back-up” gene and also produces SMN protein, but at about one-tenth the amount as SMN1. The severity of a child’s SMA is linked to how much SMN protein they have.
First came nusinersen (brand name Spinraza®), which was FDA approved in December 2016. It works by boosting the efforts of SMN2 so it makes more SMN protein. It is given as an injection in the spinal cord for patients of all ages. After four initial loading doses over two months, patients must continue receiving a dose every four months for life.
Then a gene therapy for SMA, onasemnogene abeparvovec-xioi (brand name Zolgensma®), was approved by the FDA in May 2019, limited to patients under the age of 2. Corrected copies of the SMN gene are delivered by a one-time intravenous infusion. These modified genes live in the cell nucleus and make SMN protein, so motor neurons keep firing.
In both treatments, SMA’s unrelenting march of degenerative nerve damage is stopped or at least slowed. Muscle function is restored.
“It’s very exciting to see the impact in patients,” Brandsema says. “We’re changing lives.”
The sooner the better
Research so far shows that the earlier children received treatment, the better their outcomes. Once a motor neuron dies, it’s gone forever. “The speed to treatment is big,” Kichula says. “Every week, every month ... they lose motor neurons they’re not able to get back.”
For the Figueroa family, it was a matter of only 19 days between when their daughter, Millie, was born and when she received SMA gene therapy. She is the youngest patient to be treated with Zolgensma at CHOP.
Lizmara and Angel Figueroa knew there was a 25% chance their baby would have SMA because late in the pregnancy both found out they were carriers of the defective SMN1 gene. “I did the worst thing; I Googled SMA,” Lizmara says. “I saw how their muscles stop functioning and they can’t breathe or feed. It was so scary. We wanted to be prepared, but were hoping for the best.”
Millie’s blood was drawn for the newborn screening test while she was still in the hospital. She had been home four days when Angel got the call from their pediatrician: The test was positive for SMA, and she was genetically highly likely to have the most severe type 1 form.
“They referred us to CHOP right away,” Angel says. “We had an appointment with Dr. Brandsema the very next day.”
Choosing between two good options
After describing SMA, Dr. Brandsema first told the family about nusinersen. “I was thinking to myself, ‘Yes, we can do this. It will slow down the progression of SMA,’” Lizmara remembers.
Then he described gene therapy. “To learn that it will basically replace the gene mutation and freeze the SMA, we were super excited,” Lizmara says. “We quickly jumped to that option and then hoped our insurance would cover it.”
It was approved. “When we heard, we literally jumped up and down,” Lizmara says. Millie had her infusion on Aug. 14. The IV drip took one hour. She stayed for two more hours for observation, then her parents took her home.
“In one hour, her life was changed completely,” Lizmara says. Chances are good that Millie will be able to do all the things her parents always pictured her doing: playing with her brother, riding a bike. “We call her our miracle baby.”
Millie is being closely monitored for potential liver issues, a side effect of gene therapy, but so far tests have come back normal. “She’s doing amazing,” Lizmara says.
As of March 2019, babies born in Pennsylvania, like Millie, find out within days if they have SMA because it was added to the state’s newborn screening test panel. Both Kichula and Brandsema were on the committee that pushed Pennsylvania through the complicated process to get on board after the U.S. Health and Human Services approved SMA as an addition to the Recommended Uniform Screening Panel in July 2018. CHOP is one of six hospitals in Pennsylvania where babies who test positive are referred. New Jersey has yet to add SMA to its newborn screening.
Amazing impact, uncertain future
The first trials of Zolgensma were started five years ago, and so far the genetically modified genes have continued to be effective; improvements have lasted. It’s just too soon to know if they’ll last a lifetime. Hopes are high, “but we don’t yet understand the long-term durability,” Dr. Brandsema says.
Because Spinraza has been around longer, CHOP has treated more children with it. Some children already taking the medication also received gene therapy for SMA, so it’s difficult to tease out which treatment led to a child’s improvement.
“Gene therapy is not a cure, but it’s such a good treatment,” Kichula says. “We see dramatic changes. It improves their whole life.
“I had a little boy in clinic a week ago,” she adds. “For the first time in his life, he was able to raise both arms over his head. It’s a small thing for most people, but it’s huge for his future. He may not walk or run, but every little bit of improvement gives him more independence for his future. If he can get from a wheelchair to the toilet by himself, from an independence standpoint, that’s huge.”
A current trial of Zolgensma is enrolling children up to age 5 to see if it can help children with milder types of SMA who don’t show symptoms until they are older.
“It’s still so new, and we have limited experience with older patients,” says Brandsema. “We have to be honest with families. There are some unknowns. But there is an incredible opportunity.”
For those with SMA, that opportunity means everything.
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