At 3, Anna Rose Scurria stands tentatively, her eyes big and smile a little apprehensive. Her mom, Krista Scurria, stands close, not quite touching her, but you can see an invisible thread as she forms herself around her daughter so she can catch her quickly should the child falter.

Anna Rose and her brother Joshua, almost 6, both have spinal muscular atrophy, the leading genetic killer of children younger than 2. Only within the past year has she been able to stand and take nervous little steps with a walker. Her parents give credit for that and the fact that Joshua can now straighten himself in his wheelchair to an experimental treatment.

Parents like Krista and John Scurria of Louisiana, as well as Loree and Ward Weisman of Colorado, have been bringing their children to Utah regularly recently for a monitored clinical study. Lyza Weisman is also, at 3, beginning to walk again. Like the Scurrias, the Weismans use the word “miracle” to describe what they’ve experienced in the early phase clinical trials testing new use of two proven medications — sodium phenylbutyrate and valproic acid combined with carnitine.

The children’s neurologist, Dr. Kathryn Swoboda, also a geneticist and researcher at Primary Children’s Medical Center and lead investigator of the studies, is more cautious but nonetheless pleased with early results. “These drugs are not a cure,” she said. “They will never be a cure, but if we could buy some considerable time for these kids to get old enough so that even more potent therapies are available, we will have done a huge service to these SMA kids.”

Swoboda’s just winding up the small clinical trials to test the safety of using the drugs in children with SMA. They have, she says, been well-tolerated. The next step is a bigger, multicenter study to test effectiveness — a step the FDA approved just this week for the valproic acid-carnitine regimen.

Project Cure SMA
SMA occurs in one in 6,000 births, always to children whose parents both lack one copy of SMN1, one of a pair of motor neuron survivor genes. One in 40 people have the deletion; when both parents lack the gene, there’s a 25 percent chance a child will have SMA.

It is the number of copies of the second gene, SMN2, and the resulting protein it produces that helps motor neurons survive and determines how severe the SMA will be. More copies mean better physical outcomes. SMA type 1 children, those with the fewest copies, don’t sit up or walk and most die of their fragility and complications before age 2. Type 2 children like Anna Rose, Joshua and Lyza sit up but are generally too weak to walk. Type 3 children have a range, from showing little effect to over time weakening until they can no longer walk.

SMA used to be a diagnosis without hope: muscle weakness and atrophy, inability to swallow and then death.
Lyza was almost 14 months old when she was diagnosed, says her father, Ward Weisman. At 9 months, she’d started “heading backwards” in her development, no longer trying to walk. They learned about the study online and enrolled her. They’ve been coming to Utah four times a year for follow-up ever since. “We don’t know if she’s reached a plateau” of improvement, he says. “We’re about to increase the dose a little and see if that helps. There’s a lot to learn and be careful about, but we do consider this a miracle.”

The clinical trial of the two medications, conducted solely at Primary with children brought in from all over the country, has been called Project Cure SMA, funded by Families of SMA. Sodium phenylbutyrate has been used for years to treat certain metabolic disorders in newborns, so it’s known to be safe for them, but its effectiveness with SMA is still unproven, although it seems to help mice with SMA. Valproic acid has been used for a broad range of medical reasons, including seizure control and as a mood stabilizer for bipolar disorder. But is it safe for newborns and youngsters and will it help SMA?

Earlier the better
Early indications are that the younger children receive the drugs, the better it is for them. It is only recently that Joshua has shown any benefit. And his improvement seems much subtler than that of his little sister.

“He was so weak the chance to get him walking with either drug is extremely low. He has had five years for his disease to progress,” says Swoboda. “The older children are probably too far along in the disease process to show too much benefit, at least in a short period of time.”

Still, Krista Scurria says Joshua has more endurance. He can straighten himself in the wheelchair now. And he “still doesn’t have scoliosis,” which is unusual. He’s “doing as well as the other children with his schoolwork and can open doors, cabinets and bottles.”

