Gene therapy treatment for spinal muscular atrophy (SMA)

July 15, 2021

Early Check is a pilot study 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.

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

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 confirmatory testing and to see how many copies of the SMN2 gene were 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.

“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.

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.

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