FDA Investigates Confirmed Insertional Oncogenesis With Spinal Muscular Atrophy Gene Therapy

The FDA is investigating a serious risk of malignancy associated with onasemnogene abeparvovec (Zolgensma; Novartis), the adeno-associated virus (AAV) vector-based gene therapy for spinal muscular atrophy (SMA), after postmarketing reports confirmed product-related insertional oncogenesis involving the GLI1 oncogene.¹ The agency said it is evaluating whether regulatory action is appropriate, while maintaining that the overall benefits of the therapy continue to outweigh its potential risks for its approved uses.

Critically for clinicians, the agency extended the signal beyond the intravenous product. The FDA determined that the risk of neoplasia is “applicable to both onasemnogene abeparvovec products,” Zolgensma and the intrathecal formulation Itvisma, because the 2 share the same vector and construct.

What the Postmarketing Reports Show

The reported tumors have involved the central and peripheral nervous systems, spinal and paraspinal regions, and the kidney. Three of those cases involved tumors associated with GLI1, a Hedgehog pathway transcription factor that can drive oncogenesis when overexpressed or aberrantly activated. In 2 of the 3, molecular analysis of tumor tissue demonstrated integration of Zolgensma AAV vector DNA into the host genome, with the promoter region of the onasemnogene abeparvovec construct inserted upstream of or within GLI1. The mechanism of GLI1 overexpression in the third case remains under investigation.

The agency situated the finding in a small but growing body of evidence across AAV programs, citing a GLI1 integration event reported in the FBX-101 program and a PLAG1 integration event following intracisterna magna delivery of RGX-111, both published this year in the New England Journal of Medicine.^2,3 No cases of neoplasia have been reported following Itvisma administration to date; that product was approved November 24, 2025, and the treated population remains small.¹

“We are aware of recent reports of tumors in people who have received Zolgensma (onasemnogene abeparvovec) and understand that this raises questions and concerns for families, particularly those who have made important treatment decisions for themselves or their children. We take these reports seriously and believe families deserve transparent, timely, and science-based information as more is learned,” Muscular Dystrophy Association said in a statement.⁴

Clinical Context and Mechanism

SMA is an autosomal recessive motor neuron disorder caused by biallelic deletion or mutation of SMN1, resulting in deficient survival motor neuron protein and progressive degeneration of anterior horn cells. Untreated type 1 disease has historically been the leading genetic cause of infant mortality. Zolgensma, approved May 24, 2019, delivers a functional SMN1 transgene via a self-complementary AAV9 capsid administered by intravenous infusion in patients younger than 2 years; Itvisma delivers the same construct intrathecally for patients 2 years and older. Both sit alongside the antisense oligonucleotide nusinersen and the oral small molecule risdiplam, which require ongoing administration rather than a single dose.

READ MORE: Sevasemten Misses Primary Endpoint in Pivotal Trial for Becker Muscular Dystrophy

AAV vectors are predominantly episomal, and the risk of tumorigenicity from vector DNA integration has been described in the US prescribing information only as theoretical. The new reports move at least 2 cases from theoretical to documented, with a plausible mechanistic basis: insertion of a strong constitutive promoter adjacent to or within an oncogene can drive its dysregulated expression.

What the Findings Do and Do Not Establish

The FDA’s language is specific: insertional oncogenesis is described as confirmed in cases where vector DNA integration was demonstrated in tumor tissue, not inferred across the full set of reported tumors. For the remaining reports, including the third GLI1-associated case, causality has not been established, and background malignancy rates in a medically complex, closely surveilled pediatric population are an unavoidable confounder. Neither the agency nor the sponsor has published an incidence estimate against the more than 6000 patients treated to date, and the denominator for any rate calculation is not yet public.⁴

Monitoring, Labeling, and Next Steps

The FDA advised that patients and clinical trial participants receiving either product be monitored for tumor formation, without specifying an imaging modality, interval, or duration. The agency said it is expeditiously evaluating the adequacy of the current prescribing information and of Novartis’ long-term follow-up safety studies, leaving open the possibility of labeling changes or additional postmarketing requirements. Clinicians who identify a tumor in a treated patient are directed to contact Novartis Gene Therapies at 1-833-828-3947 and to report through MedWatch.

Several questions remain unresolved for neurologists counseling families: the latency window for integration-associated tumors, which was roughly 18 to 60 months in the 2 confirmed cases per the sponsor. These questions include whether intrathecal delivery carries a comparable integration risk given CNS-directed exposure; and what surveillance is proportionate for the thousands of children already dosed. Until the FDA completes its review, the agency’s position is that the benefit-risk balance remains favorable for approved indications.

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REFERENCES
1. FDA investigating serious risk of malignancy linked to Zolgensma gene therapy. Safety communication. FDA. November 6, 2026. Accessed November 9, 2026. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-malignancy-linked-zolgensma-gene-therapy
2. Vo JN, Wu YM, Heider A, et al. Integration-associated paraspinal neoplasm after AAV gene therapy. N Engl J Med. 2026;395(15):1555-1558. doi:10.1056/NEJMc2607927
3. Ahrens-Nicklas RC, Kotch C, Roche AM, et al. Neuroepithelial tumor with AAV integration after intracisterna magna vector delivery. N Engl J Med. 2026;394(21):2126-2133. doi:10.1056/NEJMoa2601608
4. Statement from the Muscular Dystrophy Association on Reports of Tumors in People Treated with Zolgensma. News release. MDA. Novemeber 5, 2026. Accessed November 9th, 2026. https://www.mda.org/press-releases/statement-from-the-muscular-dystrophy-association-on-reports-of-tumors-in-people-treated-with