Malignant tumours have been detected in several children with spinal muscular atrophy (SMA) who received Zolgensma gene therapy. In three cases, researchers identified a link to the GLI1 gene, whose excessive activation can contribute to cancer development. Le Parisien reports this, citing the US Food and Drug Administration (FDA).
Zolgensma is used to treat children under the age of two with SMA. The drug delivers into the body's cells a gene needed to produce a protein that patients with the condition lack. An adeno-associated virus (AAV), which is generally harmless under normal conditions, is used as a carrier to transport the genetic material.
The FDA has received reports of tumours affecting the central and peripheral nervous systems, spine and kidneys in patients following treatment. In two of the three cases linked to GLI1, analysis of tumour tissue showed that the DNA of the viral vector had integrated into the patients' cellular genomes. The promoter – a DNA segment that regulates gene activity – was found either next to or within the GLI1 gene.
Scientists suspect that this positioning may have led to excessive activation of GLI1 and contributed to tumour development. The reason for the altered activity of this gene in the third case is still being investigated.
The regulator noted that a similar mechanism had previously been observed in other experimental gene therapy programmes. Consequently, the FDA considers that the potential risk of tumour formation may apply not only to Zolgensma but also to Itvisma, a drug that uses the same viral vector and genetic construct. No cases of tumours have been reported following Itvisma treatment so far.
However, the FDA emphasizes that the benefits of both approved therapies continue to outweigh their potential risks. Their prescribing information already states that integration of viral vector DNA into the genome could theoretically lead to tumour formation. Patients are advised to undergo regular monitoring.
The FDA investigation is ongoing. The regulator will assess the frequency and causes of the reported cases and determine whether additional safety measures are necessary.
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