Neurogene Details Safety Measures After Patient Death in Rett Syndrome Gene Therapy Trial

Neurogene, a biotechnology company developing gene therapies for rare neurological disorders, has revealed new information about a patient death in its Rett syndrome gene therapy trial and outlined enhanced safety protocols for the ongoing study. The disclosure came during a presentation at the American Society of Gene & Cell Therapy (ASGCT) annual meeting in New Orleans on May 16, 2025.

Fatal Adverse Event and Trial Modifications

The company reported that a young female patient in the high-dose arm of its phase 1/2 trial for NGN-401, a gene therapy candidate for Rett syndrome, died from hemophagocytic lymphohistiocytosis (HLH) approximately two weeks after receiving treatment. The patient had been administered a dose of 3E15 vector genomes of NGN-401 on November 5, 2024.

Following the incident, Neurogene has implemented several changes to its trial design:

• Discontinuation of the high-dose arm (3E15 vector genomes)
• Continuation of the lower-dose arm (1E15 vector genomes) with FDA approval
• Introduction of standard HLH monitoring protocols
• Implementation of an HLH treatment algorithm

The company emphasized that no cases of HLH have been reported at the lower dose level in AAV gene therapy trials to date.

Implications for AAV Gene Therapy Development

This event highlights ongoing safety concerns surrounding high-dose adeno-associated virus (AAV) vector therapies. Neurogene's presentation cited an FDA analysis of 4,500 Zolgensma treatment cases, which found that approximately 1.3% of serious adverse events in patients receiving high AAV doses showed signs of HLH.

In light of these findings, Neurogene has recommended that all AAV gene therapies use doses below 1E14 vector genomes per kilogram. The company also advised monitoring patients for HLH using the "three F's": fever, falling red blood cell counts, and raised ferritin levels.

The incident at Neurogene adds to a growing list of setbacks for AAV-based gene therapies:

• Vertex Pharmaceuticals recently announced it would no longer pursue AAV vectors as a gene therapy delivery tool
• Takeda ended its early-stage AAV work in 2023
• Pfizer withdrew its FDA-approved AAV-based hemophilia B gene therapy, Beqvez, from the market earlier this year due to limited patient and physician interest

As the gene therapy field continues to evolve, these developments underscore the importance of rigorous safety monitoring and dose optimization in clinical trials for novel genetic treatments.