FDA Investigates Malignancy Risk Linked to Zolgensma Gene Therapy

Vector DNA integration was identified near or within the GLI1 oncogene in tumors from two treated patients

November 11, 2026
3 min

The Medicine Maker

At a Glance

Category	Detail
Condition	Spinal muscular atrophy (SMA) and reported malignancies associated with AAV-based gene therapy
Key Mechanisms	Zolgensma and Itvisma use an AAV9 vector to deliver a functional SMN1 copy. In two reported tumors, vector DNA integrated into the genome near or within GLI1; the mechanism in a third GLI1 case remains under investigation.
Target Population	Patients treated with Zolgensma or Itvisma, and clinical trial participants receiving these products
Care Setting	Gene therapy treatment and long-term safety follow-up; Zolgensma is administered intravenously and Itvisma intrathecally

Key Highlights

The FDA is investigating postmarketing tumor reports involving the central and peripheral nervous systems, spinal and paraspinal regions, and kidney.
Three cases involved abnormal GLI1 activity; molecular testing found vector integration in two.
Novartis reported nine tumor cases among more than 6,000 Zolgensma-treated patients; two showed evidence of vector integration.
The FDA considers the risk relevant to Itvisma because it contains the same vector and genetic construct; no tumors had been reported after Itvisma treatment at the time of the article.
The FDA said the benefits of both approved therapies continue to outweigh their potential risks and advised monitoring for tumor formation.

Guideline-Based Recommendations

Diagnosis

Management

Monitoring & Follow-up

Risks

Rare integration of recombinant AAV DNA into the host genome can occur; tumorigenicity from integration is currently described in Zolgensma prescribing information as a theoretical risk.
The FDA cited two published integration-associated oncogenesis cases involving other investigational AAV therapies: one involving integration near GLI1 in the FBX-101 program and another involving PLAG1 in the RGX-111 program.

Patient & Prescribing Data

Zolgensma delivers a functional SMN1 copy using an intravenous AAV9 vector; Itvisma is an intrathecally administered onasemnogene abeparvovec product. The FDA stated that benefits of both approved therapies continue to outweigh potential risks.

Clinical Best Practices

Follow the FDA advice to monitor patients and clinical trial participants receiving these products for tumor formation.
Recognize that the FDA is investigating the reported malignancy risk and evaluating possible changes to prescribing information or long-term follow-up requirements.