She says Anna Rose, with something to hang onto, “can stand as long as she wants. She will stand and play in her toy kitchen forever.”

The longer these children can stand, the better their hip development and their later quality of life, Swoboda says.
A year ago, Lyza was falling over when sitting, her mother, Loree, says. Now she’s not. Still, while Ward Weisman calls himself “thrilled,” he admits it is “not the cure we’re hoping for.”

Window of opportunity
The hope is that, given early, one of these drugs will buy these children time until stem cell or gene therapy or some other treatment is perfected. Once symptoms occur and muscles weaken, it’s hard to get them back.

“We have to intervene in the very young to have potential benefit,” says Swoboda. Someone like Anna Rose is borderline.
“If we can keep her walking — she’s very weak — able to bear weight, keep her hips in the sockets and keep her stable, it will make her life so much better down the road. Even modest benefit will affect each of them throughout life.”

Electrophysiological studies clearly show that neurons still decline, even with the medication. “We have a window of opportunity, so we are trying to identify truly effective drugs that might be started as early as possible.” Early on, with the medication, parents report progress, then the children stabilize. “If you look at them at intervals, there’s definitely a decline over time,” Swoboda says, another reason she cringes when someone says “miracle.” She doesn’t want to raise unrealistic expectations.

Familiar medications
Both drugs work by opening up DNA to allow the expression of genes at a higher level. That’s why a drug screening survey picked them as a possible help for children with SMA. The goal is to find a drug that increases expression of that second survivor motor neuron gene, perhaps turning a type 1 child into a type 2, or a type 2 into a 3. No one expects either drug to cure the condition, Swoboda says. But until now, there has been nothing to offer parents in the way of hope.

Swoboda has used sodium phenylbutyrate in children under 2 for a couple of reasons. It’s phenomenally expensive, and the dose, based on weight, is smaller with infants. And it has been safely used for years in infants and young children. Valproic acid poses a greater risk for those under 2, so it was used in the older children for the study.

With any clinical trial, there’s a question of what happens between the time results are in and the FDA acts. It’s a little easier in cases like this, Swoboda says, because the drugs are already approved, although not for this use. Doctors could still, should the data support it, prescribe the drugs “off label,” meaning not for the approved use. That doesn’t mean, though, that insurance will cover it — or that it’s in the best interest of the patient. Both of the medications can pose serious, potentially life-threatening side effects, Swoboda says. Something as minor as increased appetite and weight gain can lead to functional decline in some patients.

Families and researchers
That’s yet another reason Swoboda is anxious to prove the medicines help or they don’t. The families are abuzz with news of anything that might work; she’s concerned that parents desperate for a measure of hope will leap to get their children on the medicines before it’s clear if they really make a difference. It’s crucial, she says, that children taking valproic acid also take carnitine, but she’s not sure that message will be understood if the medicine’s prescribed outside the trial.
Swoboda wants to help the children but in a way that’s safe and really does help. She’s not at this point even sharing dosing information with others because she doesn’t want children taking the medicine as if they were in a controlled, carefully monitored clinical study without that control and careful monitoring.

She thinks the next phase of testing valproic acid might start in a couple of months. The sodium phenylbutyrate is lagging perhaps six months behind that. If everything goes perfectly and the medications prove helpful — impossible to predict yet, despite good reports from some families in the early study (some children have seen no benefit) — within a couple of years there could be an answer with scientific heft to back it up.

“I’m not naive,” says Swoboda. “I have seen so many failed trials. If this truly works, it’s a testament to the families, physicians and scientists who have pushed this work forward. This has been an incredible collaborative international effort.”

They are enrolling different SMA children for the second phase of testing. The only way the current children could participate is to take at least three months off the drug. But the trials are hard on families.

“It’s a lot of commitment for these families, and I am amazed at the compliance,” Swoboda says. “It’s a lot of visits, of travel, of taking time off work. I don’t want to stress these families too much. We will continue to follow these kids over the long term whether they are on these drugs or not.”