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A Charlotte baby became the first at UNC Medical Center in Chapel Hill, N.C. to receive a breakthrough gene therapy treatment for spinal muscular atrophy (SMA), after his condition was discovered through the Early Check newborn screening pilot study.

It was a pregnancy that went relatively smooth. No red flags. No urgent ultrasounds. But, for this one family of Charlotte, N.C., that sense of apprehension was always lurking.

“It was like I was waiting for the other shoe to drop. After all that we went through with our first child, once we had our son, it seemed too easy to feel like everything was normal,” said the mom, who wishes to be anonymous.

Their first child was born with health issues that went undetected during the mom’s pregnancy, and it was a surprise at birth.

“So, my pregnancy with my second child, my son, was super simple aside from the fact that I would consider myself slightly traumatized from what happened with my oldest. Other than that, the pregnancy was easy and enjoyable,” she said.

Their son was born February 25th, 2021, perfect in every way, at least on the outside. Around this time the parents received an envelope in the mail informing them about Early Check, a pilot study focused on screening newborns for rare health conditions, and how parents could sign their babies up prenatally or postnatally.

Early Check newborn screening
Early Check newborn screening helps to screen babies for rare health conditions.

“After speaking with our pediatrician, and realizing how enrolling our son in this study could make a difference, we decided to register,” said the mom, whose intuition also played a role in her family’s decision. Little did she know her gut decision would allow her child to live a more normal life.

The pilot study is in collaboration between RTI International, North Carolina State Laboratory of Public Health (NCSLPH), and three major universities – the University of North Carolina at Chapel Hill, Duke University and Wake Forest University. Among many other rare conditions, Early Check launched screening for spinal muscular atrophy (SMA) in October 2018 throughout the spring of 2021.

“With Early Check, we started including SMA because it wasn’t a part of the general newborn screening for the state, so it was a pilot to see how it could work and to see if we could identify this condition in newborns,” said Cynthia Powell, MD, pediatric geneticist, UNC site principal investigator for Early Check.

Results No Parent Wants to Hear

When their baby was three-weeks-old, the parents registered their son to be a part of the study. Four days later, they received a phone call.

“It was one of those really nice spring days, a Friday afternoon. We were out getting ice cream and when we got back in the car, we both had missed calls. After listening to the voicemail, my stomach dropped,” the mom said.

Their son received an abnormal newborn screening result for SMA, a rare genetic disorder caused by deficiency of the survival motor neuron protein (SMN1), resulting in progressive degeneration and irreversible loss of cells in the spinal cord and brainstem. Without treatment, the decreased level of the SMN protein leads to muscle weakness, and wasting atrophy of muscles used for movement. Most babies diagnosed with this disorder will have weak mobility, typically shown in the extremities, such as limp legs and arms, before six-months of life. This debilitating and often fatal muscle weakness can lead to an individual not being able to perform the basic functions of life, like breathing and swallowing, eventually leading to death by two or three-years-old. SMA is the leading cause of infant mortality from a single gene disorder, and its prevalence is one per 10,000 births globally.

“This is a pretty devastating genetic disease,” said Zheng (Jane) Fan, MD, pediatric neurologist, co-investigator for the Early Check pilot study. “The severity of the disease depends on the genetic mutation subtype. For SMA babies, they have no copies of the SMN1 gene. Their disease severity depends on the number of copies of the SMN2 gene, which serves as a backup copy for the SMN1 gene,” she said.

The Early Check results showed that the son had an absent SMN1 gene. A follow-up appointment was scheduled for the family to visit UNC School of Medicine’s Clinical & Translational Research Center (CTRC) the following Tuesday for confirmatory testing and to see how many copies of the SMN2 gene were present. For the parents, it was a long, grueling three days full of questions about whether or not their son was going to live.

“We basically mourned the loss of our son that entire weekend before our visit to Chapel Hill,” said the dad.

The confirmatory testing tells how many copies of the SMN2 gene are present. If there are three or more copies of the SMN2 gene, a baby could have a moderate form of SMA, whereas if there are two or less copies of SMN2, it could lead to a more severe form. Results showed that the son had three back-up copies of the SMN2 gene.

