Will gene-targeting therapies offer unprecedented outcomes for children born with the severest forms of spinal muscular atrophy?
By Gary Logan
On the morning of Friday, Aug. 23, 2019, a newborn lies in her father’s lap at Johns Hopkins Home Care Group in Dundalk, Maryland. Her curious eyes peer up at the sea of rainbow scrubs and the wide smiles of nurses and staff around her. “Sofia, Sofia,” they say, wanting her attention as an infusion technician at her side pushes a blue button on a panel, releasing a revolutionary new therapy intravenously through a vessel in her arm and triggering applause. Sofia’s face remains pink and animated, but her arms beneath a turquoise blanket are stone still at her side, her legs seemingly lifeless, signs of the neuromuscular disease that began afflicting her before her birth.
Sofia with her parents, Brooke and Ryan
Sofia has spinal muscular atrophy (SMA), which affects 1 in 10,000 infants and results in progressive loss of mobility, respiratory complications, muscle weakness and atrophy, as well as challenges swallowing and eating. SMA is also the leading genetic cause of infant death worldwide. Sofia has the most lethal form of the disease, SMA type 1, which claims the lives of most patients by age 2. However, on this day, at this moment, this therapy, clinical trials had shown, could dramatically change the course of the disease for Sofia and patients like her.
“We had been talking about this for months — everybody was talking about it — to have everything ready for a baby like Sofia,” says her pediatric neurologist, Tom Crawford. Over the past year or two, he explains, the team felt they were at the cusp of their first gene transfer therapy for patients with SMA and now they were there. “Everyone knew their role and what they were going to do. Everybody knew this was a pivotal moment.”
What was behind this pivotal moment, this revolutionary new treatment for SMA? It is actually one of three novel gene-targeting treatments recently approved by the U.S. Food and Drug Administration (FDA). Over the past four decades, with no cure for SMA in sight, Crawford had worked with families and patients to promote their development and identity in the face of the disease. Rather than shelter and isolate these young patients, he encouraged parents to push them out into the world, no easy chore. At the same time, Crawford continued his efforts to find a cure through participating in clinical trials, though research gains were modest — until the FDA’s approval of the gene-targeting therapies. Then, everything changed.
The therapies, while not a cure, demonstrated new measurable motor milestones, such as head control, sitting, crawling and even standing for infants like Sofia with SMA type 1. In a Phase I clinical trial of 15 patients up to 6 months of age who received the same therapy Sofia received, at the study cutoff all the children were at least 20 months old and none required permanent mechanical ventilation. In comparison, only 8% of patients in a historical group survived to the same age without permanent mechanical ventilation. Seven children in the high-dose group were completely independent of ventilator assistance; 11 patients had achieved and retained the ability to swallow independently and four were able to feed orally.
Pediatric neurologist Tom Crawford tests Sofia’s reflexes at her monthly clinic visit as her parents look on.
Among the 12 infants who received the high dose, 11 were able to achieve head control. Nine were able to roll at least 180 degrees from the back to both the left and right and could sit unaided for at least 30 seconds, something normally never seen in babies with SMA type 1.
For Crawford and his patients, the sun had broken through the clouds. “For newborns with SMA, the change in their course of disease is life-changing,” says Crawford.
“Patients were able to feed themselves and get in and out of their wheelchairs by themselves, compared with certain death.”
How do the therapies work? SMA is caused by a mutation in the survival of the motor neuron 1 (SMN1) gene, which encodes a protein that motor neurons need to survive. The mutation prevents this gene from producing that protein. Every patient with SMA, however, retains at least one copy of SMN1 — the most severe patients tend to have two copies, milder patients up to four copies — which contain some protein. Two of the gene-targeting therapies are designed to splice and hijack a copy to create a molecule that can be translated into normal protein in the SMN1 gene.
The therapy Sofia received, on the other hand, works by delivering a working copy of the SMN1 gene to motor neurons in SMA patients, in effect replacing the missing or nonworking protein. In the simplest terms, Crawford suggests, rather than fixing a flat tire via the splicing approach, you are swapping it with a spare.
“You’re restoring normal function by introducing a functioning copy of the SMA gene,” Crawford explains. “The science is miraculous.”
What’s not miraculous is the ease of getting these therapies to patients — and as early as possible. For decades, patients went undiagnosed for months, (in some cases years), until physical symptoms, follow-up exams and lab tests confirmed SMA, a disease that begins its manifestations in utero. Maryland’s inclusion in May 2019 of adding SMA to its newborn screening panel, which prompted a call to Sofia’s pediatrician and Crawford during her first week of life, helped immensely.
