FDA Investigates Cancer Risk With Zolgensma After Vector DNA Found Next to a Tumor Gene

On November 6, 2026, the FDA said it is investigating a serious risk of cancer linked to Zolgensma (onasemnogene abeparvovec), Novartis's one-time gene therapy for spinal muscular atrophy (SMA). The agency says it has "confirmed reports of product-related insertional oncogenesis involving the GLI1 gene." In plain terms: in at least two children, the therapy's own DNA landed inside their chromosomes next to a cancer-related gene, and a tumor followed.

Novartis said the same day that it has received nine reports of tumors in patients treated with Zolgensma since it was first approved in 2019, out of more than 6,000 children treated worldwide, according to Reuters. In two of those cases, tumor tissue showed evidence that the vector had inserted its genetic material into the patient's DNA.

What the FDA found

The FDA has received postmarketing reports of tumors in patients treated with Zolgensma, including tumors of the central and peripheral nervous systems, the spinal and paraspinal regions, and the kidney. The agency did not give a total case count.

• Three cases involved tumors associated with the GLI1 oncogene.

• In two of the three, tumor tissue showed Zolgensma's AAV vector DNA integrated into the genome, with the promoter region of the therapy's construct inserted upstream of or within GLI1.

• In the third case, how GLI1 became overactive is still under investigation.

The warning also covers Itvisma, the newer onasemnogene abeparvovec product approved in November 2025, because both products contain the same vector and construct. The FDA says no tumors have been reported after Itvisma to date.

Why this is a surprise for AAV gene therapy

Zolgensma uses an adeno-associated virus (AAV9) vector to deliver a working copy of the SMN1 gene to motor neurons. AAV vectors are popular because their DNA mostly stays as a separate loop (an episome) inside the cell nucleus rather than becoming part of the chromosomes. A small fraction of vector DNA can integrate, though, and Zolgensma's label has always listed a "theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome."

What's new is that the risk is no longer theoretical for an approved AAV product. GLI1 is a transcription factor in the Hedgehog signaling pathway, which controls cell growth during development. A strong promoter landing next to it can switch it on when it should be quiet, which can drive uncontrolled growth.

The FDA also pointed to two published reports of AAV integration events in other gene therapy programs: one involving GLI1 (FBX-101) and one involving the PLAG1 gene (RGX-111). The agency says it is closely monitoring the risk of tumors in other AAV-based programs.

If you want a refresher on how AAV vectors carry genes into cells, and why scientists considered them relatively safe, it's the core of my beginner's guide, The Life-Changing Power of Gene Therapy (affiliate link).

What it means for families

The FDA says "the overall benefits of Zolgensma and Itvisma continue to outweigh their potential risks for their approved uses." SMA is a severe disease. Before treatments existed, most babies with the most severe form did not survive early childhood, and Zolgensma has changed that outlook for thousands of children.

• Patients and trial participants who received these products should be monitored for tumor formation.

• Families with questions should talk with their child's neuromuscular care team rather than make changes on their own.

• Doctors are asked to report tumors to Novartis Gene Therapies (1-833-828-3947) or to FDA MedWatch (1-800-FDA-1088).

The FDA has not announced a label change or boxed warning yet. It says it is "evaluating whether regulatory action is appropriate" and reviewing whether the current prescribing information and long-term follow-up studies are adequate. Novartis says it notified health authorities about both cases and that the potential tumor risk is already in Zolgensma's prescribing information. Patient advocates, including SMA Europe, have criticized the company for being slow to share details.

What it means for the gene therapy field

The FDA has issued similar investigations before, for T-cell cancers after CAR-T therapies and for blood cancers after Skysona. Those products use integrating viral vectors, where this kind of risk was expected. Zolgensma is the first approved AAV gene therapy with confirmed vector-driven cancer, and that matters because AAV is the delivery vehicle behind many approved and experimental gene therapies.

Expect regulators and developers to pay closer attention to integration-site analysis of tumors, the strength and design of the promoters packed into AAV constructs, and how long patients are followed after a one-time dose. As STAT put it, the finding "will change the calculus" for AAV therapies.

The bottom line

Zolgensma remains approved, and the FDA still judges its benefits to outweigh its risks. But two confirmed cases of the vector inserting next to GLI1 prove that AAV integration can cause cancer in people. That is a turning point for how the field designs, monitors and explains these one-time treatments.

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