Zolgensma leads to normal motor function in twins with SMA type 0
Twin girls with spinal muscular atrophy (SMA) type 0 are still alive with normal motor function more than two years after treatment with Zolgensma (onasemnogene abeparvovec-xioi).
This finding dramatically differs from the typical progression of SMA type 0, the rarest form of the disease, where symptoms start becoming apparent in the womb. Without treatment, children with SMA type 0 generally don’t survive past the first few months of life.
The case of the twins, which was presented at last year’s meeting of the American Academy of Neurology, has been published in the Annals of Clinical and Translational Neurology, in a paper titled, “Onasemnogene-abeparvovec administration to premature infants with spinal muscular atrophy.” Novartis, the company that sells Zolgensma, was not involved in the study.
In SMA, the death and dysfunction of motor neurons, the specialized nerve cells that control movement, result in symptoms like muscle weakness and wasting. The genetic disorder is caused by mutations in the SMN1 gene, which provides instructions to make the protein SMN that’s essential for motor neuron health.
Zolgensma is a gene therapy that delivers a healthy copy of SMN1 to cells. Like other SMA treatments, Zolgensma has been proven to slow the disease’s progression, but generally cannot reverse damage that’s already occurred. SMA type 0 has historically been difficult to treat because babies with this disease type have usually already experienced substantial motor neuron death by the time they are born.
When the mother started noticing one of the babies moving less, the twins were delivered by cesarean section at 30 weeks, about halfway through the third trimester. Shortly after birth, newborn screening indicated probable SMA and tests confirmed the diagnosis.
Early treatment with Zolgensma in SMA type 0
Zolgensma was administered less than a month after the babies were born. At the time of treatment, neither twin was showing overt signs of SMA, even though the mother had reported reduced movement in the womb, the researchers noted.
One twin needed to be fed via a feeding tube for the first few weeks of life. By age 3 months, both twins had normal results on swallow testing, though they had some trouble drinking thin liquids, which was managed with thickeners. Both babies had some brief hospitalizations in early infancy due to respiratory infections, but neither have needed hospitalization since 16 months of age.
As of the latest follow-up at about 2.5 years, both girls are able to walk, run, climb, and eat using utensils. and had motor function that was within normal ranges, said the researchers.. Formal language testing suggested slower than normal language development in both toddlers.
Genetic testing revealed they both had no functional version of the SMN1 gene, which is typically what happens in SMA. The SMN2 gene is able to function as a sort of backup for SMN1, but due to a quirk in the genetic sequence, SMN2 cannot make nearly as much SMN protein. Patients with more copies of SMN2 generally have less severe disease.
Testing showed the girls each had just one copy of the SMN2 gene, but the copy carried a mutation that made it more active than normal. Testing from one girl suggested the activity of this mutated SMN2 gene was roughly on par with activity seen in SMA patients with two SMN2 copies. This unusually active SMN2 copy, combined with Zolgensma having been given early in development, likely help to explain why the twins had such positive outcomes from gene therapy treatment, the researchers said.
“These cases illustrate the challenges in predicting [patterns of disease progression] based on standard SMN2 copy number testing and demonstrate that delivery of [Zolgensma] in prematurity can be both safe and highly effective,” the scientists wrote..
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