Infants with spinal muscular atrophy (SMA) who are being screened for Zolgensma may present with maternal antibodies against the therapy’s viral carrier — making them ineligible for the therapy — until the age of 8 months, a small study shows.
This means that an infant first testing positive for such antibodies may later test negative and become eligible for the one-time gene therapy.
As such, initial positive tests should be repeated until 8 months of age or if 1.5 months or more have passed to assess the infant’s true positivity, the researchers noted. In the meantime, infants may always receive other therapeutic options.
The study, “Adeno-associated virus serotype 9 antibody titers in patients with SMA pre-screened for treatment with onasemnogene abeparvovec – routine care evidence,” was published in the journal Gene Therapy.
Novartis Gene Therapies’ Zolgensma (onasemnogene abeparvovec-xioi) is available to SMA patients up to age 2 in the U.S. and other countries, and those weighing up to 21 kg (about 46 lbs) — likely including children up to age 5 — in the European Union and Canada.
Administered directly into the bloodstream, it uses a modified and harmless adeno-associated virus type 9 (AAV9) to deliver to cells a working copy of SMN1, the mutated gene in SMA.
The gene therapy can be given only once due to the body’s natural production of immune antibodies against AAV9. While the single dose may still promote an immune response, a second exposure would cause a greater immune reaction that could be harmful to the patient and render the therapy useless.
This is due to the immune system’s ability to “remember” invaders by having immune cells patrolling the body for that particular pathogen, thereby prompting a quick response upon encounter.
As such, the presence of pre-existing anti-AAV9 antibodies (AAV9-Abs) is an exclusion criterion for the use of Zolgensma. While these may be the result of the infant’s exposure to the virus, they may also be temporarily derived from the mother during early infancy.
“AAV9-Abs from a maternal source are found in newborns, as they appear to transfer via the placenta in utero, and theoretically also via breast milk, with levels tapering down within a few months,” the researchers wrote.
In previous Zolgensma trials, 15% of biologic mothers of infants screened for eligibility were positive for AAV9-Abs, “implying that most infants up to 6 weeks of age will still be eligible for gene therapy,” they added.
However, there is still limited data on the frequency of these antibodies in infants screened for Zolgensma, as well as potential influencing factors.
With this in mind, a team of researchers in Israel retrospectively analyzed the demographic, clinical, and antibody testing results of all infants under 2 years of age who were screened for Zolgensma treatment at four medical centers in Israel between 2019 and 2021.
A total of 34 infants (30 with SMA type 1 and four with type 2), with a mean age of 8.46 months, were screened. Half were girls and more than half of the infants were Muslims and born of parents who were related by blood (55.9% each)
About half (52.9%) had been previously hospitalized, over a third (38.2%) had records of prior viral infections, and 41.2% had received previous treatment with Biogen’s Spinraza (nusinersen), the first approved therapy for SMA.
Antibody results showed that six (17%) infants tested positive for antibodies against AAV9, excluding them from receiving the gene therapy.
A total of 15 patients (44%), including the six positive infants and nine negative infants whose results had passed the valid time period before treatment, were re-tested. The interval period between tests ranged from one to nine months.
Most of these children (73.3%) presented matching results in the two tests. However, two girls and one boy (20%) went from positive to negative for AAV9-Abs and one girl (6%) from negative to positive.
The three who became negative for AAV9-Abs had ages of 2, 5, and 8 months at the time of the second test, which was done at 1.5–4.5 months after the first test.
Spinraza was given to two of these infants after the first positive test, and switched to Zolgensma after the second, negative, test. The other infant was also initiated on Zolgensma after the negative test.
Follow-up assessments highlighted no major adverse events and significant improvements in motor milestones and motor skills.
“We postulate that these three patients had passive immunity to AAV9, likely by placental transfer of antibodies,” the researchers wrote.
The girl who became positive for AAV9-Abs in the second test, which was performed 5.5 months after the first, had an age of 13 months. At the time of the first, negative, test, Zolgensma was not yet available, and she was treated with Spinraza.
After the gene therapy became available in the country, the girl repeated the test and was positive for the antibodies, making her no longer eligible for Zolgensma, and she continued Spinraza treatment. It is possible that she was infected with the natural AAV9 between the first and second test, the team noted.
Notably, the researchers found no significant associations between demographic or clinical factors and positive tests, but they hypothesize that this may be due to the small number of included patients.
Based on these findings, the researchers recommended that AAV9-Ab re-tests “be performed until the age of 8 months, or, if 1.5 months or more have passed after the initial AAV9-Abs test,” and emphasized that “any prolonged delay in gene therapy treatment may increase the risk for a positive AAV9-Abs result.”
The data also highlights “the need to perform AAV9-Abs tests as early as possible, or as close as possible to treatment planned time,” the researchers added.
Future, larger studies are needed to confirm these findings and better understand “the temporal window for performing the AAV9-Abs test prior to [Zolgensma] … [to achieve] more efficacious gene therapy of SMA patients,” the team wrote.
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