“In this disease, motor neurons are dying over time. The kids we’ve treated at six months are not going to die but they had a fair amount of damage before they received the drug,” says Crawford. “If, on the other hand, I can do an infusion at two weeks, there’s very little damage, and I am stopping the process of motor neuron degeneration.”
Early detection, however, is not the only factor affecting outcomes. The cost of the new gene targeting therapies — up to $2 million — and obtaining insurance coverage, institutional approval and coordination to provide the infusion, is a complicated process, which can also cause delays.
“We worked with people across the organization, from leadership and administration, getting everyone to understand the whole process, the complexities involving treatment for these very small babies,” says Crawford. “Then there’s connecting families to additional financial resources, like grants and foundations, to help pick up the costs. Otherwise, patient families see the sticker price and abandon the drug. This is uncharted territory — no one here has written a purchase order for a $2 million drug.”
Crawford and his team, however, pulled it off, partly by collaborating with the Johns Hopkins Home Care group to hold the infusion procedure at their facility in nearby Dundalk to lower the costs associated with a hospital-based treatment.
Still, Sofia was treated four weeks after her birth and, during the time between her diagnosis and treatment, she had started to decline. When Crawford saw her the first time on August 8, her arms were stuck on her side and she could not roll her head side-to-side, signs that Sofia was on the more severe end of the SMA1 spectrum.
There is variation in how well individual patients respond to the gene therapy, but the most significant determining factor, Crawford reiterates, is when they receive it. So, how did Sofia react to the therapy?
On Aug. 31 in the neurology clinic, a week and a day after her infusion, Sofia was moving her arms: the first inkling of improvement. On her next weekly follow-up appointment, she was “moving her arms a bit more,” noted Crawford. “This is incontrovertible.”
At her mid-September check-up, Crawford reported that Sofia scored higher on the assessment scale of infant movement. Then, on Sept. 24, Sofia’s parents shared a video of Sofia moving both arms, bringing her hands up to her mouth, holding her head up and making facial expressions. Moreover, she was crying loudly, the single most critical measure of the strength of breathing muscles for babies with SMA.
“If the breathing muscles are too weak, patients cannot cough and clear their lungs, which is the most common cause of death among these children,” Crawford explains.
Since her infusion, Sofia’s parents have measured her growth weekly using their own blanket algorithm.
Pediatric physical therapist Meghan Moore heard the same thing and more: “When I saw Sofia, I said, ‘Oh my God, she’s so much louder.’ Everyone is like, okay, we got it. I wish we had a decibel tool to track it.”
Moore’s newfound enthusiasm matched Crawford’s. Before the gene therapies were developed, patients tended to decline, despite physical therapists’ best efforts. Indeed, some neurologists felt physical therapy was simply hitting patients’ limited reserves, which appeared not to be the case with Sofia.
"We’re seeing through her abs and diaphragm, her ability to take a bigger breath and get more air in and out,” says Moore. “This was the first time we’ve seen such improvement in an infant with SMA1. Yeah, it’s pretty cool, super exciting because she’s doing really well.”
Indeed, with the added-value benefits of physical therapy Moore and colleagues foresaw for Sofia, they developed a new algorithm with more frequent visits to maximize her potential. Throughout the fall of 2019, the combination of the gene therapy and physical therapy appeared to be paying off. At Sofia’s mid-October appointment with Crawford, Sofia’s dad, Ryan, noted that her legs were still moving and getting thicker. Also, she had doubled her birth weight, at that point 11 lbs. 5 ounces.
Crawford’s response: “Oh my God, you’re a bigger baby!”
By early December, on a return visit, more signs of improved mobility had emerged. “There’s more movement from the elbow and now she’s starting to reach straight up,” Ryan said. “She’s grabbing my beard with her right hand. I said to myself, ‘Wow, that’s pretty cool.’ On her back, she’s lifting her legs straight up more, too.”
Sofia had been lifting her head up more, too, but sluggishly. For babies with SMA1, that’s an extremely challenging task because of their weak back and neck muscles. Ryan took it in stride: “All the changes are really slow but they’re still happening.”
Perhaps more meaningful for Ryan and Brooke than any recorded milestones, however, may have been the question from a nurse from an outside hospital when they brought Sofia in with cold symptoms: “Why would you bring a baby to a hospital with a simple cold?”
Among neuroscientist Charlotte Sumner’s goals is understanding why SMA progresses so quickly during the first weeks of life.
When Ryan explained that they were being extra vigilant because of Sofia’s condition, the nurse replied, “What condition?”
Another sign? When Sofia’s pediatrician started to check her ears at a checkup, the baby reached up to stop him. Such instances, Ryan says, put a wide smile on his face.