“All the types of SMA are caused by the same gene variant, but are different in severity that will influence the age of onset and how quickly and severe it will manifest. Classification is based on the clinical age of onset and rate of regression,” said Yael Shiloh-Malawsky, MD, pediatric neurologist and associate professor in the UNC Department of Neurology. “With the more severe form, a child will never gain the milestone of sitting. This is Type I. Type II are kids who will be able to sit, but will never gain independent walking and later on can lose the ability to sit without help. Type III are children who gain walking, and later on will have decline in their strength.”

Just looking at the child with the naked eye, no one could tell that he had a debilitating disorder forming on the inside. No symptoms were shown at all. For this particular case, the son fell within the Type II range.

“For babies with Type I or II, the recommendation is to start treatment as soon as possible,” said Dr. Fan.

“We didn’t even think treatment was an option,” said the mom as her eyes begin to fill with tears.

“During our first appointment with Dr. Fan, she showed us videos of children jumping rope and running. Children who had SMA, but received treatment. We never thought our son was going to be able to do any of those things,” her voice trembled.

Life-Saving New Treatments for SMA

New medical advances are changing the course of SMA by helping thousands of children diagnosed with the disease experience better outcomes. For this family specifically, treatments were narrowed down to two choices; Spinraza, an FDA approved drug at $125,000 per one dose that is continued every four months for the duration of the individual’s life, or they could choose the recent FDA approved gene therapy called Zolgensma, a $2-million dollar one-time treatment.

Time was of the essence. With SMA, once symptoms start to appear, it’s a red flag that motor neurons have already been lost. A decision needed to be made quickly.

“After discussions with our pediatrician, Dr. Fan, Dr. Shiloh, and other medical professionals, we decided to choose Zolgensma,” said the mom.

Zolgensma, the first gene therapy approved to treat children with SMA less than two-years-old, is a one-time intravenous infusion that takes about an hour. It involves a safe virus, AAV9, that delivers a fully functional human SMN1 gene to the targeted motor neurons, which in turn improves muscle movement and function, and also improves survival and quality of life.

Multiple testing went underway to see if the child was eligible for the Zolgensma treatment.

“If the baby had antibodies against the AAV9 virus, then the gene therapy wouldn’t have been effective,” Dr. Fan said. This is because once the therapy penetrates the blood, the antibodies would kill the virus, even though the virus was harmless and carrying potentially life-saving cargo.

Luckily, test results showed that the baby did not have antibodies against the virus. It took two weeks for the treatment to be approved from insurance and to be delivered to UNC Children’s Hospital. Then on April 21st at eight-weeks-old, the baby became the first at UNC Medical Center to receive the life-saving gene therapy treatment.

“I have a real appreciation for our doctors. They are so brilliant and they want to use that towards the good of our children. There’s hope,” said the dad.

From checking in, receiving the treatment, to monitoring for side effects, the whole process took about seven hours. After staying in town for a couple days, the family headed back home. However, the son was monitored continuously to check for potential side effects – the biggest being elevated liver enzymes, due to an inflammatory response.

“This baby tolerated the gene therapy treatment well, with no apparent side effects and his liver enzymes remained in normal range throughout the monitoring period,” Dr. Fan said.

For children diagnosed with SMA Type II, muscle weakness develops between ages 6 and 12 months. However, because the Early Check newborn screening was available for SMA and the child received the gene therapy early before the onset of symptoms, the outcome is in his favor.

“If the child had been born in a different state that already started newborn screening on a population basis, he would have been screened, but because North Carolina hadn’t started screening for SMA yet, he would’ve been missed if his family hadn’t signed up for the study. It’s pretty remarkable,” said Dr. Powell.

As of May 1, 2021, SMA has been part of newborn screening statewide, and North Carolina is among the more than 30 states with this screening.

“Our expectation is that this child will have normal development, normal strength like any other baby,” said Dr. Shiloh-Malawsky.

For now, the parents continue to be observant of their son while being cautiously optimistic.

“It’s the nature of parenting that you’re going to worry about your child,” said the mom. “I was thinking it was a death sentence when I heard about my son’s diagnosis. We’re only three months into it, but from what the doctors have said, it doesn’t have to be a death sentence. My son can live a fulfilling life. We’re grateful for that.”

“So far, he’s right on track for his physical therapy evaluation, and recently, he rolled over for the very first time,” she said, and she smiled.

Written by Brittany Phillips, UNC Health Communications Specialist