Crawford’s assessment at the end of 2019? These were all early signs that Sofia was re-establishing the course of normal infancy: “In a child with SMA1, especially one who had shown such a precipitous decline, this is extraordinary. It’s clearly working. Every case is different but this is so amazing from what used to happen before gene therapies.”
Would Sofia continue to achieve such milestones in the new year — even walk — unheard of in a child with SMA1? Finding the answers to such questions through studies of the gene-targeting therapies is the work of clinicians and researchers like Crawford, including neurologists Charlotte Sumner, Jessica Nance and Matthew Elrick.
In the Lab
In 2001, following doctoral training at the National Institute of Neurological Disorders and Stroke, where she says she “stumbled upon SMA,” Charlotte Sumner arrived at Johns Hopkins’ East Baltimore medical campus for a clinical neuromuscular fellowship. Why did she choose Johns Hopkins?
“It’s hard to find a place that is strong in both clinical neuromuscular disease and neuroscience,” she says. In other words, she wanted to treat patients with diseases like SMA but also study the underlying science to advance treatments. Neuromuscular disorders were a bit neglected by neurologists, she believed, and thus more fertile for new research discoveries.
“Neuromuscular disease, while not getting the attention that central nervous system diseases get, is satisfying because we can often make clear diagnoses based on the evaluations we can do,” says Sumner. “Also, there’s been an explosion of genetic understanding, which has allowed us to molecularly delineate the diseases, and with that molecular delineation come the promise of treatment. This is really what’s gotten me so excited about it.”
Among Sumner’s current pursuits is understanding why SMA progresses so quickly during the first weeks of life. What are the underlying mechanisms at play that could help her and other researchers come up with new combination treatments to improve their efficacy? The challenge, she explains, is that motor neuron cells live in the spinal cord, which does not allow sampling in living patients.
“So, it’s very difficult for us to know how much of the drug is getting to motor neurons and how well that cell is responding to the drug,” says Sumner. “Is the SMN induction even happening in those cells, and happening adequately? How well are these drugs actually working in individual patients? We have very little insight into that now.”
One answer, she notes, is the development of biomarkers to allow monitoring of disease activity in living patients, a collaborative research initiative Sumner and Crawford are conducting with industry partners. Among those biomarkers is a neuronal skeletal protein called neurofilament, which is released into the blood when motor neurons degenerate.
“With modern technologies, we can measure and monitor neurofilament and determine whether it’s going down, as we hope,” says Sumner. “If not, in this era of three gene targeting therapies we can think about adding something else in.”
Would such biomarkers also offer predictive or prognostic value for patients, as well, influencing treatment?
“That’s the idea,” says Sumner “We don’t quite know yet, but that’s the hope.”
In a related protocol for those infants who unfortunately, do not survive, Sumner and Crawford perform expedited autopsies to retrieve tissues to study how SMN expression varies and changes over time. They’ve found that expression tends to be very high in utero and then begins to decline postnatally, which raised the question of potential treatments in utero.
Sumner and Crawford are looking into it, noting that one of the new gene targeting therapies is permeable to the central nervous system and may safely cross the placental barrier as a treatment for the fetus. Mouse studies have been underway.
“When we treat mice in utero, they do better than when we wait to treat postnatally,” says Sumner. “I don’t think that would be necessary for all SMA patients, but potentially for some cases that are very severe.”
Sumner has already had conversations with maternal-fetal physicians at Johns Hopkins who have caught wind of gene therapy successes for SMA patients and are thinking of ways to offer treatments in utero. Pediatric neurologist Jessica Nance is on a similar track to pave the way for earlier gene-targeting interventions. She’s reaching out to genetic counselors and physicians in maternal fetal medicine to promote ideas across sites. The stakes, she says, are high.
“Even if you treat a child a week or two out, if they’re symptomatic, they’re still not going to be on a typical developmental trajectory. They may walk, but they may not walk on time or as vigorously as a child who does not have SMA,” says Nance, who was attracted to neuromuscular disease because it calls for “a special kind of sleuthing” to develop novel treatments. “We think we lose pretty quickly a fair number of motor neurons that we can rescue at the beginning of the disease, especially in the more severe types.”
Mat Elrick, now in his first year on faculty as a pediatric neurologist, expects that newborn screening for SMA will become increasingly sophisticated beyond the current panel of metabolic tests. In utero diagnosis of SMA is a possibility, too, he notes.
“Not only did the gene therapy stop the decline of Sofia’s disease but she got quite a bit better. It’s not a 100 percent cure, but it is a dramatic improvement,” says neurologist Mat Elrick.
“Potentially, with sequencing the entire genome, the whole panel will be supplanted with genetic testing,” says Elrick. “The question is: Does it make sense to push it to a prenatal test — and is that feasible?”
One thing’s for certain: Elrick agrees with his colleagues that this new era is a game changer. Prior to the gene-targeting therapies, patients were destined to die early or survive but were dependent on a tracheostomy and a g-tube, trapped in bodies they could not move, facing a very difficult and brief life. Sofia is proof, notes Elrick: “Not only did the gene therapy stop the decline of Sofia’s disease but she got quite a bit better. It’s not a 100 percent cure, but it is a dramatic improvement.”
Sumner, with an eye on the horizon, agrees: “SMA will be completely different now. We are now going to be able to treat a much larger proportion of patients with disease-modifying drugs. We will have many, many individuals living with SMA into adulthood.”
Still, many questions remain in both the clinic and lab. There may be long-term toxicities associated with the genetic therapies; questions about their effects long term; whether they would be fully sustained over a lifetime. Will patients hit a plateau and decline? How would a child’s growth influence the outcome of a one-hour infusion?
“It’s kind of the wild, ‘Wild West’ right now — we’re all sort of watching and waiting,” says Sumner. “It’s remarkable how little toxicity there’s been so far, but there’s a lot to do.”
What keeps them going? Whether a deeply experienced veteran like Crawford, a mid-career scientist like Sumner, young research-minded clinician researchers like Nance and Elrick, they are all intensely tied to their patients and looking around the next corner for answers. Perhaps they did not find their niche in medicine so much as their niche found them.
“I found the way patients dealt with disability very inspiring,” says Elrick, who also studies the emerging polio-like neuromuscular disease acute flaccid myelitis in the lab.
Adds Nance, “I’m comfortable with relentless progressive disease and making lemonade,” a euphemism for facing adversity.
Nance and her colleagues do so in ways that reveal conviction: It’s apparent in all who play a role caring for these young patients, greeting them and parents in clinic with warm smiles; building relationships; treating them like members of their own family; and creating a caring medical home model for these fragile infants and anxious families, including Sofia and her parents.
As this story went to press, Brooke reported that Sofia can now sit unassisted for up to one minute and roll from her back to her tummy, physical movements she was previously unable to attain. “The fact that she is able to have enough head control to sit unassisted is remarkable, and her ability to roll shows her continued strength and development combined with that curiosity she has always had,” says pediatric physical therapist Meghan Moore.
A New Year
On the morning of Jan. 18, 2020, a week shy of the six-month anniversary of Sofia’s infusion, Ryan noted that she was progressing more slowly now, in contrast to the rapid, encouraging signs he and Brooke saw in Sofia’s initial response to the infusion. She was still lifting her arms and hands up high, increasing her back and neck strength, but her legs were not showing the increasing mobility her parents hoped to see.
“Right now the concern is her leg movement,” or lack of it, Ryan explained in the living room of the family’s Odenton, Maryland townhouse. “Dr. Crawford said her leg reflexes were gone, but our pediatrician felt them. Maybe it’s a testament to her recovery?”
“She doesn’t move her legs up to her chest, but she can lift them off the ground,” added Brooke.
To demonstrate Sofia’s leg strength, Brooke grabbed her hands and pulled her up. Sofia was standing, albeit with some assistance. Brooke then lightened her grip and Sofia stood tall.
“That’s all her, not me,” Brooke said.
Other positive signs? In her high chair, her mother noted, Sofia holds her own bottle, grabs a spoon and brings soft solid foods like avocado, kale and sweet potato food to her mouth. She had grown longer — adding an inch — and heavier, reaching the 50th percentile. Cognitively, she appeared to suffer no deficits.
“She’s very aware,” said Brooke. “She said ‘Mama’ at three months.”
“Sofia is so curious about what’s going on,” added Ryan. “She’s really responsive.”
Another remarkable achievement they point to is her hair.
“The majority of my day with her is spent on hair control — it’s really wild; there’s nothing you can do about that mullet,” Brooke said, pointing to the long strands stretching down Sofia’s back.
Observers can see they enjoy their time with Sofia, as does she with them. She reveals a puckered smile in their interactions, leaving her parents beside themselves. One moment they cannot get enough of her, overjoyed to have her in their life; the next moment they are working with her on at-home physical therapy exercises to continue her progress and, hopefully, ward off potential deficits that come with SMA1.
“She keeps surprising us,” says Ryan. “Maybe she will walk one day.”
This feature originally appeared the spring 2020 issue of Hopkins Children's magazine.
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